The Effects of Environmental Chemical Carcinogens On The microRNA Machinery

G Model
IJHEH-12752; No. of Pages 27 ARTICLE IN PRESS

International Journal of Hygiene and Environmental Health xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Hygiene and

Environmental Health
journal homepage: www.elsevier.com/locate/ijheh
Review
The effects of environmental chemical carcinogens on the

microRNA machinery
A. Izzotti a,b,∗ , A. Pulliero a
a
Department of Health Sciences, University of Genoa, Italy
b
Mutagenesis Unit, IRCCS University Hospital San Martino – IST National Research Cancer Institute, Genoa, Italy
a r t i c l e i n f o a b s t r a c t
Article history: The first evidence that microRNA expression is early altered by exposure to environmental chemical
Received 24 October 2013 carcinogens in still healthy organisms was obtained for cigarette smoke. To date, the cumulative experi-
Received in revised form 3 January 2014 mental data indicate that similar effects are caused by a variety of environmental carcinogens, including
Accepted 6 January 2014
polycyclic aromatic hydrocarbons, nitropyrenes, endocrine disruptors, airborne mixtures, carcinogens
in food and water, and carcinogenic drugs. Accordingly, the alteration of miRNA expression is a general
Keywords:
mechanism that plays an important pathogenic role in linking exposure to environmental toxic agents
MicroRNA
with their pathological consequences, mainly including cancer development.
Environmental chemical carcinogens
Carcinogenesis
This review summarizes the existing experimental evidence concerning the effects of chemical car-
Dicer cinogens on the microRNA machinery. For each carcinogen, the specific microRNA alteration signature,
as detected in experimental studies, is reported. These data are useful for applying microRNA alterations
as early biomarkers of biological effects in healthy organisms exposed to environmental carcinogens.
However, microRNA alteration results in carcinogenesis only if accompanied by other molecular dam-
ages. As an example, microRNAs altered by chemical carcinogens often inhibits the expression of mutated
oncogenes. The long-term exposure to chemical carcinogens causes irreversible suppression of microRNA
expression thus allowing the transduction into proteins of mutated oncogenes.
This review also analyzes the existing knowledge regarding the mechanisms by which environmental
carcinogens alter microRNA expression. The underlying molecular mechanism involves p53-microRNA
interconnection, microRNA adduct formation, and alterations of Dicer function.
On the whole, reported findings provide evidence that microRNA analysis is a molecular toxicology
tool that can elucidate the pathogenic mechanisms activated by environmental carcinogens.
© 2014 Elsevier GmbH. All rights reserved.
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Airborne carcinogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Cigarette smoke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
NNK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Diesel exhaust particles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Volatile organic compounds (benzene, toluene, xylene, and formaldehyde) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Coal fumes, black carbon dust, and oil fly ash . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
RDX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
PAHs: B[a]P and DMBA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Benzo[a]pyrene (B[a]P) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Dimethylbenz[a]anthrance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Abbreviations: CS, cigarette smoke; NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; DEP, diesel exhaust particles; PRMT5, protein arginine methyltrans-
ferase; ROFA, residual oil fly ash; PM, particulate matter; RDX, hexahydro-1,3,5-trinitro-1,3,5-triazine; B[a]P, benzo[a]pyrene; DMBA, 7,12-dimethylbenz[a]anthrance;
PTEN, phosphatase and tensin homolog; HNSCC, human non-small cell lung cancer; EC, ethyl carbamate; BPA, bisphenol A; DDT, dichloro-diphenyl-trichlorethane; DES,
diethylstilbestrol; PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine; MeIQx, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline; 2-AAF, 2-acetylaminofluorene; ENU,
N-ethyl-N-nitrosourea; CP, cyclophosphamide; TPA, 12-O-tetradecanoylphorbol-13 acetate; BHP, tert-butyl hydroperoxide.
∗ Corresponding author at: Department of Health Sciences, University of Genoa, Via A. Pastore 1, I-16132, Genoa, Italy. Tel.: +39 010 3538522; fax: +39 0103538504.
E-mail address: izzotti@unige.it (A. Izzotti).
1438-4639/$ – see front matter © 2014 Elsevier GmbH. All rights reserved.
http://dx.doi.org/10.1016/j.ijheh.2014.01.001
Please cite this article in press as: Izzotti, A., Pulliero, A., The effects of environmental chemical carcinogens on the microRNA machinery.
Int. J. Hyg. Environ. Health (2014), http://dx.doi.org/10.1016/j.ijheh.2014.01.001
G Model
2 A. Izzotti, A. Pulliero / International Journal of Hygiene and Environmental Health xxx (2014) xxx–xxx
Asbestos . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Radon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Vinyl carbamate (urethane) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Pesticides and endocrine disruptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Bisphenol A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Diethylstilbestrol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Nonylphenol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Propiconazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Carcinogens in food and water . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Pyrolysis products (furan, PhIP, and MeIQx) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Furan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
PhIP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
MeIQx . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Ethanol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Arsenic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2-AAF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Microcystin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Ethylene oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
N-ethyl-N-nitrosourea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Tamoxifen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Cyclophosphamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
TPA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
tert-Butyl hydroperoxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Nanoparticles (gold and titanium dioxide) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Mechanisms of miRNA responses to carcinogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
p53-mediated DNA-damage response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
MiRNA adducts suppress the binding of pre-miRNAs to Dicer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Carcinogen binding to Dicer hampers the access of pre-miRNAs to catalytic sites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Carcinogen-induced alteration of miRNA expression is a dose–response mechanism with a threshold . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
MiRNA gene deletions in cancer cell lines and their relevance to testing carcinogenic agents in vitro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Introduction The early sensitivity of miRNA to environmental carcinogens

can be explained on a mechanistic base. It has been established
It is well established that the expression of microRNA (miRNA), that irreversible loss of miRNA function in cancer cells is a result of
the main post-transcriptional regulation mechanism, is dramat- the homozygous deletion of miRNA genes (Calin et al., 2004). How-
ically altered in cancer cells. However, a body of evidence has ever, similar genetic damage does not occur in non-cancerous cells.
accumulated concerning the early alteration of the miRNA machin- Several hypotheses have been raised to explain the early sensitiv-
ery (before the onset of cancer) in healthy organisms exposed to ity of the miRNA machinery to environmental carcinogens. These
environmental carcinogens. Accordingly, altered miRNA levels can hypotheses mainly include the activation of miRNA gene expres-
be proposed as biomarkers of early biological effects. The predictive sion as a consequence of DNA damage (Suzuki and Miyazono, 2010)
value of early miRNA alterations remains to be established. A recent and alterations in the miRNA-processing machinery (Ligorio et al.,
study reported that the miRNA alterations induced by environmen- 2011). These studies provided evidence that early miRNA alter-
tal carcinogens that occur in healthy organisms are predictive of the ations can be interpreted as adaptive mechanisms that increase
future appearance of cancer only when these miRNA alterations the expression of the defensive genes involved in metabolic detox-
are irreversible (Izzotti et al., 2011). Conversely, reversible miRNA ification, DNA and protein repair, and apoptosis activation. Indeed,
alterations represent adaptive rather than pathogenic mechanisms. the early miRNA downregulation induced by CS is paralleled by
The irreversibility of a miRNA alteration is reflected in the inabil- increasing messenger RNA (mRNA) and protein expression (Izzotti
ity of the cell to restore the physiological miRNA expression level et al., 2009a). This view is consistent with the established role of
despite the cessation of exposure to the environmental carcinogen. miRNA in suppressing gene expression at the post-genomic level.
The change from reversibility to irreversibility of miRNA alter- Initially, experimental evidence indicated a strict inter-
ation mainly depends on the duration of the exposure. Indeed, relationship between exposure to environmental carcinogens and
only long-term exposures are able to induce an irreversible alter- early miRNA alterations in CS-exposed rodents and humans (Izzotti
ation of the miRNA machinery (Izzotti et al., 2011). These findings et al., 2009b; Schembri et al., 2009). Further studies demonstrated
were obtained in a study of the lungs of mice that were exposed that this phenomenon occurs in cases of exposure to a wide variety
to mainstream cigarette smoke (CS), in which lung cancer was of environmental carcinogens and mutagens.
induced according to the perinatal carcinogenic model (Balansky A peculiar aspect of miRNA is the high conservation through-
et al., 2012). The exposure dose also influences miRNA alterations. out phylogenesis. Accordingly, the data obtained in experimental
Indeed, in a recent study, the expression of lung miRNA was not animal models are effectively transferred to humans (Izzotti et al.,
significantly altered after 1 month of exposure to low doses of 2009b; Perdomo et al., 2011).
CS, whereas it was dramatically altered by exposure to high doses Although many miRNAs behaves as cancer protective agents,
(Izzotti et al., 2011). These findings indicate that early miRNA alter- other miRNAs possess pro-oncogenic activities thus being refer-
ations reflect both the intensity and the duration of the exposure eed as oncomiRNA (Esquela-Kerscher and Slack, 2006). Typical
and that threshold mechanisms affect these biomarkers. oncomiRNA are miR-17, miR-19, miR-21, miR-155 whose main
IJHEH-12752; No. of Pages 27
G Model
Table 1
Environmental chemical carcinogens and miRNA.
Environmental chemical carcinogens Animal species Tissue or cell type Analytical method Modulated miRNA (validated miRNA and/or References
most altered)
Airborne pollutants
Cigarette smoke Mouse Lung Microarray, qPCR let-7a/b/f↓, miR-26↓, miR-30b/c↓, miR-34b↓, Izzotti et al., 2009a
miR-99b↓, miR-124a↓, miR-125a/b↓,
miR-140↓, miR-192↓, miR-431
Rat Lung Microarray, qPCR let-7a/b/c/f↓, miR10a↓, miR-26↓, miR-30a/c↓, Izzotti et al., 2009a
miR-34b/c↓, miR-99b↓, miR-123a↓,
miR-124a↓, miR-125a/b↓, miR-140↓,
miR-145↓, miR-146↓, miR-191↓, miR-192↓,
A. Izzotti, A. Pulliero / International Journal of Hygiene and Environmental Health xxx (2014) xxx–xxx
miR-219↓, miR-222↓, miR-223↓
Human Bronchial epithelium Microarray, qPCR miR30a↓, miR-125b↓, miR-128↓, miR-146↓, Schembri et al., 2009
miR-181↑, miR-218↓, miR-223↓, miR-500↓
Human Placental cells qPCR miR-16↓, miR-21↓, and miR-146a↓ Maccani et al., 2010
Mice Lung cancer RT-PCR let-7a↑ He et al., 2010
Human Bronchial tissue Microarray, RT-PCR miR-32↓, miR-34c↓, miR-9↓↑, miR-10b↓↑, Mascaux et al., 2009
ARTICLE IN PRESS
miR-17↑, miR92↑, miR-99a↑, miR-142-3p↓↑,
miR-142-5p↓↑, miR-142-3p↑, miR-142-5p↑,
miR-214↓↑, miR-301↓
In vitro Oral fibro-blasts Microarray, RT-PCR miR-145↓ Pal et al., 2013
Mice Lung Microarray, RT-PCR let-7↓, miR-30↓, miR-153↑, miR-214↑, Izzotti et al., 2011
miR-297↑, miR-301↑ miR-324↑ miR-34b↓,
miR-345↓, miR-421↓, miR-450b↓, miR-466↓,
miR-469↓
Cigarette smoke and betel nut Human Oral squamous cell carcinoma PCR-RFLP and qPCR miR-499↑ Chu et al., 2012
CSC (condensate cigarette smoke) Human Human lung cancer tissue q-PCR miR-487b↓ Xi et al., 2013
Tobacco carcinogens Human Human bronchial epithelial qPCR miR-200b↑, miR-200c↑, miR-205↑ Tellez et al., 2011
cells
NNK (4-methylnitrosamino-1-(3- Mice Liver RT-PCR miR-34c↑ Yamakawa et al., 2010
pyridyl)-1-butanone)
Rat Lung Microarray, qPCR, Northern miR-34↓, miR-101↓, miR-126↓, miR-199↓ Kalscheuer et al., 2008
blot
4-methylnitrosamino)-1-(3-pyridyl)- Rat Lung RNA solexa sequencing RT-PCR miR-206↑, miR-133b↑ Wu et al., 2013
1-butanone
Diesel exhaust particles In vitro Human bronchial epithelial Microarray miR-96↓miR-494↑, miR-513↑, miR-923↑ Jardim et al., 2009
cells
In vitro Biliary epithelial cells Microarray, qPCR miR-513↓ Gong et al., 2009
Human Lymphoid cancer cell lines qPCR miR-92b↓, miR-96↓ Pal et al., 2007
In vitro Human bronchial epithelial qPCR miR-375↓ Bleck et al., 2013
cells
Volatile organic compounds (benzene, Human Maternal and cord blood Microarray, qPCR miR-155↑ and miR-223↑ Herberth et al., 2013
toluene)
Formaldehyde In vitro Human bronchial epithelial Microarray, qPCR miR-10b↓, miR-33↓, miR-181a↓, miR-330↓ Rager et al., 2011
cells
In vivo Cynomolgus macaques Microarray, qPCR miR-125b↓, miR-142-3p↓, miR-145↓, Rager et al., 2013
miR-152↑, miR-203↓
Aromatic benzene-pyridine In vitro Human melanoma cells qPCR miR-205↓ Noguchi et al., 2013
Toluene 2,4-diisocyanate (TDI) Mice Parotid lymph nodes Microarray, qPCR miR-21↑, miR-22↑, miR-27b↑, miR-31↑, Anderson et al., 2013
miR-126↑, miR-155↑, miR-210↑, and
miR-301a↑
Particulate oil fly ash (residue of fossil Rat Heart Microarray, Northern blot miR-1↓, miR-21↓, miR-26↓, miR-125↓, Farraj et al., 2011
fuel combustion rich in Fe, Ni, V) miR-133↓, miR-150↓, miR-191↓, miR-375↓
3
4

G Model
Table 1 (Continued)
most altered)
Human Left ventriculum endocardium qRT-PCR miR-1↑ Yang et al., 2007

Mice Heart qRT-PCR miR-1↑ Yang et al., 2007
Metal rich fumes in steel industry Human Blood lymphocytes Microarray, qPCR miR-21↑, miR-146↓, miR-222↑ Bollati et al., 2010
(particulate matter, PM10)
In vitro Human endothelial cells Microarray, qPCR miR-221↑, miR-222↑ Suarez et al., 2007
Rat Cardiac myocytes qPCR miR-21↑ Cheng et al., 2009
Black carbon and coal dust (urban Human Blood samples Microarray, qPCR let-7g↑, miR-29↑, miR-146↑, miR-421↑ Motta et al., 2013
traffic particulate matter)
Human Blood lymphocytes SNPs genotyping SNPs in miRNA processing genes (DICER, Wilker et al., 2010
DGCR8 (interacting with DROSHA to cleave
pri-miRNA), Gemin3/4 (guiding miRNA into
RISC) associated with high arterial pressure
ARTICLE IN PRESS
Silica dust Rat Lung tissue Microarray, qPCR let-7d↓, let-7f↓, miR-17-1-3p↑, miR-22↑, Faxuan et al., 2012
miR-25↓, miR-26a↓, miR-26b↓, miR-28↓,
miR-29c↓, miR-30a↓, miR-30c↓, miR-30d↓,
miR-96↑, miR-98↓, miR-99a↓, miR-101a↓,
miR-126↓, miR-138-1↑, miR-140↓, miR-141↑,
miR-144↓, miR-145↓, miR-146↑, miR-181b↓,
miR-182↑, miR-183↑, miR-200b↓, miR-204↑,
miR-299↑, miR-300-5p↑, miR-344b↑,
miR-345-5p↓ miR-352↓, miR-375↓, miR-322↓,
miR-505↓, miR-675↑
Coal fumes (miners) Human Blood lymphocytes SNPs genotyping SNPs in pre-miRNA genes of miR-149 Wang et al., 2010a
associated with pneumoconiosis
RDX (explosive industry, mining, Mouse Brain Microarray, qPCR miR-10b↓, miR-15↑, miR-206↑, miR-497↑ Zhang and Pan, 2009
building, etc.) in water
Mouse Liver qPCR let-7e↓, miR-15↑, miR-29c↑, miR-30e↑, Zhang et al., 2007
miR-574↓, miR-466f↓, miR-689↑, miR-802↑
Dimethylhydrazine Rat Colon, mucosa cells Microarray, qPCR miR-21↑ Nautiyal et al., 2012
Benzo[a]pyrene In vitro Human bronchial epithelial Microarray, qPCR miR-10a↓, miR-106a↑, miR-129↑, miR-320↑, Shen et al., 2009
cells miR-363↓, miR-493↓, miR-494↑, miR-498↑
In vitro Human bronchial epithelial Microarray, qPCR miR-506a↑ Zhao et al., 2011a
cells
In vitro Human bronchial epithelial qPCR miR-106a↑ Jiang et al., 2011
cells
In vitro Human bronchial epithelial qPCR miR-22↓ Liu et al., 2010b
cells
In vitro Murine bronchial cells Microarray, qPCR miR-10a↓, miR-320↑, miR-494↑ Duan et al., 2010
In vitro Mouse lung Microarray miR-29b↑, miR-34b↑, miR-34c↑, miR-122↓, Halappanavar et al., 2011a
miR-142-5p↓, miR-150↓, miR-638↑
In vitro Human non-small-cell lung miRNA array, qPCR miR-638↑ Li et al., 2012a
cancer, peripheral lymphocytes
In vitro Human hepatocellular miRNA array, qPCR miR-29a↑, miR-99a↓, miR-139-3p↑, miR-197↑, Lizarraga et al., 2012
carcinoma miR-210↑, miR-294↑, miR-574-5p↑, miR-467f↑
In vitro Lung cancer cells qPCR miR-346↓, miR-483↓, miR-466f-5p↓, Barkley and Santocanale, 2013
miR-1896↓, miR-1906↓
In vitro Mouse embryo Microarray, qPCR miR-290↑ Brevik et al., 2012
In vitro Liver tissue Microarray, qPCR miR-34a↑ Malik et al., 2012
7,12-Dimethyl-benz[a]anthrance Hamster Oral squamous cell carcinomas Microarray, qPCR miR-16↓, miR-21↑, miR-26a↓, miR-29a↓, Yu et al., 2009

G Model
miR-124a↓, miR-125b↓, miR-126↓, miR-143↓,

miR-145↓, miR-148b↓, miR-155↓, miR-199a↓,
miR-203↓, miR-200↑, miR-221b↑, miR-338↑,
miR-762↑
Benzo[a]anthracene In vitro Human hepatocellular qPCR, miRNA array miR-21↑ miR-181a↑, miR-181b↑, miR-181d↑ Song et al., 2013
carcinoma
Benzo[k]fluoranthene Mice Liver, spleen and kidneys qPCR miR-21↑, miR-34a↓ and miR-155↓ Juhász et al., 2013
Asbestos Human Lung Microarray let-7d↑, let-7e↑, miR-24↑, miR-96↑, Nymark et al., 2011
miR-148b↑, miR-199b↑, miR-202↓,
miR-374a↑, miR-331↑, miR-671↓, miR-605↓,
miR-939↓, miR-1224↓
Human Human peripheral blood Microarray, qRT-PCR miR-103↑ Weber et al., 2012
Human Pleural mesothelioma qPCR miR-126↓ Santarelli et al., 2011
Radon In vitro Human bronchial epithelial qPCR miR-17↑, miR-18a↑, miR-33b↑, miR-125b↑, Cui et al., 2013
cells miR-483-3p↑, miR-494↑, miR-886-3p↑,
miR-2115↑, miR-1246↑, miR-3202↑,
Ethyl carbamate (urethane) (rubber Mice Lung Microarray, qPCR miR-1↓, miR-21↑, mir-31↑, miR-130a↑, Melkamu et al., 2010
industry) miR-143↓, miR-146b↑, miR-377↑
ARTICLE IN PRESS
Mice Lung cancer Microarray, qPCR miR-1a↓ Li et al., 2013
Pesticides and endocrine disruptors

Bisphenol A In vitro Human placental cells Microarray, qPCR let-7f↑, let-7g↑, miR-20↑, miR-21↑, miR-146↑, Avissar-Whiting et al., 2010
miR-335↑
In vitro Breast cancer epithelial cells Microarray, qPCR let-7c/f/g↓, miR-15b↓, mir-21↑, miR-26b↓, Tilghman et al., 2012
miR-27b↓, miR-93↑, miR-149↑, miR-222↑,
miR-320a↑, miR-342↓, miR-638↑, miR-663↑,
miR-923↓, miR-1275↑, miR-1308↑, miR-1915↑
In vitro Embryonic stem cells qPCR miR-134↓ Chen et al., 2013
Dichloro-diphenyl-trichlorethane In vitro Breast cancer epithelial cells Microarray, qPCR miR-15b↓, miR-16↓, mir-21↑, miR-27b↓, Tilghman et al., 2012
miR-92↓, miR-99↓, miR-149↑, miR-193a↑,
miR-342↓, miR-638↑, miR-663↑, miR-1915↑,
miR-923↓, miR-1308↑
Diethylstilbestrol In vitro Breast epithelial cells Microarray, qPCR miR-9-3↓, miR-15b↓, miR-25↓, miR-92b↓, Hsu et al., 2009
miR-106a↓, miR-181↑, miR-194↑, miR-320↓,
miR-345↑, miR-375↑
Nonylphenol In vitro TM4 Sertoli cells Microarray let-7g↓, miR-10a↓, miR-15a↓, miR-15b↓, Choi et al., 2011
miR-26a↓, miR-29c↓, miR-107↓,
miR-125a-3p↑, miR-199b↓, miR-297c↑,
miR-324-5p↓, miR-331-3p↓, miR-342-3p↓,
miR-421↑, miR-452↑, miR-483↑, miR-574-3p↑,
miR-574-5p↑, miR-669a↑, miR-720↑
Conazoles (triadimefon, In vitro Breast epithelial cells, q-pCR let-7c, miR-16, miR-195, miR-200b, miR-200c, Paul et al., 2009
propiconazole) (antifungal agent hepatocarcinoma cells miR-205, miR-589
used in agriculture)
Mouse Liver q-PCR miR-9↓, miR-135b↓, miR-302↓, miR-380↓, Ross et al., 2010
miR-466↑, miR-509↓, miR-684↓, miR-758↓,
miR-875↓
In vitro Hepatoma cell line Microarray, qPCR miR-1274a↑, miR-1274b↑ An et al., 2013
Food and water carcinogens

Furan (food pyrolisate product) Rat Liver qPCR let-7a↑, let-7e↓, miR-28↑, miR-296↓, miR-489↓ Chen et al., 2010
Rat Liver Microarray, qPCR miR-22↑, miR-181c↑, miR-192↑, miR-193↑, Chen et al., 2012
miR-194↑, miR-203↑, miR-335↑, miR-448↑,
miR-451↑
PhIP (heterocyclic amine carcinogen Rat Colon Microarray, qPCR let-7a↓, let-7b↓, let-7c↓, let-7d↓, let-7e↓, Parasramka et al., 2012
from cooked meat) let-7f↓, let-7i↓, miR-21↑, miR-29↓, miR-98↓,
5
miR-126↑, miR-145↑, miR-215↓
6

G Model
Table 1 (Continued)
most altered)
MeIQx Mice Liver qPCR let-7a↓, miR-125a↓ Yamakawa et al., 2010
Ethanol Human Liver (hepatocellular qPCR miR-126↓ Ladeiro et al., 2008

carcinoma)
Human Pharingeal and laringel qPCR miR-375↑ Avissar et al., 2009
carcinomas
Mice Liver qPCR miRNA assays miR-27b↓, miR-182↓, miR-183↓, miR-199↓, Dolganiuc et al., 2009
miR-200↓, miR-214↓, miR-320↑, miR-322↓,
miR-486↑, miR-705↑, miR-1224↑
Rat Liver qPCR miR-21↑ Dippold et al., 2012
In vitro Human qPCR miR-34a↑ Meng et al., 2012
hepatocytes/cholangio-cytes
Mice Human hepatoma cells qPCR miR-214↑ Dong et al., 2013
Rat Gastric mucosa epithelial cells qPCR miR-145↑miR-17↓, miR-19a↓, miR-21↓, Luo et al., 2013
miR-181a↓, and miR-200c↓
ARTICLE IN PRESS
Rat Dorso-lateral striatum qPCR miR124a↓ Bahi and Dreyer, 2013
Mice Brains of adult mice qPCR miR-26b↑ Stringer et al., 2013
Mice Primary mouse microglia qPCR miR-155↑, miR-132↑ Lippai et al., 2013
Arsenic In vitro Lymphoblastoid cells Microarray miR-22↑, miR-34↑, miR-221↑, miR-222↑ Marsit et al., 2006
In vitro Human bronchial epithelial qPCR miR-190↑ Beezhold et al., 2011
cells
In vitro Human bronchial epithelial qPCR miR-200↓ Wang et al., 2011
cells
In vitro Human blood and B-cell qPCR miR-2909↑ Sharma et al., 2013
lymphoma cells
In vitro Retinoblastoma cells Microarray, RT-PCR miR-376a↑ Zhang et al., 2013
Guinea pig Cardiomyocytes RT-PCR miR-1↑, and miR-133↑ Shan et al., 2013
In vitro Humbelical human vein Microarray, RT-PCR miR-19b↑, miR-29b↑, miR-33a↑, miR-21↑, Li et al., 2012b
endothelial ells miR-24↑, miR-198↓, miR-874↑, miR-508-5p↓,
miR-1252↓
Human Urine RT-PCR miR-21↑, miR-126↑, miR-155↑ and miR-221↑ Kong et al., 2012a
2-Acetylaminofluorene Rat Liver qPCR miR-17↑, miR-18↑, miR-20↑, miR-93↑ Pogribny et al., 2011
Rat Liver qPCR miR-22↓, miR-29b↓ Koturbash et al., 2013
Rat Liver Microarray, qPCR miR-34↑, miR-200a/200b/429↑ Koufaris et al., 2012
Microcystin (Cyanobacteria produced In vitro Human liver embryo cell Microarray, qPCR miR-21↑, miR-122↓, miR-221↑ Xu et al., 2012
food and water contaminant
associated with hepatocelullar
carcinoma)
Zebrafish Embryo Microarray, qPCR miR-31↑, miR-125↓, miR-126↓, miR-430↑ Zhao et al., 2011b
Whitefish (Coregonus Liver qPCR let-7c↑, miR-122↑ Brzuzan et al., 2012
lavaretus)
Ethylene, hydrogen peroxide (H2 O2 ), Plants Sweet potato qPCR, Northern blot miR828↑ Lin et al., 2012
nitric oxide (NO)
Drugs
N-ethyl-N-nitrosourea (ENU) Mice Spleen qPCR miR-34↑ Chen et al., 2011a
Rat Colon mucosa qPCR let-7d↑, miR-15b↑, miR-34a↑, miR-107↑, Davidson et al., 2009
miR-191↑, miR-324-5p↑, miR-132↑, miR-223↑,
miR-224↑, miR-192↓, miR-194↓, miR-215↓,
miR-375↓
Tamoxifen Rat Liver Microarray, qPCR miR-17-92 cluster↑, miR-34↑, miR-106a↑ Pogribny et al., 2007
In vitro Breast ER+ epithelial cells qPCR, RT-PCR miR-451↓ Bergamaschi and
(MCF7) Katzenellenbogen, 2012
G Model
A. Izzotti, A. Pulliero / International Journal of Hygiene and Environmental Health xxx (2014) xxx–xxx 7
target has been identified in E2F1, PTEN, PDCD4, and SOCS1 gene
products whose suppression results in increased cell proliferation,
Halappanavar et al., 2011b

decreased apoptosis, invasion and metastatization. As reported in
Table 1, these miRNAs are upregulated by environmental carcino-
Kasashima et al., 2004
Balansky et al., 2013
Bourdon et al., 2012

gens. Indeed, miR-17 is upregulated by cigarette smoke, silica dust,
Alencar et al., 2011
Wang et al., 2010b

Hoppe et al., 2013
Gueta et al., 2010
Chen et al., 2008

radon, 2AAF; miR-19 by arsenic; miR-21 by TPA; miR-155 by ben-
Hou et al., 2012

Chu et al., 2013
Bai et al., 2013
Hu et al., 2013
Ng et al., 2011
He et al., 2013
Le et al., 2009
zene, toluene, ethanol, TPA.
Thus environmental carcinogens alter miRNA expression
by downregulating oncoprotective miRNA and upregulating
oncomiRNA. The purpose of the current review is to summarize the
existing experimental evidence concerning the effects of chemical
carcinogens on the miRNA machinery. For each carcinogen, the spe-
miR-155↑, miR-199a↓, miR-181c↓, miR-221↑,
let-7a/f/g↑, miR-185↑, miR-297↑, miR-297a↑,

miR-21↑, miR-26a↑, miR-92↓, miR-146a/b↑,
cific miRNA alteration signature found in experimental studies is

miR-31↑, miR-10a↑, miR-126↑, miR-210↑,
miR-27↑, miR-142↓, miR-142↓, miR-320↓

reported. These data are useful for applying miRNA alterations as
miR-17↓, miR-21↑, miR-23↑, miR-24↑,
miR-34a/b/c↑, miR-125b↓, miR-155↓
early markers of the biological effects of exposure to environmental

miR-18a↑, miR-181a↑, miR-222↑
miR-150↑, miR-375↑, miR-342↑,
carcinogens in healthy organisms. The possibility of using miRNAs
miR-466↑, miR-467↑, miR-466↑

miR-21↑, miR-135b, miR-146b↑
miR-1↑, miR-135b↑, miR-449a↑
for biomonitoring purposes is substantiated by the fact that miR-
NAs are released from the target tissues into the blood stream; thus,
let-7b↓, let-7c↓, miR-98↓
their analysis is feasible via noninvasive sampling (Etheridge et al.,

miR-29↑, miR-203↓
2011).
miR-1225-5p↑
miR-125b↑
miR-342↑
miR-663↑
miR-222↑
miR-211↑
miR-155↑
miR-200↓
Airborne carcinogens
Cigarette smoke
The first evidence that miRNA expression is altered by exposure

to carcinogens in healthy organisms was obtained in rodents that
Microarray, Northern blot
were exposed to CS. Large alterations in miRNA expression, pri-

RT-PCR, Northern blot
Microarray, RT-PCR
Microarray, RT-PCR
Microarray, RT-PCR
marily downregulation, occurred in the lungs of rats (Izzotti et al.,

Microarray, qPCR
Microarray, qPCR
Microarray, qPCR
2009a) and adult and post-weanling mice (Izzotti et al., 2009b).

These alterations triggered a variety of defensive mechanisms
Microarray
Microarray
Microarray
aimed at counteracting the effects of CS. However, the persistence

RT-PCR
RT-PCR
RT-PCR
of this downregulated expression in mice that were exposed to

qPCR
qPCR
CS for 4 months resulted in the irreversible loss-of-function of

miRNA-based suppression of the expression of oncogenes. This par-
Human neuroblastoma cell line
ticularly applied to let-7, suppressing the expression of a mutated

Human fetal lung fibroblasts
Head and neck carcinomas
k-ras oncogene, whose role in lung carcinogenesis is well estab-

Human breast cancer cells
ER-positive breast cancer
HL-60 human leukocyte
HL-60 human leukocyte

Endometrial cancer cell
lished (He et al., 2010). The CS-induced mutation of the k-ras

Human hepatoma cell
gene was initially devoid of functional consequences because of

Organ of Corti cells
B-cell lymphoma
Embryonic limbs
the existence of let-7. However, in the case of the irreversible

Leukemia cells
Breast cancer
downregulation of let-7 that was induced by long-term exposure

to CS, mutated k-ras was no longer silenced, thus activating car-
cinogenic events. A similar situation has been reported for other
Lung
Lung
Lung
oncogenes or tumor suppressor genes in the case of exposure to

CS. In rats that were exposed to CS for 4 weeks, the levels of 24
lung miRNAs were downregulated. The most extensively downreg-
ulated miRNAs were let-7, miR-34, and miR-125, which are known
Mice p53 mutant
to play a role in the development of non-small cell lung cancer

(Calin et al., 2004). miR-34 is involved in the p53-dependent cel-
Mice fetus
lular responses to DNA damage. miR-125 regulates the activation

Human
Human
Human
In vitro
In vitro
In vitro
In vitro
In vitro
In vitro
In vitro
In vitro
of ERBB2, which plays an important role in lung carcinogenesis

Mice
Mice
Mice
(Stephens et al., 2004). Maternal cigarette smoking during preg-

nancy is associated with poor fetal outcome and aberrant miRNA
expression. An in vitro study indicated a potential cascade of molec-
TPA (12-O-tetradecanoylphorbol-13-
ular changes that occur in the placenta upon exposure to cigarette

tert-Butyl hydroperoxide (BHP)
Titanium dioxide nanoparticles
smoke. This study demonstrated that exposure to CS during preg-

nancy is associated with the downregulation of miR-16, miR-21,
4-Nitroquinoline 1-oxide
and miR-146a expression in the human placenta (Maccani et al.,

2010).
Cyclo-phosphamide
Gold nanoparticles
MiRNA expression in the human bronchial epithelium was

compared between 10 never smokers and 10 current smok-
acetate)
ers through an analysis of the expression of 467 miRNAs using

microarrays. Twenty-three miRNAs were downregulated and 5
were upregulated in the smokers. The most extensively downreg-
ulated miRNAs were miR-218, miR-15a, miR-199b, and miR-125b.
G Model
These human data closely resemble the situation observed in CS- In another study (Kalscheuer et al., 2008), 7-week-old male
exposed rats and mice (Perdomo et al., 2011). The downregulation F344 rats received NNK (10 ppm) in drinking water and were
of miRNA expression was observed in smokers’ bronchial biop- killed at 1, 5, 16, and 20 weeks. At these time points, no tumors
sies with a normal or hyperplastic appearance, compared with were visible. Based on microarray, Northern blotting, and real-
those of never smokers (Mascaux et al., 2009). CS-condensate time PCR data, the expression of miR-34b, miR-101, miR-126,
promoted pro-tumorigenic stromal-epithelial interactions in oral and miR-199 decreased very early in the lung. miR-126 regu-
fibroblasts by suppressing the expression of miR-145 (Pal et al., lates the expression of CYP2A3, the principal catalyst of NNK
2013). a-hydroxylation in the lungs, which is the primary bio-activation
In the case of long-term exposure to CS, altered miRNA expres- pathway for NNK (Jalas et al., 2005). miR-34 is functionally related
sion persisted following the interruption of CS exposure. In mice to the activation of the p53 pathway (Yamakuchi and Lowenstein,
that were exposed to CS for 1 month, physiological miRNA 2009; Ji et al., 2008) and, thus, is involved in the DNA damage
expression was fully restored after 1 week of smoking cessation. response, cell cycle progression, and apoptosis. These results indi-
Conversely, in mice that were exposed to CS for 4 months, miRNA cate that NNK activates the p53 pathway during the early stages
alteration persisted after 1 week of smoking cessation (Izzotti of tumorigenesis, i.e., during cancer initiation, before neoplastic
et al., 2011). Similar results have been obtained in humans. Specif- transformation (Kalscheuer et al., 2008). Of note, the downregu-
ically, CS-related altered miRNA expression remained detectable lation of miR-34b in the lungs due to CS exposure occurs early,
in the bronchial epithelium of ex-smokers who stopped smok- both in rats (Izzotti et al., 2009a) and mice (Izzotti et al., 2009a,
ing 2–3 years prior to the study (Schembri et al., 2009). Nicotine 2009b).
alters the miRNA expression profile of human mesenchymal stem NNK causes a significant alteration of serum miRNA expression.
cells and periodontal ligament-derived stem cells (Ng et al., Compared to the control group, the expression of serum miR-206
2013). and miR-133b was significantly upregulated in the early stage of
A recent study evaluated miRNA expression in normal human NNK-induced lung carcinogenesis. These results indicate that expo-
respiratory epithelial cells and lung cancer cells that were cul- sure to the lung carcinogen NNK changes the expression of serum
tured in the presence or absence of CS-condensate. Exposure to miRNAs (Wu et al., 2013).
the CS-condensate significantly repressed miR-487b expression.
This miRNA directly targets SUZ12, BMI1, WNT5A, MYC, and KRAS Diesel exhaust particles
genes. MYC and KRAS are involved in the activation of a variety of
pathways that facilitate the initiation and progression of lung can- Diesel exhaust particles (DEPs) are the largest single type of
cer. BMI1 is required for the expansion of bronchioalveolar stem vehicular-emitted airborne particulate matter (PM), and they can
cells, the putative cells of origin of pulmonary adenocarcinomas, persist in the air, where they are readily inhaled and deposited
and WNT5A activates planar cell polarity pathways during nor- throughout the respiratory tract (Cao et al., 2007). DEP-induced
mal organogenesis and cancer dissemination (Xi et al., 2013). DNA toxicity is mainly attributed to the chemical composition of DEPs,
methylation silences tumor suppressive miRNAs miR-200b, miR- consisting of a carbonaceous core that organic and inorganic species
200c, and miR-205, implicated in the dedifferentiation program in can absorb.
human bronchial epithelial cells exposed to tobacco carcinogens The effect of DEPs (10 ␮g/cm2 ) on miRNA levels was evaluated
and in primary lung tumors (Tellez et al., 2011). A significant asso- in vitro in primary human bronchial epithelial cells obtained from
ciation of miR-499 with CC genotype, as compared to the subjects healthy, nonsmoking adult donors (Jardim et al., 2009). Microar-
with TT genotype, had a higher risk (95% CI = 1.24–16.48) of oral ray analysis showed that the miR-494, miR-513a, and miR-923
squamous cell carcinoma (Chu et al., 2012). levels were increased in response to DEPs, whereas the level of
miR-96 was decreased in the DEP-treated samples. miR-513a was
NNK the most remarkably upregulated miRNA, whereas miR-96 was
the most remarkably downregulated miRNA. To assess the poten-
Nicotine-derived nitrosamine ketone (NNK), or 4- tial biological mechanisms of the effects of acute DEP exposure,
(methylnitrosamino)-1-(3-pyridyl)-1-butanone, is a carcinogenic putative targets for miR-513a, miR-494, and miR-96 were identi-
nitrosamine that is present in tobacco smoke and is activated by fied. The putative target mRNAs of miR-494 indicated an enriched
CYP2A3/6. gene network for canonical NF-␬B and virus-activated signaling.
The miRNA expression in the livers and lungs of 7-week old In line with these results, in addition to increasing the suscepti-
female A/J mice that were intraperitoneally administered a single bility to influenza virus, DEPs can enhance viral attachment and
dose of NNK (2 mg/0.1 ml saline/mouse) was examined. These mice entry into human airway epithelial cells (Ciencewicki et al., 2006;
developed lung cancer without additional treatment until their sac- Jaspers et al., 2005).miR-513 plays a role in the regulation of
rifice at 52 weeks of age (Yamakawa et al., 2010.) The expression interferon-␥ (IFN-␥)-induced apoptosis. In response to the proin-
of miR-34c in the liver was significantly increased, by 3.5-fold, in flammatory cytokine IFN-␥, miR-513 expression levels decrease
the NNK group compared with the control group at 8 days after and B7-H1 protein levels increase, subsequently leading to apop-
treatment. At day 15, the level of miR-34c expression in the group totic cell death (Gong et al., 2009).miR-96 regulates the expression
that was administered NNK alone was upregulated by 1.5-fold com- of protein arginine methyltransferase (PRMT5). PRMT5 interacts
pared to that of the controls, but this difference was not statistically with human SWI/SNF and methylates histones H3R8 and H4R3,
significant. ultimately suppressing gene expression through chromatin modi-
There was no significant variation in the expression levels of fications. PRMT5 is highly expressed in some cancer cell lines. When
these miRNAs in the lungs at either day 15 or day 22, despite the late knocked down, PRMT5 interferes with cell growth, indicating that
development of cancer in this organ. These findings are in contrast it plays a crucial role in silencing tumor-suppressor genes (Pal et al.,
to the dramatic early alterations induced in the mouse lung by CS. 2007).
This indicates that the effect of CS is poorly reproduced by adminis- DEPs and airborne PM upregulate the level of thymic stromal
tering a single component of this complex mixture to experimental lymphopoietin in human bronchial epithelial cells by altering miR-
animals through an exposure route other than airborne exposure. 375 expression. Thymic stromal lymphopoietin is a pivotal cytokine
Indeed, the liver, in contrast to the lung, has a remarkable detoxi- that links innate and Th2-adaptive immune disorders (Bleck et al.,
fication capacity. 2013).
G Model
Volatile organic compounds (benzene, toluene, xylene, and include ash, slag, and the particulates removed from fuel gas. Fugi-
formaldehyde) tive fly ashes from the combustion of oil and residual fuel oil
significantly contribute to the ambient air particle burden. Resid-
Volatile organic compounds (VOCs) are organic chemicals that ual oil fly ash (ROFA), a residue of fossil fuel combustion, displays
have a high vapor pressure and, thus, are volatile at room temper- marked oxidative and inflammatory activities due to its high con-
ature. Anthropogenic VOCs include carcinogens such as benzene, tent of bioavailable transition metals, including Ni, V, and Fe. The
toluene, xylene, and formaldehyde (Wang et al., 2012) exposed transition metals that are present in ROFA, especially vanadium,
male Kunming mice to an airborne mixture of benzene, toluene, participate in Fenton-like reactions that produce reactive oxygen
xylene, and formaldehyde for 2 h per day for 2 weeks. VOC expo- species.
sure altered the miRNA expression in mice’s lungs, inducing the Farraj et al. (2011) found that particulate oil fly ash induces
upregulation of miR-125a and miR-466 expression and the down- the downregulation of several miRNAs in spontaneously hyperten-
regulation of miR-125b expression. These miRNA alterations were sive SH rats, including miR-1, miR-21, miR-26, miR-125, miR-133
related to the increased production of pro-inflammatory IL-8 and miR-150, miR-191, and miR-375, as evaluated by microarray and
nitric oxide synthetase and the depletion of reduced glutathione. Northern blotting analysis. miR-1 exacerbates arrhythmogene-
miR-125 plays an important role in lung carcinogenesis. Its genetic sis while decreasing the expression of kir2.1 and connexin43,
targets include the ERBB2 proto-oncogene that encodes the EGF which are myocardial proteins that are involved in maintaining
receptor, which is highly expressed in carcinomas (Fujimoto et al., the resting membrane potential and the intercellular conductance
2005). CS is a potent downregulator of miR-125a expression in the in the ventricular myocardium, respectively (Yang et al., 2007).
lung, which in turn is associated with the activation of the oncogene miR-133 inhibits the ERG-related gene, which encodes for IKr in
ERBB2 (Izzotti et al., 2009a, 2009b). miR-125b regulated by environ- diabetic rabbits (Xiao et al., 2007). Both miR-1 and miR-133 also
mental CS is involved in the stress response (Izzotti et al., 2009a, inhibit cardiac hypertrophy in mice and are key modulators of
2009b) and linked with the occurrence of pneumonia (Izzotti et al., cardiac development. miR-21 has been implicated in heart failure
2011).miR-466 is highly expressed in the lung, downregulated by CS (Divakaran and Mann, 2008).
exposure, and functionally related to cell proliferation, apoptosis, The particulate matter contained in the metal-rich fumes in
k-Ras activation, and protein repair (Izzotti et al., 2012a). Results the steel industry that is produced while welding and cutting car-
similar to those obtained using a VOC mixture have been obtained bon and alloy steels can alter miRNA expression. Metal fumes are
using gaseous formaldehyde alone (1 ppm for 4 h) in human lung formed by the evaporation, condensation, and oxidation of airborne
epithelial cells in vitro (Rager et al., 2011). The levels of 89 miR- metals. Steel fumes are primarily composed of oxides of iron, man-
NAs were significantly downregulated in formaldehyde-exposed ganese, calcium, magnesium, aluminum, silicon, chromium, and
samples compared with controls. The predicted miRNA targets nickel. Particulate fumes from medium- and low-carbon steel typ-
indicate that formaldehyde alters pathways associated with cancer, ically consist of iron oxide plus some manganese oxide as well
the inflammatory response, and the endocrine system. IL-8 release as barium from the self-shielded wires and inorganic fluorides
was increased in cells that were exposed to formaldehyde. The (Tossavainen, 1976). Exposure to this PM upregulates the expres-
same authors investigated formaldehyde’s ability to alter miRNA sion of miR-21 and miR-222 in the peripheral blood leukocytes
expression profiles in vivo. Cynomolgus macaques were exposed of workers, as revealed by qPCR (Bollati et al., 2010). miR-21 and
to formaldehyde at 0, 2, or 6 ppm. These concentrations represent miR-222 expression was significantly increased in post-exposure
potential occupational exposure levels. Specifically, formaldehyde samples. In particular, the miR-222 level was positively associated
levels up to and greater than 6 ppm have been measured in occupa- with the mean lead level in the PM10 fraction, whereas the miR-
tional settings, including industries related to formaldehyde-based 21 level was associated with the level of 8-hydroxyguanosine in
resin production and plastic production and in biology/pathology the blood, but not with individual PM size fractions or metal com-
laboratories. Under these experimental conditions, formaldehyde ponents. These miRNAs regulate the expression of genes involved
altered the expression of miR-145 and miR-142-3p, miR-203, miR- in pathways related to oxidative stress (Babar et al., 2008) and
125b, and miR-152 and concomitantly decreased the expression of inflammation (Xiao and Rajewsky, 2009). In particular, the upregu-
genes involved in apoptosis signaling. This finding suggests a pos- lation of miR-222 expression reduces the expression of endothelial
sible link between formaldehyde exposure, altered miRNA expres- nitric oxide synthetase in Dicer short interfering RNA-transfected
sion, and the altered regulation of cell death (Rager et al., 2013). cells (Suarez et al., 2007), an inflammation-related hallmark of
Exposure to toluene 2,4-diisocyanate changed the levels of atherosclerosis and ischemic cardiomyopathy (Zeiher, 1996). miR-
expression of miR-21, miR-22, miR-27b, miR-31, miR-126, miR-155, 222 has also been associated with altered redox signaling (Sen
miR-210, and miR-301a in a murine model. These results were et al., 2009). miR-21 has been shown to respond to hydrogen
related to the activation of mechanisms involved in allergic diseases peroxide stimulation and to participate in coordinated protective
(Anderson et al., 2013). responses to oxidative stress (Cheng et al., 2009) and inflammatory
Exposure to benzene-pyridine downregulates the expression of responses, as demonstrated using animal models of an allergic air-
miR-205, which serves as a tumor suppressor in human melanoma way (Lu et al., 2009) and lipopolysaccharide-induced inflammation
cells. Indeed, in vitro transfection of miR-205 inhibited the growth (Moschos et al., 2007).
of human melanoma cells (Noguchi et al., 2013). Another study MiRNAs are environmentally sensitive inhibitors of gene
showed that the levels of miR-223 in maternal and cord blood were expression that may mediate the effects of metal-rich particulate
strongly associated with the indoor concentrations of benzene and matter and toxic metals in humans. After 3 days of working in a
toluene. This study correlated high miR-223 expression with lower foundry, the levels of miR-421, miR-146a, miR-29a, and let-7g in the
numbers of Treg cells in maternal and cord blood. Furthermore, blood of workers were upregulated compared with those in the
children with fewer Treg cells at birth had a higher risk of atopic baseline samples (Motta et al., 2013).
dermatitis during the first 3 years of life (Herberth et al., 2013). The exposure of rats to silica dust altered the expression of 39
miRNAs involved in lung fibrosis. The expression of 14 miRNAs was
Coal fumes, black carbon dust, and oil fly ash significantly upregulated and that of 25 was downregulated in the
silicosis samples. These differentially expressed miRNAs play an
Coal fuel combustion residues are the wastes produced from important role in the development of fibrosis and silicosis (Faxuan
burning fossil fuels (i.e., coal, oil, and natural gas). These residues et al., 2012).
G Model
Regarding the cardiovascular effects of black carbon, research carcinoma, and chronic lymphocytic leukemia (Zhang et al.,
found that single nucleotide polymorphisms in miRNA processing 2007). These findings suggest that miRNAs may be involved in
genes influenced blood pressure variation in 789 exposed subjects. RDX-induced carcinogenesis. The carcinogen dimethylhydrazine
Indeed, SNPs in the Dicer, GEMIN4, and Di-George critical region-8 increases expression of miR-21 in colon and this is correlated with
(DGCR8) genes, as well as in the GEMIN3 and GEMIN4 genes (which age (Nautiyal et al., 2012).
encode proteins that guide miRNA into the RNA-induced silenc-
ing complex (RISC), are related to the diastolic and systolic blood PAHs: B[a]P and DMBA
pressure increases induced by black carbon (Wilker et al., 2010). An
evaluation of 496 CWP patients and 513 control subjects found that The term polycyclic aromatic hydrocarbons (PAHs) refers to a
SNPs in the pre-miRNA genes of miR-149 were associated with the ubiquitous group of several hundred chemically related, environ-
risk of pneumoconiosis in miners who were exposed to coal fumes mentally persistent organic compounds with two or more single or
(Wang et al., 2010a). fused aromatic rings that share a pair of carbon atoms. The major
source of PAHs is the incomplete combustion of organic materials
RDX such as coal, oil, and wood. The most toxic and best studied PAHs
are benzo([a])pyrene (B[a]P) and 7,12-dimethyl benz[a]anthrance
Hexahydro-1,3,5-trinitro-1,3,5-triazine, commonly known as (DMBA), both of which are well-known carcinogens.
RDX or cyclonite, is a white crystalline solid that is extensively
used as an explosive in mining, military, and industrial applica- Benzo[a]pyrene (B[a]P)
tions. RDX is slightly soluble in water and apolar organic solvents
but is readily soluble in polar organic solvents (Sax and Lewis, Benzo(a)pyrene is metabolically activated to form
1987). RDX can enter the aquatic environment through waste- benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE). BPDE induces
water discharges from manufacturing plants and can migrate from the downregulation of several miRNAs, including miR-506 (Zhao
settling ponds into the soil, subsequently leaching into groundwa- et al., 2011a) and miR-10a (Shen et al., 2009), and the upregula-
ter. Direct photochemical degradation is the major removal process tion of miR-106a (Jiang et al., 2011), miR-494 (Shen et al., 2009),
for water. Atmospheric releases may result from the incineration of and miR-22 (Liu et al., 2010b) in transformed malignant human
RDX-containing mixtures, with dry or wet deposition as the major bronchial epithelial cells (16HBE-T), as evaluated using qPCR.
atmospheric removal processes (Etnier, 1989). The primary occu- miR-506 functions as an anti-oncogene, suppressing cell prolif-
pational exposure to RDX during its manufacture occurs through eration and decreasing the degree of malignancy. The expression
the inhalation of fine dust particles. Ingestion may also be a possi- levels of miR-506 and N-Ras are inversely correlated, indicating that
ble route of exposure, whereas RDX is poorly absorbed through the N-Ras oncogene is a target of miR-506, thus providing a mech-
the dermis. The greatest potential for occupational exposure to anistic basis for miR-506 to function as a suppressor of cell growth
RDX occurs at ammunition plants during loading, assembly, and and tumorigenesis (Zhao et al., 2011a).
packing operations, and workers who are involved in melt-pouring miR-22 engages in the process of cell growth in soft agar and
and maintenance operations have the greatest potential for expo- cell motility because anti-miR-22 promotes cell apoptosis and
sure. RDX is moderately toxic for the central nervous system and is decreases the colony formation and motility of malignant cells. The
classified by IARC as a possible human carcinogen. increased expression of miR-22 results in the decreased expres-
The expression profile of 567 miRNAs was analyzed by microar- sion of the phosphatase and tensin homolog (PTEN) gene. qPCR
ray and qPCR assays in B6C3F1 mice that were fed diets with and Western blotting assays of the PTEN expression levels have
or without 5 mg/kg of RDX for 28 days (Zhang and Pan, 2009). indicated that miR-22 regulates PTEN expression by binding to a
In the brain, of the 84 miRNAs for which the expression was target site in the PTEN 3 -untranslated region, leading to resistance
altered by RDX exposure, the levels of 38 were upregulated and to cellular apoptosis (Liu et al., 2010b).
those of 46 were downregulated. The expression levels of miR-206 Decreased expression of miR-10a is correlated with human
and miR-497 were significantly increased by 26-fold and 9-fold, megakaryocytopoiesis and adult acute myeloid leukemia
respectively, whereas the expression level of miR-10b was signif- (Debernardi et al., 2007). Downregulated miR-10a expression
icantly decreased by 14-fold. RDX exposure significantly affected and upregulated expression of its predicted target HOXA1 occur
the expression of 56 miRNAs in the liver, with 31 upregulated reciprocally in 16HBE-T cells, suggesting that miR-10a is involved
and 15 downregulated. The most strongly upregulated miRNAs in the transformation of 16HBE-T cells and might be a tumor
were miR-689, miR-802, miR-29c, and miR-30e. By contrast, the suppressor.
expression of some miRNAs was significantly inhibited by RDX The functional role of miR-106a was demonstrated by loss-
exposure. The miRNAs that displayed at least 4-fold inhibition of-function and gain-of-function experiments that showed that
were miR-574-5p, miR-466f-3p, and let-7e. The brain was more miR-106a repression induced G0/G1 arrest and decreased the num-
sensitive to RDX exposure than was the liver. miR-15 expression ber of cells in S phase. Conversely, its overexpression increased the
was upregulated in both the livers and brains of the RDX-treated number of cells in S phase, suggesting that miR-106a overexpress-
mice. The transcript for the anti-apoptotic Bcl2 is one of the tar- ion provides a proliferative advantage to malignantly transformed
gets of miR-15, and the level of this miRNA is inversely correlated cells. miR-106a has been reported to act as a potential oncogenic
with the Bcl2 level (Cimmino et al., 2005). The change in miR-206 noncoding RNA in T-cell lymphoma (Lum et al., 2007). The pre-
expression was greater than that in the other miRNAs that were dicted targets of miR-106a include RB1, p21, and RBP1-like, which
affected in this study. This result suggests that miR-206 may play are associated with tumor development. Increased expression of
an important function in an animal’s response to RDX exposure. miR-106a decreases the expression of RB1 mRNA and protein. The
The candidate targets include several transcriptional factors, brain- retinoblastoma tumor suppressor gene product RB1 regulates dif-
derived neurotrophic factors that may cause neurologic disorders, ferentiation, apoptosis, and cell cycle control by coordinating the
and cancer-related genes, such as met proto-oncogene and v-ets cell cycle at G1/S (Volinia et al., 2006).
erythroblastosis virus E26 oncogene homolog 1. BPDE increases miR-320 and miR-494 expression in pri-
The expression profiles of the RDX-altered miRNAs are signifi- mary murine bronchial epithelial cells. One study indicated
cantly altered in many types of cancer, such as breast, lung, ovarian, that miR-320 and miR-494 affect G1 arrest by regulating CDK6
liver, and prostate cancer, colorectal neoplasia, hepatocellular (Duan et al., 2010).miR-494 suppresses the cell proliferation and
G Model
colony-forming activities of A549 human lung cancer cells and The levels of miR-21 and miR-155 are known to be upregulated in
induces their senescence (Ohdaira et al., 2012). miR-494 over- HNSCC primary tissues and cell lines. One study found that the
expression causes apoptosis and inhibited GIST cell growth, level of cytochrome was decreased by a miR-21 knockdown and
accompanied by changes in the content of cells in G1 and S phase that miR-21 inhibited the expression of several mRNAs, leading to
(Kim et al., 2011). Other studies have reported the overexpression a cascade of events that prevented apoptosis and increased cellular
of miR-320 or miR-494 in a human Burkitt lymphoma-derived cell proliferation (Chang et al., 2008).
line (Sander et al., 2008) and a leukemic cell line (Schaar et al., 2009). Treatment of human HepG2 hepatocellular carcinoma cells
The effects of B[a]P on pulmonary mRNA and miRNA levels was with benzo[a]anthracene and benzo[k]fluoranthene upregulates
examined in adult male B6C3F1 mice that were exposed to 150 or the expression of miR-181a/b/d. Depletion of miR-181 family
300 mg/kg B[a]P by oral gavage for 3 consecutive days and were members using miRNA inhibitors enhances the expression of
sacrificed 4 h after the last exposure (Halappanavar et al., 2011a). MKP-5 and suppresses the phosphorylation of p38 MAPK. Further-
Using cDNA microarrays, pulmonary mRNA and miRNA expression more, depletion of miR-181 family members inhibits cancer-cell
levels were analyzed. Over 1000 genes were significantly differen- migration. Therefore, the miR-181 family plays a critical role in
tially expressed in control and B[a]P-treated mice. The analysis of PAH-induced hepatocarcinogenesis by targeting MKP-5, resulting
the miRNA expression profiles revealed the downregulation of miR- in p38-mediate MAPK activation (Song et al., 2013). MiR-21, miR-
150, miR-142-5p, and miR-122 expression and the upregulation of 146a and let-7a levels were significantly higher in the vital organs
miR-34c, miR-34b-5p, and miR-29b expression. These miRNAs are of the mice 24 hours after DMBA exposure compared to the controls
involved in the immune response, cell proliferation, and the cell (Juhász et al., 2013).
cycle, which are also the main pathways that are affected at the
mRNA level (Halappanavar et al., 2011a). Asbestos
The miRNA expression profiles of human bronchial epithelial
cells expressing an oncogenic allele of H-Ras (HBER) at different Asbestos-related lung cancer is one of the leading occupational
stages of transformation induced by benzo[a]pyrene revealed that cancers.
12 miRNAs were differentially expressed. Among these miRNAs, Integrated analysis of the miRNA expression profiles with
the downregulation of miR-638 expression was found in 68% of pri- the CGH and mRNA expression profiles was performed on 26
mary human non-small-cell lung cancer tissues. The expression of lung tumor samples and the corresponding normal lung tissue
miR-638 in HBER cells increased upon treatment of B[a]P in a dose- samples from highly asbestos-exposed and non-exposed lung
dependent manner. The expression of miR-638 was also examined cancer patients and 8 control lung tissue samples. DNA copy
in peripheral lymphocytes from workers who were exposed to number alterations (e.g., gain at 12p13.31) were correlated with
86 polycyclic aromatic hydrocarbons, revealing an increase of 72% the deregulated expression of miRNAs. Specifically, 13 miRNAs
compared with that of the control group (Li et al., 2012a). that were affected by asbestos exposure (over-expressed miR-
The analysis of mRNA and miRNA levels in HepG2 hepatoma 148b, miR-374a, miR-24, let-7d, let-7e, miR-199b-5p, miR-331-3p,
cells and in a human liver cell line expressing p53 that was and miR-96; under-expressed miR-939, miR-671-5p, miR-605, miR-
treated with B[a]P demonstrated remarkable alterations. Eight of 1224-5p, and miR-202) were identified. The inversely correlated
the affected miRNAs (see Table 1) participated in specific B[a]P- target genes included GADD45A, LTBP1, FOSB, NCALD, CACNA2D2,
responsive pathways, such as apoptotic signaling, cell-cycle arrest, MTSS1, and EPB41L3. In addition, the over-expression of the well-
the DNA-damage response, and DNA-damage repair (Lizarraga known squamous cell carcinoma-associated miR-205 was linked
et al., 2012). to the downregulation of DOK4 gene expression (Nymark et al.,
miR-29a regulates the BPDE-induced DNA-damage response 2011).miR-103 was identified as a potential biomarker of malignant
through Cdc7 kinase in lung cancer cells. Indeed, in response to mesothelioma based on the analysis of the blood of mesothelioma
DNA damage, the upregulation of Cdc7 kinase expression corre- patients and asbestos-exposed controls (Weber et al., 2012). Malig-
lates with the downregulation of miR-29a expression (Barkley and nant pleural mesothelioma patients were tested for the expression
Santocanale, 2013). of 88 miRNAs involved in carcinogenesis. The levels of most of
Chemical environmental contaminants have been shown to the tested miRNAs were downregulated in malignant tissues com-
negatively affect reproduction and embryonic development in ani- pared with normal tissues. The performance of miR-126 as a
mals. Spermatozoa from infertile men exhibit higher levels of DNA biomarker of malignant mesothelioma was evaluated by compar-
damage compared to those of fertile men, and sperm DNA dam- ing the serum samples of asbestos-exposed subjects and malignant
age is associated with low sperm quality and reduced fertility. pleural mesothelioma patients with those of controls. miR-126
In mice, paternal B[a]P exposure modulates the miRNA expres- expression was not affected by asbestos exposure, whereas it was
sion patterns in the developing embryo (Brevik et al., 2012). These strongly associated with VEGF serum levels. The level of miR-126
findings provide evidence that B[a]P-induced miRNA alterations in in serum was proposed as a biomarker to identify subjects at a high
germ cells may be inherited, producing transgenerational effects. risk of developing malignant pleural mesothelioma (Santarelli et al.,
An in vivo microarray study of the livers of mice treated with 2011).
B[a]P found a significant dose-dependent increase only for miR-
34a expression. These findings suggest that liver miRNAs are largely Radon
unresponsive to B[a]P, which causes both DNA adducts and muta-
tions (Malik et al., 2012). According to the United States Environmental Protection
Agency, radon is the second most frequent cause of lung cancer,
Dimethylbenz[a]anthrance after cigarette smoking, causing approximately 21,000 lung can-
In a study that utilized miRNA microarray and qPCR, cer deaths every year. Whereas radon is the second most frequent
7,12-dimethyl benz[a]anthrance (DMBA) treatment induced the cause of lung cancer among smokers, it is the number one cause
upregulation of miR-21, miR-200b, miR-221, miR-338, and miR-762 of lung cancer among non-smokers, according to EPA estimates
expression and the down-regulation of miR-16, miR-26a, miR- (www.epa.gov, United States Environmental Protection Agency,
29a, miR-124a, miR-125b, miR-126-5p, miR-143, miR-145, miR-148b, October 12, 2010 (retrieved January 29, 2012)).
miR-155, miR-199a, and miR-203 expression in hamster oral squa- Human bronchial BEAS2B cells that were exposed to
mous cancer tissues compared with normal tissues (Yu et al., 2009). 20,000 Bq/m(3) of radon gas displayed increased colony-formation
G Model
efficiency on soft agar. Furthermore, enhanced apoptosis resistance These endocrine disruptors increase the estrogen receptor trans-
was observed in the cells with significant differential expression of criptional activity in MCF-7 breast cancer cells. DDT and BPA
some miRNAs, including miR-483-3p, miR-494, miR-2115, miR-33b, treatment alters the miRNA profiles in MCF-7 cells with similar
miR-1246, miR-3202, miR-18a, miR-125b, miR-17, and miR-886-3p. trends. Indeed, BPA alters the expression of 17 miRNAs. Of the
The expression of miRNA target genes that are predominantly 14 miRNAs altered by DDT, 10 are also altered by BPA and only 4
involved in the regulation of cell proliferation, differentiation, are specific for DDT (miR-16, miR-92, miR-99, and miR-193a). Con-
and adhesion during the process of malignant transformation was versely, let-7 miRNA expression is altered by BPA but not by DDT
observed. This transformation is associated with signaling path- (Tilghman et al., 2012). The expression of one miRNA, miR-21, is
ways that are involved in protein kinase activation, the response potently upregulated by both endocrine disruptors, as confirmed
to reactive oxygen species, the activation of nuclear factor ␬B, and by qPCR.
the regulation of cell cycle (Cui et al., 2013). MiRNAs play central roles in a wide variety of key biological pro-
cesses, including the maintenance of stem-cell pluripotency and
Vinyl carbamate (urethane) differentiation ability. Recently, the level of miR-134 was shown to
be downregulated in mouse embryonic stem cells that were treated
Vinyl carbamate is a metabolite and a structural analog of ethyl with BPA, thus increasing the expression of Oct4, Sox2, and Nanog,
carbamate (EC), a byproduct of fermentation that is found in alco- which are powerful inducers of pluripotent stem-cell differentia-
holic beverages and a variety of food products, including yogurt, tion (Chen et al., 2013).
bread, soy sauce, cheese, and apple cider vinegar (Battaglia et al.,
1990; Zimmerli and Schlatter, 1991). The highest concentrations Diethylstilbestrol
of EC (100–20,000 ng/g) have been detected in alcoholic beverages,
including stone-fruit brandies (plums, apricots, or cherries), sherry, Diethylstilbestrol (DES) is a synthetic nonsteroidal estrogen that
and bourbon. It is also a natural constituent of tobacco, at concen- also acts as an endocrine disruptor. From approximately 1940 to
trations ranging from 310 to 375 ng/g (Schmeltz et al., 1978). It has 1970, DES was given to pregnant women in the mistaken belief that
been estimated that adults’ mean daily intake of EC from various it would reduce the risk of pregnancy complications and losses. DES
food items is approximately 10–20 ng/kg body weight (Zimmerli was shown to cause a rare vaginal tumor in girls and women who
and Schlatter, 1991). had been exposed to this drug in utero. Early exposure to xenoe-
Vinyl carbamate was found to change the expression of miRNAs strogens, including DES, may increase breast cancer risk later in
in the lungs of A/J mice. In particular, microarray and qPCR assays adult life.
revealed that vinyl carbamate induced the upregulation of miR- DES alters the miRNA expression profile of progenitor-
21, miR-31, miR-130a, miR-146b, and miR-377 expression, whereas containing mammospheres in vitro. Indeed, research found that
miR-1 and miR-143 expression was downregulated in lung tumors relative to control cells, the levels of 9.1% of the affected miRNAs (82
compared with normal lungs (Melkamu et al., 2010). Among the of 898) were altered in the epithelial progeny of mammospheres
miRNAs that exhibit differential expression, miR-21 is the most fre- that had been exposed to diethylstilbestrol. The upregulated miR-
quently upregulated oncomiR in solid tumors (Volinia et al., 2006). NAs included miR-181, miR-194, miR-345, and miR-375, and the
Research found that miR-21 expression was upregulated in nearly downregulated miRNAs included miR-15b, miR-25, miR-92b, miR-
75% of breast cancer specimens, and this modulation was signifi- 320, miR-106a, and miR-9-3. Downregulation miR-9-3 expression
cantly correlated with a shortened survival time (Qian et al., 2009). was functionally linked with the recruitment of DNA methyltrans-
miR-21 acts as an oncogenic miRNA by downregulating the expres- ferase 1, which caused an aberrant increase in DNA methylation.
sion of the tumor-suppressor genes PTEN (Meng et al., 2007), p53, Functional analyses have suggested that miR-9-3 plays a role in the
transforming growth factor-beta (Papagiannakopoulos et al., 2007), p53-related apoptotic pathway. Epigenetic silencing of this gene,
tropomyosin 1 (Zhu et al., 2007), PDCD4 (Zhu et al., 2008b), and therefore, reduces this cellular function and promotes the prolif-
RECK (Gabriely et al., 2008). The sustained downregulation of the eration of breast cancer cells (Hsu et al., 2009). Increased miR-9
miR-1a level in lung tissues during lung carcinogenesis induced by expression increases the malignant phenotype of breast cancer in
urethane indicates that urethane exposure alters the expression of humans (Krell et al., 2012).
a cluster of miRNAs (Li et al., 2013).
Pesticides and endocrine disruptors Nonylphenol
Bisphenol A Nonylphenol is a family of closely related organic compounds,

a subset of the alkylphenols. This collection of compounds is a pre-
Bisphenol A (BPA) is used to make polycarbonate polymers and cursor to commercially important detergents.
epoxy resins, along with other materials used to produce plas- In a recent study, miRNA modulation in mouse TM4 Sertoli cells
tics. BPA is a typical endocrine disruptor that exhibits detectable treated with nonylphenol for 3 or 24 h was evaluated by microar-
hormone-like properties. However, BPA metabolites are also able ray analysis. The expression of 9 of the 186 affected miRNAs was
to induce genotoxic damage in the liver and breast, as demon- upregulated (see Table 1) at both times, whereas the expression
strated in vivo in mice (Izzotti et al., 2009c). It was recently reported of 11 was downregulated (Table 1) (Choi et al., 2011). Nonylphe-
that BPA exposure leads to specific alterations in miRNA levels in nol treatment of breast cancer MCF-7 and hepatoma HepG2 cell
cytotrophoblast cell lines in vitro, as evaluated by microarray and lines altered the expression of let-7c, miR-16, miR-195, miR-200b,
qPCR assays. The miRNAs with altered expression levels included miR-200c, miR-205, and miR-589, which are related to metabolism,
miR-146, let-7f, let-7 g, miR-20, miR-21, and miR-335, with a trend immune responses, apoptosis, and cell differentiation (Paul et al.,
toward upregulation. The expression of miR-146a was particu- 2009).
larly strongly induced by BPA exposure, and its overexpression in
cells led to slower proliferation and higher sensitivity to the DNA- Propiconazole
damaging agent bleomycin (Avissar-Whiting et al., 2010).
Both BPA and dichloro-diphenyl-trichlorethane (DDT) alter Conazoles are an important class of agricultural fungicide. Prop-
miRNA expression in breast carcinoma cells (Tilghman et al., 2012). iconazole is a mouse liver carcinogen.
G Model
Using a microarray, miRNA expression was analyzed in con- These targets of the miRNAs with altered expression in colon can-
trol and conazole-treated mice after 90 days of administration in cers have been implicated in tumor recurrence and reduced patient
feed. Groups of mice were fed either a control diet or a diet that survival. These findings demonstrate that the let-7/c-Myc/Lin28
contained 1800 ppm of triadimefon, 2500 ppm of propiconazole, axis is dysregulated in heterocyclic amine-induced rat colon car-
or 2000 ppm of myclobutanil. Triadimefon and propiconazole are cinogenesis (Parasramka et al., 2012).
mouse liver tumorigens, whereas myclobutanil is not. The tumori-
genic conazoles induced many more changes in miRNA expression MeIQx
than did the nontumorigenic conazole. The expression of a group The heterocyclic amine 2-amino-3,8-dimethylimidazo[4,5-
of 19 miRNAs was significantly altered in both the triadimefon- f]quinoxaline (MeIQx) exists in cooked meat and fish. It causes
and propiconazole-treated animals but not in the myclobutanil- mutations in bacterial and mammalian assays and induces tumors
treated animals. All but one (miR-466) of the altered miRNAs was in mammals. MeIQx is converted within cells to a reactive deriva-
downregulated compared to that of the controls. The miRNAs with tive that forms a major covalent adduct at carbon-8 of guanine in
the highest level of downregulation were miR-135b, miR-684, miR- DNA. This adduct may alter the DNA conformation at critical stages
875, miR-380, miR-302, miR-758, miR-509, and miR-9. This pattern of the replicative process, causing mutations. The IARC classifica-
of altered miRNA expression represents a signature for tumorigenic tion of MeIQx is Group 2B, i.e., possibly carcinogenic to humans.
conazole exposure in mouse liver after 90 days of treatment (Ross MiRNA expression was evaluated in the livers and lungs of A/J
et al., 2010). mice during NNK- and MeIQx-induced lung tumorigenesis. In addi-
Myclobutanil, propiconazole, and triadimefon, three triazole tion, the incidences of Egfr and Kras gene mutations in rat and
fungicides, upregulated the expression of miR-1274a and miR- mouse lung tumors that were induced by the chemical carcinogens
1274b and downregulated the expression of miR-1246, miR-363, NNK, MeIQx, and N-bis (2-hydroxypropyl)nitrosamine were exam-
miR-574-3p, and miR-20b in the human hepatoma HepG2 cell line ined. In rat lung tumors, a silent mutation was detected in exon 20
(An et al., 2013). of the Egfr gene. Activating mutations of the Kr␣s gene at codon
12 were detected in neoplastic lesions induced by NNK and MeIQx,
caused by G/C-A/T transitions. NNK or MeIQx administration con-
Carcinogens in food and water
comitantly reduced the expression level of miR-125a-5p and let-7a
in the liver (Yamakawa et al., 2010).
Pyrolysis products (furan, PhIP, and MeIQx)
Ethanol
Furan
Furan is a heterocyclic organic compound that consists of five
Ethanol is a major cause of human diseases that mainly affect
aromatic rings that contain four carbon atoms and one oxygen.
the liver and central nervous system and is an established human
Furan is soluble in organic solvents but is insoluble in water.
carcinogen that is classified in IARC Group 1.
Furan is present in various foods, leading to the intake of up
One study found that miR-126 expression was downregulated
to 3.5 ␮g/kg body weight (bw)/day, thus representing a potential
in alcohol-related human hepatocellular carcinoma, as revealed by
risk to human health. Furan formation originates with the ther-
quantitative reverse-transcriptase polymerase chain reaction per-
mal degradation of sugars (Maillard reaction), amino acids, ascorbic
formed in liver biopsy specimens (Ladeiro et al., 2008). miR-126
acid, poly-unsaturated fatty acids, and carotenoids.
is involved in the regulation of angiogenesis and acts as a tumor
Rats that were treated with furan for 5 days did not dis-
suppressor. The downregulation of miR-126 expression in cancer-
play a change in the expression profiles of apoptosis-related and
ous vs. noncancerous tissues has been reported for cancers of the
cell-cycle-related genes in their livers, whereas a change in the
lung, stomach, cervix, bladder, and prostate (Meister and Schmidt,
expression levels of genes related to cell-cycle control and apopto-
2010). The miR-126 gene is encoded within an intron of the egfl7
sis was observed. These changes were reversed after an off-dose
gene. Mature miR-126 binds to a complementary sequence within
period of 2 weeks. Changes in the miRNA expression profile were
EGFL7 mRNA, preventing its translation and resulting in a decrease
detected, with the levels of 5 of the 349 assessed miRNAs altered.
of the EGFL7 protein level. EGFL7 is known to be involved in cell
The levels of 2 of these miRNAs were upregulated (let-7a and
migration and blood vessel formation (Sun et al., 2010).
miR-28) and those of 3 were downregulated (let-7e, miR-296, and
In the pharyngeal and laryngeal carcinoma specimens of strong
miR-489) (Chen et al., 2010).
alcohol consumers, the expression of miR-375 was upregulated
The levels of 18 miRNAs were found to be significantly changed
compared to that of non-drinkers, as inferred from qPCR anal-
in furan-induced rat cholangiocarcinoma samples. Furthermore,
yses (Avissar et al., 2009). miR-375 acts as a tumor suppressor
the levels of 14 of them, including mir-141 and mir-200b, were also
through repressing the activity of insulin-like growth factor 1
altered in the rat liver samples after 3 months of furan treatment,
receptor (Kong et al., 2012b), oncogene AEG-1/MTDH (Nohata et al.,
indicating their importance for cholangiocarcinoma development.
2011), and 3-phosphoinositide-dependent protein kinase-1 (PDK1)
These miRNAs are mainly involved in the regulation of cell prolif-
(Li et al., 2011b).
eration and apoptosis. Of the 349 miRNAs examined, the levels of
Dolganiuc et al. (2009) found that alcohol downregulated
18 were upregulated and those of 12 were downregulated in sam-
the expression of several miRNAs, including miR-27b, miR-
ples after 3 months of furan treatment compared to controls (Chen
214, miR-199a-3p, miR-182, miR-183, miR-200a, and miR-322,
et al., 2012).
while upregulating the expression of miR-320, miR-486, miR-705,
and miR-1224 in the mouse liver, as evaluated by microarray
PhIP analysis.miR-27b controls endothelial cell repulsion and angiogen-
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a esis by targeting semaphorin 6A (Urbich et al., 2012), PPAR␣ (Kida
heterocyclic amine formed in meat cooked at high temperatures. et al., 2011), and NF-␬B (Thulasingam et al., 2011).
Research found that PhIP altered miRNA expression in the rat Chronic ethanol consumption inhibits and delays liver regen-
colon. Among the most highly dysregulated miRNAs were those eration in experimental animals. Research found that a partial
belonging to the let-7 family. Subsequent computational modeling hepatectomy was associated with an increase in hepatic miR-21
and target validation identified c-Myc and the miRNA-binding pro- expression in both ethanol-fed and paired control rats (Dippold
teins Lin28A/B as key targets, along with Sox2, Nanog, and Oct-3/4. et al., 2012). Additionally, miR-34a expression was increased in
G Model
the livers of mice that were exposed to ethanol, and miR-34a was Arsenic disrupts ATP production through several mechanisms. At
overexpressed in ethanol-treated hepatobiliary cell lines. miR-34a the level of the citric acid cycle, arsenic inhibits lipoid acid, such as
contributes to alcoholic liver injury and tissue repair by modu- pyruvate dehydrogenase. Furthermore, by competing with phos-
lating cell proliferation, remodeling, and migration (Meng et al., phate, it uncouples oxidative phosphorylation, thus inhibiting the
2012).miR-214 is involved in inflammation (through the modu- energy-linked reduction of NAD+, mitochondrial respiration and
lation of the adenosine A2A receptor) (Heyn et al., 2012) tumor ATP synthesis. Arsenic exposure also increases hydrogen perox-
proliferation and metastasis (through targeting TFAP2, Plexin-B1, ide production, which is speculated to have the potential to form
MEK3, and JNK1) (Penna et al., 2011; Qiang et al., 2011; Yang et al., reactive oxygen species and create oxidative stress. These types
2009) and muscle cell differentiation (Liu et al., 2010a). of metabolic interference lead to death from multi-system organ
In human and rat liver cells, ethanol exposure upregulated failure, presumably from necrotic cell death rather than apopto-
miR-214 expression, triggering the downregulation of glutathione sis (Klaassen and Watkins, 2003). A major public health problem
reductase and cytochrome P450 oxidoreductase protein levels and in Southeast Asia (Das et al., 2012) and South America (Aballay
activities and inducing oxidative stress (Dong et al., 2013).miR- et al., 2012) is the presence of high amounts of arsenic in the drink-
199a-3p is involved in cell proliferation and survival (Shatseva et al., ing water. Arsenic-related health hazards are particularly relevant
2011; Duan et al., 2011).miR-182 acts as a tumor suppressor by when exposure begins in utero and during early life (Smith et al.,
inhibiting the proliferation and invasion of various types of cancer 2012).
cells (Kong et al., 2012c; Zhang et al., 2011).miR-183 has a potential Marsit et al. (2006) conducted an in vitro experiment using the
oncogenic role through regulation of the tumor suppressor genes human immortalized lymphoblast cell line TK-6. They reported that
EGR1 and PTEN (Sarver et al., 2010). Furthermore, miR-183 targets 6 days of arsenic exposure significantly upregulated the expres-
VIL2 and plays a role in the regulation of migration and metasta- sion of 4 miRNAs (miR-22, miR-34, miR-221, and miR-222) more
sis in breast cancer (Lowery et al., 2010).miR-200 acts as a tumor than 2-fold and downregulated the expression of miR-210 more
suppressor (Schliekelman et al., 2011) and is involved in the oxida- than 6-fold compared to those of the control groups. The miRNA
tive stress response (Mateescu et al., 2011).miR-322 is orthologous expression levels were evaluated using a miRNA microarray and
to the experimentally validated miR-424 sequence in endothelial confirmed using qPCR.miR-22 has tumor-suppressor properties (Li
cells of humans, which is involved in angiogenesis (Ghosh et al., et al., 2011a), is involved in NF-␬B suppression by regulating the
2010) and promotes cell cycle quiescence and differentiation by expression of two of its coactivators (Takata et al., 2011), is involved
downregulating Cdc25A (Sarkar et al., 2010).miR-320 is involved in in anti-angiogenesis (Yamakuchi et al., 2011), and induces cellular
the regulation of cardiac ischemia/reperfusion injury through tar- senescence (Xu et al., 2011).miR-34 is a tumor suppressor miRNA
geting heat-shock protein 20 (Ren et al., 2009). The downregulation that plays a role in cell cycling, differentiation, and apoptosis (Chang
of miR-320 results in the upregulation of one of its direct targets, et al., 2012).miR-210 acts as an oncogene and is involved in cell
ETS2 (v-ets erythroblastosis virus E26 oncogene homolog 2), pro- proliferation and metastasis and the inhibition of apoptosis (Yang
moting angiogenesis and cell invasion (Bronisz et al., 2011).miR-486 et al., 2012; Ying et al., 2011).miR-221 is an oncogenic miRNA that
is involved in cell differentiation (Dey et al., 2011) and tumor pro- is involved in the regulation of cell migration and proliferation.
gression (Mees et al., 2009).miR-1224 negatively regulates tumor miR-222 is clustered with miR-221. It is involved in apoptosis, cell
necrosis factor-␣ gene expression by modulating Sp1 (Niu et al., growth, and cell-cycle progression (Rao et al., 2011).
2011). Beezhold et al. (2011) demonstrated the overexpression of
High ethanol exposure dramatically induces cellular apoptosis miR-190 in vitro in human bronchial epithelial cells after arsenic
and significantly alters the expression of several miRNAs. In the treatment using qPCR analysis. miR-190 is involved in cell prolifer-
rat model of ethanol-induced gastric mucosal injury, miR-145 (pro- ation and malignant transformation (Beezhold et al., 2011).
apoptotic) expression was upregulated, whereas the expression of An in vitro experiment based on the prolonged exposure of
miR-17, miR-19a, and miR-21 (anti-apoptotic) was downregulated immortalized p53-knockdown human bronchial epithelial cells
(Luo et al., 2013). miR-124a expression was downregulated in the (p53lowHBECs) to low levels of arsenite demonstrated their malig-
dorso-lateral striatum of rats following alcohol consumption (Bahi nant transformation, which was accompanied by an epithelial to
and Dreyer, 2013). mesenchymal transition and the reduction in the levels of miR-
Prenatal alcohol exposure results in life-long disorders that lead 200 family members, as shown by qPCR analysis (Wang et al.,
to persistent alterations of cognitive function and behavioral phen- 2011).
otypes. The upregulation of miR-26b expression was correlated The arsenic-mediated regulation of apoptosis was found to be
with a reduced level of the Canabinoid receptor 1 transcript in the modulated through its capacity to induce mir-2909 expression,
brains of adult mice that were exposed to alcohol during neurode- thus antagonizing the expression of transcription factors and b-cell
velopment. The stable alteration of miRNA expression as a result of lymphoma 3 (Sharma et al., 2013). The arsenic trioxide-induced
neurodevelopmental teratogenesis may affect the expression of its apoptosis of retinoblastoma cells is mediated by the decreased
target transcripts long after the ethanol exposure (Stringer et al., expression of miR-376a, which subsequently increases caspase-3
2013). expression (Zhang et al., 2013). Arsenic trioxide, a highly effec-
Chronic alcohol consumption induced the upregulation of miR- tive antitumor drug, has been shown to cause QT prolongation and
155 expression in the mouse cerebellum in a TLR4-dependent even sudden cardiac death. The upregulation of miR-133 and miR-
manner. The alcohol-induced upregulation of miR-155 expres- 1 expression underlies arsenic trioxide-induced cardiac electrical
sion triggered the expression of TNF␣ and monocyte chemotactic disorders, and these miRNAs may serve as potential therapeutic tar-
protein-1, resulting in neuroinflammation (Lippai et al., 2013). gets for treating arsenic trioxide cardiotoxicity (Shan et al., 2013).
The expression profiles of miRNAs upon arsenic exposure of human
Arsenic umbilical vein endothelial cells was examined using miRNA chips
to explore the molecular mechanisms of arsenic-induced vascular
Arsenic occurs in many minerals, typically in conjunction with toxicity. It was found that the expression of 85 miRNAs was upregu-
sulfur and metals, and as a pure elemental crystal. Metallic arsenic is lated and that of 52 miRNAs was downregulated in arsenic-treated
primarily used to strengthen alloys of copper and lead. Arsenic and cells compared to control group cells (Li et al., 2012b). MiR-21 was
arsenic-containing compounds, particularly arsenic trioxide, are associated with microalbuminuria heavy metals in Hong Kong Chi-
used in the production of pesticides, herbicides, and insecticides. nese adolescents (Kong et al., 2012a).
G Model
2-AAF Research on Cancer (IARC) classifies ethylene oxide into group 1,

meaning it is a proven carcinogen (IARC, 1999).
2-acetylaminofluorene (2-AAF) is a carcinogenic and mutagenic The expression of miR-828 was detected in leaves, and was
derivative of fluorene. It is extensively used in experimental car- induced by wounding rather than by ethylene, hydrogen peroxide,
cinogenesis. methyl jasmonate or nitric oxide. Transgenic sweet potato overex-
An experiment conducted using a rodent animal model (rat) pressing miR-828 precursor affected lignin and hydrogen peroxide
demonstrated that dietary exposure to 2-AAF led to the upregulated contents (Lin et al., 2012).
expression of miR-17-5p, miR-18, miR-20, and miR-93, as assayed
using qPCR (Pogribny et al., 2011). miR-17-5p is involved in the reg-
Drugs
ulation of cell proliferation and apoptosis (Wei et al., 2012). miR-18
is involved in the regulation of cell proliferation through targeting
N-ethyl-N-nitrosourea
K-Ras (Tsang and Kwok, 2009). miR-20 is involved in cell migration
and invasion (Kang et al., 2012). miR-93 promotes tumor growth
N-ethyl-N-nitrosourea (ENU) is a potent mutagen that is also
and angiogenesis (Fang et al., 2011).
toxic at high doses. This chemical is an alkylating agent that acts
A recent study demonstrated the critical contribution of
by transferring the ethyl group of ENU to the nucleotides (typically
miR-22 and miR-29b in inhibiting Mat1a and Mthfr gene expres-
thymine) of nucleic acids.
sion during 2-AAF-induced rat hepatocarcinogenesis (Koturbash
Using qPCR, miR-34a expression was evaluated in the splenic
et al., 2013). Male Fischer rats exposed through their diet to
tissues of control mice and mice treated with ENU (120 mg/kg
genotoxic (2-acetylaminofluorene) R reveals a high induction of
bw). One dose of ENU increased the level of miR-34a expression
miR-200a/200b/429, and of miR-34, which was associated with DNA
5.5-fold at one day after treatment. This result suggests that miR-
damage and oxidative stress in vivo and in vitro (Koufaris et al.,
34a expression responds sensitively to genotoxic insults within a
2012).
short period after exposure to this mutagen. Therefore, this miRNA
has the potential to be used as a biomarker for ENU exposure
Microcystin
(Chen et al., 2011a). miR-34a has been identified as a miRNA com-
ponent of the p53 tumor suppressor network (He et al., 2007a)
Microcystin-LR is a naturally occurring toxin that is produced
that arrests cell growth, repairs DNA damage, and induces apo-
by Cyanobacteria that live in warm water bodies. It is the most
ptosis when DNA damage is not repairable (Shackelford et al.,
toxic compound of the large family of microcystins. The IARC clas-
1999). Research found that miR-34a expression was upregulated
sified microcystin-LR as possibly carcinogenic to humans (Group
in azoxymethane-induced colon cancer (Davidson et al., 2009) and
2B), mainly due to its association with primary hepatocellular car-
was downregulated in rodents during folate-deficient diet-induced
cinoma.
liver carcinogenesis (Tryndyak et al., 2009) and in lungs during
Xu et al. (2012) conducted a study of the effect of microcystin
exposure to cigarette smoke (Izzotti et al., 2009a).
on a human embryonic liver cell line and reported that it upre-
Upregulated miR-34a and miR-34b/c expression causes cell-
gulated the expression of miR-221 and miR-21 and downregulated
cycle arrest in the G1 phase (Raver-Shapira et al., 2007). MiR-34b/c
the expression of miR-122 compared to those of control cells, as
inhibits cell proliferation and colony formation in soft agar (Corney
assessed by qPCR analysis. miR-21 is considered an oncomiR due
et al., 2007). The introduction of miR-34a and miR-34b/c into pri-
to its involvement in anti-apoptosis, cell proliferation, and cellular
mary human diploid fibroblasts induces cellular senescence (He
invasion (Gao et al., 2012).
et al., 2007b). The re-expression of miR-34a in tumor cells induces
Zhao et al. (2011b) observed the upregulation of miR-31 and
apoptosis (Chang et al., 2007).
miR-430 expression and the downregulation of miR-125 and miR-
126 expression after microinjecting microcystin into zebrafish
embryos. miR-125 is an important negative regulator of p53 and Tamoxifen
p53-induced apoptosis during development and in the stress
response (Le et al., 2009). miR-31 has been shown to contribute Tamoxifen is a drug that is widely used for chemotherapy and
to vascular development (Pedrioli et al., 2010). miR-430 regulates the chemoprevention of breast cancer. However, a number of stud-
morphogenesis during early development by promoting the dead- ies have demonstrated that tamoxifen is hepatocarcinogenic in
enylation and clearance of maternal mRNAs (Giraldez et al., 2006). rats, exhibiting both tumor-initiating and -promoting properties.
Microcystin treatment of whitefish induced rapid changes in the The mechanism of cancer initiation by tamoxifen in rats is due
liver miRNA levels with a rapid and transient increase of miR-122 to the genotoxic reactivity of tamoxifen metabolic products that
and let-7c levels compared to the respective levels in the control result in the formation of tamoxifen–DNA adducts However, this
fish, which generally peaked at 24 h of the experiment (Brzuzan event occurs in rodents but not in humans (Glatt et al., 1998). DNA
et al., 2012). adducts are not detectable in the blood lymphocytes of tamoxifen-
treated subjects (Bartsch et al., 2000), and their detection in the
Ethylene oxide endometrium is questionable (Beland et al., 2004). The tumor-
promoting activity of tamoxifen is associated with its ability to
Ethylene oxide is one of the most important raw materials used induce cell proliferation in the liver. Due to the wide usage of this
in the large-scale chemical production. Most ethylene oxide is drug, it is important to establish the role of epigenetic mechanisms,
used for synthesis of ethylene glycols, including diethylene gly- including miRNA modulation, in tamoxifen pharmacodynamics.
col and triethylene glycol, that accounts for up to 75% of global MiRNA microarrays were used to analyze the miRNA expres-
consumption. Other important products include ethylene glycol sion profiles in the liver tissues of Fischer rats that were exposed
ethers, ethanolamines and ethoxylates. Among glycols, ethylene to a tamoxifen-containing diet and control rats (Pogribny et al.,
glycol is used as antifreeze, in the production of polyester and 2007). The administration of tamoxifen for 24 weeks upregu-
polyethylene terephthalate (PET – raw material for plastic bottles), lated the expression of oncogenic miRNAs in the liver, including
liquid coolants and solvents. Ethylene oxide is an alkylating agent; miR-17-5p, miR-92, and miR-106a, as well as miR-34. Changes in
it has irritating, sensitizing and narcotic effects. Chronic exposure the expression of proteins targeted by these miRNAs were also
to ethylene oxide is also mutagenic. The International Agency for detected, including cell cycle regulators, chromatin modifiers, and
G Model
expression regulators involved in carcinogenesis. These findings miR-125b expression in zebrafish embryos (Le et al., 2009). p53 and
indicate that changes in miRNA expression occur prior to tumor for- its directly related miRNA, miR-34, act to intensify both CP-induced
mation and are not merely a consequence of the transformed state. apoptosis and the suppression of cell cycling through the activation
The upregulation of the expression of the miR-17-92 cluster is asso- of effector caspases (Raver-Shapira et al., 2007; Chang et al., 2007).
ciated with pro-proliferative and antiapoptotic effects. This miRNA miR-34a may act in cooperation with miR-34c, which is predicted
cluster, which consists of 6 miRNAs (miR-17-5p, miR-18, miR-19a, to have the same seed regions and mRNA targets (Raver-Shapira
miR-19b, miR-20, and miR-92), is highly expressed in many human et al., 2007). This interaction is further highlighted by the finding
cancers (Hwang and Mendell, 2006). Two of the miRNAs in this clus- that in cells exposed to a DNA double-strand breaking agent, i.e.,
ter, miR-17-5p and miR-20, directly regulate the expression of the doxorubicin, only the simultaneous inhibition or forced expression
pro-proliferative transcription factor E2F1, leading to increased cell of miR-34a and miR-34c resulted in the inhibition or induction of
proliferation and decreased cell death (Hwang and Mendell, 2006). doxorubicin-mediated apoptosis (Rokhlin et al., 2008).miR-155 has
c-Myc has also been shown to play a direct role in the activation been shown to regulate apoptosis and suggested to block caspase 3
of the miR-17-92 cluster (O’Donnell et al., 2005). A high level of c- and NF-␬B signaling (Faraoni et al., 2009). miR-125b has been sug-
Myc expression was observed in the livers of tamoxifen-treated rats gested to control the expression of the tumor necrosis factor alpha,
after 12 and 24 weeks of exposure (Kasahara et al., 2003) and was a cytokine that is a powerful activator of NF-␬B (Tili et al., 2007).
related to the ability of c-Myc to promote oncogenesis by driving Thus, normal embryonic development results from the equi-
unrestricted cell proliferation (Adhikary and Eilers, 2005). librium between the expression of pro-apoptotic miR-34a/b/c and
In breast cancer cells in vitro, tamoxifen downregulated miR-125b and that of miR-155, which function as inhibitors of
miR-451 expression, which was related to the acquisition of CP-induced p53-mediated apoptosis. miR-155 suppresses the 53-
resistance to treatment with selective estrogen receptor mod- induced expression of the tumor protein nuclear protein 1, which
ulators (Bergamaschi and Katzenellenbogen, 2012). This effect induces apoptosis and cell cycle arrest (Gironella et al., 2007).miR-
is the molecular mechanistic basis of the tamoxifen-associated 663 overexpression induces CP chemoresistance in breast cancer
development of endocrine resistance. miR-451 is also involved cells by down-regulating the level of heparin sulfate proteoglycan
in the regulation of multidrug resistance protein 1 (Zhu et al., 2, whereas miR-663 downregulation sensitizes them to CP therapy
2008a), which is a pivotal mechanism for acquiring resistance to (Hu et al., 2013).
chemotherapy. The expression of 11 miRNAs was measured in 176 tumor
MiRNA screening was performed on the primary tumors of samples from patients with diffuse large B-cell lymphoma who
6 matched pairs of postmenopausal, estrogen receptor-positive were uniformly treated with multi-chemotherapy that included CP.
breast cancer patients treated with tamoxifen. Higher levels of miR-18a expression was correlated with overall survival, whereas
miR-126 and miR-10a expression were associated with a longer the expression of miR-181a and miR-222 was correlated with
relapse-free period. Indeed, miR-126 and miR-10a were indepen- progression-free survival (Alencar et al., 2011).
dent predictors of tumor relapse in early postmenopausal breast
cancer patients who were treated with adjuvant tamoxifen (Hoppe TPA
et al., 2013). miR-342 expression upregulated the estrogen receptor
␣ mRNA levels and promoted tamoxifen sensitivity in MCF-7 breast The phorbol ester 12-O-tetradecanoylphorbol-13 acetate (TPA)
cancer cells, whereas the knockdown of miR-342 reduced estrogen is the active component of croton oil and a potent tumor promoter.
receptor ␣ mRNA expression and weakened tamoxifen sensitivity TPA mimics the second messenger diacylglycerol to activate pro-
(He et al., 2013). An inverse correlation between the expression tein kinase C (PKC) and affect cell signaling pathways (Gottlicher,
of miR-375 and its target, the metadherin oncogene, was observed 1999).
in primary breast cancer samples (Ward et al., 2013). Tamoxifen Chen et al. (2008) analyzed miRNA and messenger RNA alter-
repressed the expression of the miR-200 family and induced the ations in vitro in a human promyelocytic leukemia cell line HL-60
epithelial-mesenchymal transition via the upregulation of c-Myc that was treated with TPA. The expression of miR-21, miR-26a,
expression in endometrial cancer cells (Bai et al., 2013). miR-146a/b, miR-155, miR-221, and miR-222 was significantly upre-
gulated, whereas the expression of miR-92, miR-142, miR-181c, and
Cyclophosphamide miR-199a was downregulated. The functions of miR-21, miR-199a,
miR-221 and miR-222 were previously discussed in the current
Cyclophosphamide (CP) is a nitrogen mustard alkylating agent. review.
CP attaches an alkyl group to the guanine base of DNA at the number miR-26a is involved in cell growth regulation (Chen et al.,
7 nitrogen atom of the imidazole ring. It is used to treat various 2011b). The miR-146a/b pair is primarily involved in the downregu-
types of cancer and some autoimmune disorders. CP is a group 1 lation of the expression of genes that are related to cell growth, such
IARC carcinogen and an established teratogenic agent. as PANE1 (C22orf18), CABC1, and YEATS4 (Chen et al., 2008). miR-
CP treatment (12.5 and 20 mg/kg bw) of pregnant p53-mutant 155 has been reported to play a role in apoptosis, differentiation,
mice upregulated the expression of miR-34a/b/c in the embry- angiogenesis, and cell proliferation (Mattiske et al., 2012). miR-92
onic forelimbs and hindlimbs (Gueta et al., 2010). High CP doses is involved in cell-cycle regulation and cell signaling. miR-142 is
(40 mg/kg) induced the downregulation of miR-125b and miR-155 involved in the modulation of DNA methylation (Andreopoulos and
expression in the same body parts. At the phenotypic level, these Anastassiou, 2012). miR-181c is involved in the modulation of cell
miRNA alterations were related to the occurrence of teratogenic proliferation (Río et al., 2012) and lymphocyte activation (Xue et al.,
events that affect the forelimbs. Thus, teratogen-induced limb 2011).
dysmorphogenesis is associated with alterations in miR-34a/b/c, Kasashima et al. (2004) analyzed miRNA modulation follow-
miR-125b, and miR-155 expression. ing the TPA treatment of HL-60 human leukocytes. The expression
The roles of miR-125b and miR-155 as teratogenic regulators of miR-17-5p, miR-142-5p, miR-142-3p, and miR-320 was down-
are related to the excessive apoptosis consequent to their downregulated, whereas the expression of miR-21, miR-23, miR-24, and
regulated expression, a major event in the CP-induced process of miR-27a was upregulated by TPA treatment. The functions of miR-
maldevelopment. Indeed, miR-125b is an established negative reg- 17-5p, miR-21, miR-142, and miR-320 were previously discussed
ulator of p53 (Le et al., 2009). Two teratogens other than CP, i.e., in the current review. miR-23, miR-24, and miR-27 are involved in
ionizing radiation and camptothecin, have been shown to suppress angiogenesis (Zhou et al., 2011).
G Model
TPA also induced the upregulation of miR-212 expression in non- regulatory components and chromatin-binding/-modifying pro-
small cell lung cancer cells, promoting cell-cycle progression and teins in the development of the condensed chromatin state.
cellular proliferation, migration, and invasion (Li et al., 2012c). Gold nanoparticles significantly altered the expression of 19
genes in human fetal lung fibroblasts. Among the differentially
tert-Butyl hydroperoxide expressed genes, up-regulation of miR-155 was observed concomi-
tant with down-regulation of the PROS1 gene (Ng et al., 2011).
tert-Butyl hydroperoxide (BHP) is an organic peroxide that is In vivo studies of the lungs of mouse embryos transplacentally
widely used in the chemical industry in a variety of oxidation pro- treated with gold nanoparticles revealed the upregulation of miR-
cesses. It is an important inducer of reactive oxygen species and a 297a, miR-185, miR-466, miR-467, let-7a/f/g, miR-466, and miR-297
cancer-promoting agent. levels (Balansky et al., 2013).
Microarray analysis of BHP-treated auditory cells derived from Pulmonary miRNA expression following intratracheal instilla-
the organ of Corti revealed the downregulation of the levels of 40 tion of black carbon nanoparticles was investigated in mice. This
and the upregulation of 35 miRNA in parallel with the downreg- treatment upregulated the levels of miR-135b, miR-146b, and miR-
ulation of 580 and the upregulation of the levels of 2076 mRNAs. 21 up to 28 days post-exposure. A remarkable increase (up to
These comparative findings demonstrated that mRNAs are redun- 84-fold) of miR-135b expression was observed (Bourdon et al.,
dant compared with miRNAs and are scantly related to alterations 2012).
in protein expression (Izzotti et al., 2009a). This redundancy is
because only 5.7% of mRNA transcripts reach ribosomes and are
Mechanisms of miRNA responses to carcinogens
translated into proteins due to the existence of miRNA-mediated
postgenomic regulation (Izzotti, 2012b). Among the miRNAs dys-
A review of the experimental data indicates that exposure to
regulated by BHP in auditory cells, upregulated miR-29a expression
carcinogens induces early alterations in miRNA expression both
and downregulated miR-203 expression were confirmed by qPCR.
in vitro and in vivo. The occurrence of miRNA alterations in vivo
Upregulated miR-29a expression was functionally related to the
indicates their relevance to cancer development. Such alterations
decreased production of IGF-1, which displays neuroprotective
should be considered to be a contributing cause of cancer onset
effects in the cochlea (Riva et al., 2007).
rather than a consequence of cancer. However, it is inconceivable
Treatment of House Ear Institute-Organ of Corti 1 (HEI-OC1)
that miRNA alteration alone results in carcinogenesis. Indeed, onco-
cells with different concentrations of tert-butyl hydroperoxide
protective miRNAs suppress the expression of mutated oncogenes.
(t-BHP) up-regulated the transcription of 2076 mRNAs, and down-
For example, let-7a represses the expression of the mutated onco-
regulated the levels of 580 mRNA transcripts. The up-regulated (or
genic k-ras gene (He et al., 2010). This mechanisms explains why,
down-regulated) miRNAs were associated with the decreased (or
despite the early over-expression of mutated k-ras in CS-exposed
increased) expression of predicted targeted mRNAs (Wang et al.,
mice, cancer does not occur until irreversibly downregulated let-
2010b).
7a expression is induced by long-term exposure to CS (Izzotti et al.,
Cells that were transfected with let-7b/c or miR-98 mimics
2011). Indeed, upregulated k-ras expression was observed in the
showed increased resistance to the oxidative injury induced by
lungs after only 1 month of exposure to CS. This situation does
BHP. The mechanism of this resistance is related to the let-7b/c and
not result in cancer development when CS exposure lasts only 1
miR-98 downregulation of Bach1 protein expression and upregu-
month because this exposure induces a reversible let-7a down-
lation of heme oxygenase 1 expression (Hou et al., 2012).miR-211
regulation that recovers after smoking cessation. Conversely, lung
promotes the progression of head and neck carcinomas by targeting
cancer appears when CS exposure lasts at least 4 months because
TGF␤RII miR-211 facilitates head and neck carcinomas progression
such exposure induces the irreversible downregulation of let-7a
via the inhibition of TGF␤RII, disrupted Smad3 phosphorylation and
expression. Accordingly, multiple events, e.g., k-ras mutation and
up-regulated c-Myc expression (Chu et al., 2013).
overexpression accompanied by the irreversible downregulation of
let-7a expression, are required for the development of lung cancer.
Nanoparticles (gold and titanium dioxide)
In full-blown cancer, the irreversible silencing of oncoprotective
miRNA expression is caused by genetic deletions that preferen-
Titanium dioxide (TiO2 ) is the naturally occurring oxide of tita-
tially target the loci encoding these miRNAs (Calin et al., 2004).
nium. It is widely used in industry as a white pigment. It has a wide
This consideration is relevant to the possibility of using miRNAs as
range of applications, from paint to sunscreen to food coloring.
predictive cancer biomarkers. Indeed, although pathogenic miRNA
Mice were exposed to the inhalation of TiO2 nanoparticles
alterations occur early in organisms that are exposed to carcino-
for 11 days. The upregulated expression of miR-1 (2.6-fold), miR-
gens and are pathogenetically related to cancer, the occurrence of
135b (60-fold), and miR-449a (6.0-fold) was observed in the lungs
other molecular events is also required to complete the carcino-
(Halappanavar et al., 2011b). The bioinformatically predicted tar-
genesis process. Accordingly, multiple biomarkers should be used
gets for miR-135b included checkpoint suppressor 1, runt-related
in a rational approach to predictive medicine as applied to cancer
transcription factor 2 (runx2), and phosphodiesterase 8b. The pre-
prevention. For example, let-7a downregulation may be predictive
dicted targets of miR-449a included lymphoid enhancer-binding
of cancer only when it is irreversible and occurs in the presence of
factor 1 (lef1). Runx2 and lef1 are the downstream targets of WNT
the mutation and overexpression of k-ras.
signaling, suggesting that miR-135b and miR-449a may have a com-
Because the mechanisms of miRNA alteration are highly rel-
mon function in regulating the WNT signal-transduction pathway.
evant to the application of these biomarkers, it is necessary to
Thus, these miRNAs play a role in the induction of several inflam-
explore the mechanisms by which miRNA expression is altered by
matory chemokines and acute phase components in response to
exposure to environmental carcinogens (Fig. 1).
TiO2 nanoparticle.
The effects of gold nanoparticle exposure on the genomic pro-
file of lung fibroblasts in vitro include the upregulation of miR-155, p53-mediated DNA-damage response
and the PROS1 gene was found to be a putative target gene of miR-
155 (Halappanavar et al., 2011b). In response to gold nanoparticle The alteration of miRNA expression by genotoxic agents, such as
exposure, cells undergo nuclear chromatin condensation. Accord- ionizing radiation, has been ascribed to the fact that p53 interacts
ingly, it has been postulated that miR-155 interacts with chromatin with the Drosha/DGCR8 processing complex through an association
G Model
Fig. 1. Mechanisms of miRNA-expression alteration as induced by environmental carcinogens. (A) In response to DNA damage, the p53/miRNA interconnection modifies the
expression of miRNA genes in the nucleus; (B) Electrophilic metabolites of environmental carcinogens bind to nucleophilic sites of miRNA precursors thus forming miRNA
adducts, which cannot access the catalytic pockets of DICER in cytoplasm; (C) Metabolites of environmental carcinogens bind to DICER in the proximity of miRNA catalytic
sites thus blocking maturation of miRNA precursors.
with RNA helicase p68, which modulates the processing of pri- has been established (Pothof et al., 2009). MiRNA production in
miRNAs to pre-miRNAs (Suzuki et al., 2009; Suzuki and Miyazono, UV-B-damaged cells is at the basis of the inflammatory response
2010). triggered in vivo by UV exposure (Bernard et al., 2012). TLR3 is the
Indeed, p53 enhances the post-transcriptional maturation of main intracellular sensor that detects miRNA overload and triggers
several miRNAs with a growth-suppressive function, including the inflammatory response. A similar inflammatory response has
miR-16-1, miR-143, and miR-145, in response to DNA damage. Fur- been observed in the human brain undergoing endogenous miRNA
thermore, transcriptionally inactive p53 mutants interfere with the overload due to silencing mutations in RNase genes (Pulliero et al.,
assembly of a functional Drosha-p68 complex, leading to the atten- 2011).
uation of miRNA processing activity. MiRNAs also play a role in the negative modulation of the p53
According to these data, DNA damage modulates miRNA expres- machinery. The lack of p53 induction in fish liver following expo-
sion via a p53-dependent mechanism (Boominathan, 2010). The sure to many genotoxic compounds is controlled by the miRNA
number of components of the miRNA processing machinery that network. For example, miR-125b has been confirmed to be a nega-
serve as direct transcriptional targets for p53 in response to DNA tive regulator of p53 in both zebrafish and humans (Le et al., 2009).
damage has recently expanded and now also includes the pivotal The tight crosstalk between the p53 pathway and the miRNA
intracellular miRNA processor Dicer (Hu and Gatti, 2011). The cen- maturation system adequately explains the occurrence of altered
tral role of Dicer in the cellular response to UV-induced damage miRNA expression in the case of exposure to DNA-damaging agents,
G Model
such as ionizing gamma radiation, exciting UV-B radiation, and purified using commercially available kits (MIRCURY RNA Isolation
genotoxic carcinogens. However, as previously reported, altered Kit-Biofluids, Exiqon, Woburn, MA, USA). The purity and struc-
miRNA expression also occurs in the case of exposure to non- tural integrity of the miRNAs were evaluated using fiber optic
genotoxic agents (e.g., TBA, BHP, ethanol, titanium oxide, and gold spectrophotometry and capillary electrophoresis. The standard 32 P
nanoparticles). Furthermore, it was recently established that can- postlabeling procedure was performed, except that the nucleic
cer chemopreventive agents, which are not genotoxic, are potent acids were depolymerized using a mixture of RNase A and T1 rather
modulators of miRNA expression (Izzotti et al., 2012a). In all of than DNAses. The results indicated that the patterns of the DNA and
these situations, it is unlikely that miRNA expression is modulated miRNA adducts induced by exposure to CS were similar, tending
through DNA damage or p53 activation. Thus, other mechanisms to form the characteristic diagonal radioactive zone in the thin-
that cause the early occurrence of altered miRNA expression should layer chromatography plates examined using a 32 P imager (Fig. 3).
be taken into account. However, the amount of adducts was 5.67-fold higher in the miR-
NAs than in the nuclear DNA. These data indicated that miRNAs are
dramatically more sensitive than DNA to the formation of adducts
MiRNA adducts suppress the binding of pre-miRNAs to Dicer induced by exposure to CS.
Based on this finding, it is conceivable that environmental car-
RNA is not complexed with histones or embedded in chromatin cinogens that form miRNA adducts modify the structure of miRNAs,
structures. Accordingly, its nucleotides are particularly sensitive thus blocking their access to the catalytic pockets of Dicer and
to the binding of electrophilic metabolites, as demonstrated by arresting the miRNA maturation process (Fig. 1, main panel).
the heterocyclic amines derived from aniline metabolism ten-
ding to form G adducts in RNA structures (Totsuka et al., 2007).
Indeed, G is the most sensitive nucleotide base, forming bulky DNA Carcinogen binding to Dicer hampers the access of pre-miRNAs to
adducts when DNA is exposed to genotoxic agents of environmental catalytic sites
origin.
Bioinformatic analysis indicates that the G content of the ter- Recent bioinformatic analyses indicated that Dicer, the enzyme
minal loop of miRNAs that are involved in the stress response is involved in the cytoplasmic phase of miRNA maturation, is a pref-
higher than that of the total miRNAs (Fig. 2). erential cytoplasmic target of mutagens. The binding affinity of 25
We evaluated the formation of G-adducts in the miRNAs of mutagens for Dicer’s RNase III domain was estimated by calculat-
the lungs of mice that were exposed to MCS and found that the ing the global contact-energy and the number of intermolecular
G-adducts level was far higher than that detectable in the DNA contacts. The tested mutagens formed complexes with Dicer that
of the same animals (Fig. 3). Albino Swiss mice were exposed were more stable than those formed by Dicer and its natural sub-
to cigarette smoke for 1 month, as elsewhere described (Izzotti strate, i.e., pre-miRNAs (Ligorio et al., 2011). These data indicated
et al., 2011). Adducts in the DNA and miRNAs of the lungs of that mutagens affect miRNA maturation by competing with pre-
sham and CS-exposed mice were evaluated comparatively using miRNA for Dicer binding. This is a short-term adaptive response
32 P postlabeling. The standard butanol-enriched procedure was of the cell to mutagen exposure, resulting in the blockage of the
used to induce DNA adducts (Izzotti et al., 1999). To assess the maturation of the miRNAs that act as negative regulators of genes
miRNA adducts, the total RNA was extracted and the miRNAs were involved in the stress response. However, the long-term alteration
Fig. 2. Bioinformatic analysis indicating that guanine (G) content of the terminal loop in miRNAs involved in stress response (such as let-7a represented in left panel) is higher
than those of other miRNAs. Guanine is the most sensitive nucleotide to the binding of electrophilic metabolites of environmental carcinogens forming miRNA-G-adducts.
G Model
Fig. 3. Adducts, as detected by 32 P-postlabelling, in the lung of mice exposed to cigarette smoke. MiRNA-adduct pattern (right panel) is similar to those of DNA-adducts (left
panel), tending to form the characteristic diagonal radioactive zone in the thin-layer chromatography plates examined using a 32 P imager. However, miRNA-adduct amounts
are 5.7-fold higher than DNA-adducts.
of miRNA maturation resulting from long-term exposure consti- Carcinogen-induced alteration of miRNA expression is a
tutes a carcinogenic stimulus (Izzotti et al., 2011). dose–response mechanism with a threshold
The same bioinformatic approach revealed that chemo-
preventive agents are also characterized by an affinity for Dicer. Overwhelming experimental evidence has demonstrated that
Indeed, it was reported that isothiocyanates and indole-3-carbinole exposure to chemical and physical environment carcinogens
exhibit a strong affinity for Dicer (Ligorio et al., 2011). Further anal- results in the early alteration of miRNA expression in the target
yses using the same approach indicated that resveratrol, epigallo- organs, as triggered by genotoxic or epigenetic mechanisms. The
catechin gallate, and beta-naphthoflavone display Dicer affinity by genotoxic mechanisms include p53-network activation in response
binding the catalytic site of Dicer sub-units. These findings indi- to DNA damage. The epigenetic mechanisms include the binding of
cate that chemopreventive agents may compete with mutagens for carcinogenic metabolites to Dicer. However, there is evidence that
Dicer binding. According to this view, chemopreventive agents act these mechanisms involve threshold regulation and are activated
through hormetic effects and have the same molecular effects of in experimental animal systems only in the case of exposure to high
mutagens at the Dicer epigenetic level. Therefore, chemopreventive levels of carcinogens.
agents compete with these mutagens for the activation of adverse In the case of short-term (1 month) exposure to CS, the dramatic
mechanisms, such as the alteration of miRNA expression. downregulation of miRNA expression in the lung was obtained
These bioinformatic data are supported by experimental evi- only by exposing animals to CS at 438 mg/m3 of total particulate
dence that we obtained in vitro. We reconstructed the miRNA matter, whereas only minor alterations were observed at lower
maturation system by mixing Dicer (Invitrogen, Carlsbad, CA, USA) exposure doses (Izzotti et al., 2011). However, certain miRNAs, such
and 400-bp pre-miRNAs (Invitrogen). as miR-30, were also sensitive to CS-induced downregulation at low
MiRNA maturation occurred during incubation at 37 ◦ C for 1 h, exposure doses.
and the kinetics of this process was quantified by analyzing the A similar phenomenon occurred when mouse embryos were
amount of 22-bp oligonucleotides produced, using optic fiber spec- transplacentally exposed to cyclophosphamide (CP) (Gueta et al.,
trophotometry after spin-column centrifugation (MIRCURY RNA 2010). Indeed, 40 mg/kg, but not 20 or 12.5 mg/kg, of CP downreg-
Isolation Kit-Biofluids, Exiqon). As shown in Fig. 4, the amount of ulated the expression of miR-125 and miR-155 in mouse embryonic
mature miRNA was decreased 3-fold in the presence of the CS con- forelimbs, whereas miR-34 a/b/c expression was upregulated at the
densate compared with that of the sham control sample. These data lower exposure doses.
indicate that the CS condensate directly hampered Dicer activity Another factor that affects the miRNA response to carcinogens
and the miRNA maturation process in the absence of DNA damage. is the duration of the exposure. Indeed, altered miRNA expression
Based on this hypothesis, Dicer can be envisaged as a cytoplas- persists after the discontinuation of exposure only in the case of
mic sensor that detects the presence of carcinogenic metabolites long-term exposure (Izzotti et al., 2011). Accordingly, the dose and
and triggers the miRNA response. In line with this interpretation, duration of exposure are critical factors in the miRNA response to
Dicer protein expression in various cell types was found to be carcinogens. This is a major problem when miRNA data obtained
inhibited by multiple stressors, including reactive oxygen species, using high doses for short periods, as typically occurs in short-term
phorbol esters, and the Ras oncogene. This result suggests that Dicer experiments using animals, are compared with the data obtained
is a main component of the stress-response machinery (Wiesen and using low dose exposure for long periods, as typically occurs in
Tomasi, 2009). humans. This practice partially explains the discrepancies observed
G Model
Fig. 4. Incubation of DICER with cigarette smoke condensate (CSC) results in a 3-fold decrease in DICER kinetic rate. DICER activity was measured by quantifying the amounts
of 400 bp RNA double strands (left side) transformed into 22 bp double strand short RNA (right side).
in miRNA data obtained by testing the same carcinogens under these mechanisms, cancer cells undergo irreversible miRNA alter-
different experimental conditions (see Table 1). For example, the ations through miRNA gene deletion, which typically occurs in
expression of miR-21, miR-146a, and let-7a was increased after 24 h human cancers (Calin et al., 2004). This phenomenon is a major
in DMBA-treated mice. Conversely, downregulated miRNA expres- problem when carcinogens are tested in cancer-derived immortal-
sion was observed 7 days after DMBA administration (Juhász et al., ized cell lines. Indeed, these cells conserve the genetic alteration
2012). that characterized the original tumor, including miRNA gene dele-
MiRNA is a well conserved mechanism throughout phylogen- tion. Accordingly, the miRNA gene status of each cell line should be
esis. Accordingly, whenever the exposure conditions of humans characterized in considering its suitability for testing carcinogenic
are adequately reproduced in experimental animal systems, the agents. Moreover, genetic alterations that occur in the proximity of
miRNA data have good transalability to the human situation. For miRNA genes play a role in the early response to carcinogens (see
example, short-term exposure of rodents to high doses of single Table 1) and could result in the poor transferability of the obtained
components of CS, such as NNK or B[a]P, does not produce miRNA data to the in vivo situation.
levels similar to those detected in human smokers. Conversely, in
the case of exposure of both rats and mice to a CS mixture for a long- Conclusions
term period, the correlation of the detected miRNA alterations in
their lungs with those observed in the respiratory system of human The alteration of miRNA expression is an established mecha-
smokers is remarkable (Perdomo et al., 2011). nism by which chemical carcinogens induce alterations in target
cells. These alterations occur early during exposure, initially repre-
MiRNA gene deletions in cancer cell lines and their relevance to senting adaptive events that aim to defend the cells by activating
testing carcinogenic agents in vitro detoxifying mechanisms. The protective mechanisms, at least in
continuously dividing cells, include the p53-related activation of
The miRNA response plays a critical role in defining the phe- DNA-repair processes, cell-cycle arrest, and apoptosis that are
notypic consequences of exposure to environmental carcinogens. induced by changes in members of the miR-34 family. When
Indeed, the miRNA response is crucial for the following process: oncogene mutations occur due to early genotoxic events, their
(a) activating the defensive machinery that triggers the adaptive phenotypic consequences are blocked by the activation of onco-
response in case of short-term exposure (Izzotti et al., 2011); protective miRNAs, as observed for k-ras, the expression of which
(b) committing cells to lung carcinogenesis in the case of long- is hampered by the expression of let-7 family members.
term exposure (Izzotti et al., 2011; Schembri et al., 2009); and However, when exceedingly high exposure doses or long-term
(c) inducing phenotypic alteration in embryos that are exposed to exposure overwhelm the miRNA-based adaptive response, the
teratogenic agents (Gueta et al., 2010). Due to the importance of irreversible alterations that occur play a pathogenic role in cancer
G Model
development. For example, the irreversible downregulated expres- Bartsch, H., Phillips, D.H., Nair, J., Hewer, A., Meyberg-Solomeyer, G., Grischke, E.M.,
sion of miR-34 and let-7 family members results in the suppression 2000. Lack of evidence for tamoxifen- and toremifene-DNA adducts in lympho-
cytes of treated patients. Carcinogenesis 21 (4), 845–847.
of the p53 oncosuppressor gene and the activation of the k-ras Battaglia, R., Conacher, B.S., Page, B.D., 1990. Ethyl carbamate (urethane) in alcoholic
oncogene, respectively. These conditions are established in can- beverages and foods: a review. Food Addit. Contam. 7, 477–496.
cer cells in which miRNA alterations were obtained by irreversible Beezhold, K., Liu, J., Kan, H., Meighan, T., Castranova, V., Shi, X., Chen, F., 2011.
miR-190-mediated downregulation of PHLPP contributes to arsenic-induced
genetic changes. These conditions also explain why it is difficult to Akt activation and carcinogenesis. Toxicol. Sci. 123 (2), 411–420.
correct the carcinogenic phenotype after irreversible miRNA alter- Beland, F.A., Churchwell, M.I., Hewer, A., Phillips, D.H., da Costa, G.G., Marques, M.M.,
ations are established. Conversely, alterations in miRNAs might be 2004. Analysis of tamoxifen-DNA adducts in endometrial explants by MS and
32
P-postlabeling. Biochem. Biophys. Res. Commun. 320 (2), 297–302.
corrected, for preventive purposes, before the onset of cancer. The
Bergamaschi, A., Katzenellenbogen, B.S., 2012. Tamoxifen downregulation of miR-
aim of such correction is to establish a physiological miRNA profile 451 increases 14-3-3␨ and promotes breast cancer cell survival and endocrine
and, thus, block or at least slow the process of carcinogenesis. resistance. Oncogene 31 (1), 39–47.
Bernard, J.J., Cowing-Zitron, C., Nakatsuji, T., Muehleisen, B., Muto, J., Borkowski,
Basing on these premises, modulation of miRNA expression
A.W., Martinez, L., Greidinger, E.L., Yu, B.D., Gallo, R.L., 2012. Ultraviolet radi-
in organisms exposed to environmental chemical carcinogens is ation damages self noncoding RNA and is detected by TLR3. Nat. Med. 18 (8),
a future directions for cancer prevention. Furthermore, it remain 1286–1290.
to be clarified the interplay between epigenetic mechanisms and Bleck, B., Grunig, G., Chiu, A., Liu, M., Gordon, T., Kazeros, A., Reibman, J., 2013.
MicroRNA-375 regulation of thymic stromal lymphopoietin by diesel exhaust
miRNA alteration as induced by carcinogens. Emerging evidence particles and ambient particulate matter in human bronchial epithelial cells. J.
suggests that environmental carcinogens also act through a variety Immunol. 190 (7), 3757–3760.
of epigenetic mechanisms. The characterization of genome-wide Bollati, V., Marinelli, B., Apostoli, P., Bonzini, M., Nordio, F., Hoxha, M., Pegoraro, V.,
Motta, V., Tarantini, L., Cantone, L., Schwartz, J., Bertazzi, P.A., Baccarelli, A., 2010.
DNA-methylation patterns, histone modification, mitochondrial Exposure to metal-rich particulate matter modifies the expression of candidate
damage, and alteration of miRNA expression represents a new microRNAs in peripheral blood leukocytes. Environ. Health Perspect. 118 (6),
frontier toward the understanding of the relationship between 763–768.
Boominathan, L., 2010. The tumor suppressors p53, p63, and p73 are regulators of
exposure to environmental carcinogens and cancer onset. microRNA processing complex. PLoS ONE 5 (5), e10615.
Bourdon, J.A., Saber, A.T., Halappanavar, S., Jackson, P.A., Wu, D., Hougaard, K.S.,
Jacobsen, N.R., Williams, A., Vogel, U., Wallin, H., Yauk, C.L., 2012. Carbon black
Acknowledgement nanoparticle intratracheal installation results in large and sustained changes
in the expression of miR-135b in mouse lung. Environ. Mol. Mutagen. 53 (6),
We acknowledge Dr. Patrizio Arrigo (Institute for the Study of 462–468.
Brevik, A., Lindeman, B., Brunborg, G., Duale, N., 2012. Paternal benzo[a]pyrene expo-
Macromolecules (ISMAC) Genoa, Italy) for the bioinformatic anal- sure modulates microRNA expression patterns in the developing mouse embryo.
yses of the miRNA structures. Int. J. Cell. Biol. 2012, 407431.
Bronisz, A., Godlewski, J., Wallace, J.A., Merchant, A.S., Nowicki, M.O., Mathsyaraja,
H., Srinivasan, R., Trimboli, A.J., Martin, C.K., Li, F., Yu, L., Fernandez, S.A., Pécot, T.,
References Rosol, T.J., Cory, S., Hallett, M., Park, M., Piper, M.G., Marsh, C.B., Yee, L.D., Jimenez,
R.E., Nuovo, G., Lawler, S.E., Chiocca, E.A., Leone, G., Ostrowski, M.C., 2011.
Aballay, L.R., Díaz Mdel, P., Francisca, F.M., Muñoz, S.E., 2012. Cancer incidence and Reprogramming of the tumour microenvironment by stromal PTEN-regulated
pattern of arsenic concentration in drinking water wells in Córdoba, Argentina. miR-320. Nat. Cell Biol. 14 (2), 159–167.
Int. J. Environ. Health. Res. 22 (3), 220–231. Brzuzan, P., Woźny, M., Wolińska, L., Piasecka, A., 2012. Expression profiling
Adhikary, S., Eilers, M., 2005. Transcriptional regulation and transformation by Myc in vivo demonstrates rapid changes in liver microRNA levels of whitefish (Core-
proteins. Nat. Rev. Mol. Cell Biol. 6, 635–645. gonus lavaretus) following microcystin-LR exposure. Aquat. Toxicol. 122–123,
Alencar, A.J., Malumbres, R., Kozloski, G.A., Advani, R., Talreja, N., Chinichian, S., 188–196.
Briones, J., Natkunam, Y., Sehn, L.H., Gascoyne, R.D., Tibshirani, R., Lossos, I.S., Calin, G.A., Sevignani, C., Dumitru, C.D., Hyslop, T., Noch, E., Yendamuri, S., Shimizu,
2011. MicroRNAs are independent predictors of outcome in diffuse large B-cell M., Rattan, S., Bullrich, F., Negrini, M., Croce, C.M., 2004. Human microRNA genes
lymphoma patients treated with R-CHOP. Clin. Cancer Res. 17 (12), 4125–4130. are frequently located at fragile sites and genomic regions involved in cancers.
An, Y.R., Kim, S.J., Oh, M.J., Kim, H.M., Shim, I.S., Kim, P.J., Choi, K., Hwang, S.Y., 2013. Proc. Natl. Acad. Sci. U. S. A. 101 (9), 2999–3000.
Analysis of microRNA and gene expression profiling in triazole fungicide-treated Cao, D., Bromberg, P.A., Samet, J.M., 2007. COX-2 expression induced by diesel parti-
HepG2 cell line. Toxicology 303, 94–98. cles involves chromatin modification and degradation of HDAC1. Am. J. Respir.
Anderson, S.E., Beezhold, K., Lukomska, E., Richardson, J., Long, C., Anderson, K., Cell Mol. Biol. 37 (2), 232–239.
Franko, J., Meade, B.J., Beezhold, D.H., 2013. Expression kinetics of miRNA Chang, S.S., Jiang, W.W., Smith, I., Poeta, L.M., Begum, S., Glazer, C., Shan, S., Westra,
involved in dermal toluene 2,4-diisocyanate sensitization. J. Immunotoxicol. W., 2008. MicroRNA alterations in head and neck squamous cell carcinoma. Int.
[Epub ahead of print]. J. Cancer 123 (12), 2791–2800.
Andreopoulos, B., Anastassiou, D., 2012. Integrated analysis reveals hsa-miR-142 Chang, T.C., Wentzel, E.A., Kent, O.A., Ramachandran, K., Mullendore, M., Lee, K.H.,
as a representative of a lymphocyte-specific gene expression and methylation Feldmann, G., Yamakuchi, M., Ferlito, M., Lowenstein, C.J., Arking, D.E., Beer,
signature. Cancer Inform. 11, 61–75. M.A., Maitra, A., Mendell, J.T., 2007. Transactivation of miR-34a by p53 broadly
Avissar, M., McClean, M.D., Kelsey, K.T., Marsit, C.J., 2009. MicroRNA expression in influences gene expression and promotes apoptosis. Mol. Cell 26 (5), 745–752.
head and neck cancer associates with alcohol consumption and survival. Car- Chang, T.C., Wentzel, E.A., Kent, O.A., Ramachandran, K., Mullendore, M., Lee, K.H.,
cinogenesis 30 (12), 2059–2060. Feldmann, G., Yamakuchi, M., Ferlito, M., Lowenstein, C.J., Arking, D.E., Beer, M.A.,
Avissar-Whiting, M., Veiga, K.R., Uhl, K.M., Maccani, M.A., Gagne, L.A., Moen, E.L., Maitra, A., Mendell, J.T., Chen, F., Hu, S.J., 2012. Effect of microRNA-34a in cell
Marsit, C.J., 2010. Bisphenol A exposure leads to specific microRNA alterations cycle, differentiation, and apoptosis: a review. J. Biochem. Mol. Toxicol. 26 (2),
in placental cells. Reprod. Toxicol. 29 (4), 401–406. 79–86.
Babar, I.A., Slack, F.J., Weidhaas, J.B., 2008. miRNA modulation of the cellular stress Chen, A., Luo, M., Yuan, G., Yu, J., Deng, T., Zhang, L., Zhou, Y., Mitchelson, K., Cheng,
response. Fut. Oncol. 4 (2), 289–298. J., 2008. Complementary analysis of microRNA and mRNA expression during
Bahi, A., Dreyer, J.L., 2013. Striatal modulation of BDNF expression using phorbol 12-myristate 13-acetate (TPA)-induced differentiation of HL-60 cells.
microRNA124a-expressing lentiviral vectors impairs ethanol-induced Biotechnol. Lett. 30 (12), 2045–2050.
conditioned-place preference and voluntary alcohol consumption. Eur. J. Chen, D., Li, Z., Chen, T., 2011a. Increased expression of miR-34a in mouse spleen one
Neurosci. 38 (2), 2328–2330. day after exposure to N-ethyl-N-nitrosourea. J. Appl. Toxicol. 31 (5), 496–498.
Bai, J.X., Yan, B., Zhao, Z.N., Xiao, X., Qin, W.W., Zhang, R., Jia, L.T., Meng, Y.L., Jin, B.Q., Chen, L., Zheng, J., Zhang, Y., Yang, L., Wang, J., Ni, J., Cui, D., Yu, C., Cai, Z., 2011b.
Fan, D.M., Wang, T., Yang, A.G., 2013. Tamoxifen represses miR-200 microRNAs Tumor-specific expression of microRNA-26a suppresses human hepatocellular
and promotes epithelial-to-mesenchymal transition by up-regulating c-Myc in carcinoma growth via cyclin-dependent and -independent pathways. Mol. Ther.
endometrial carcinoma cell lines. Endocrinology 154 (2), 635–645. 19 (8), 1521–1530.
Balansky, R., Ganchev, G., Iltcheva, M., Nikolov, M., Steele, V.E., De Flora, S., 2012. Chen, T., Mally, A., Ozden, S., Chipman, J.K., 2010. Low doses of the carcinogen furan
Differential carcinogenicity of cigarette smoke in mice exposed either transpla- alter cell cycle and apoptosis gene expression in rat liver independent of DNA
centally, early in life or in adulthood. Int. J. Cancer 130 (5), 1001–1010. methylation. Environ. Health Perspect. 118 (11), 1597–1600.
Balansky, R., Longobardi, M., Ganchev, G., Iltcheva, M., Nedyalkov, N., Atanasov, Chen, T., Williams, T.D., Mally, A., Hamberger, C., Mirbahai, L., Hickling, K., Chip-
P., Toshkova, R., De Flora, S., Izzotti, A., 2013. Transplacental clasto- man, J.K., 2012. Gene expression and epigenetic changes by furan in rat liver.
genic and epigenetic effects of gold nanoparticles in mice. Mutat. Res., Toxicology 292 (2–3), 63–70.
http://dx.doi.org/10.1016/j.mrfmmm.2013.08.006 [Epub ahead of print]. Chen, X., Xu, B., Han, X., Mao, Z., Talbot, P., Chen, M., Du, G., Chen, A., Liu, J., Wang,
Barkley, L.R., Santocanale, C., 2013. MicroRNA-29a regulates the benzo[a]pyrene X., Xia, Y., 2013. Effect of bisphenol A on pluripotency of mouse embryonic stem
dihydrodiol epoxide-induced DNA damage response through Cdc7 kinase in cells and differentiation capacity in mouse embryoid bodies. Toxicol. In Vitro,
lung cancer cells. Oncogenesis 2, e57. http://dx.doi.org/10.1016/j.tiv.2013.09.018 [Epub ahead of print].
G Model
Cheng, Y., Liu, X., Zhang, S., Lin, Y., Yang, J., Zhang, C., 2009. MicroRNA-21 protects Gao, W., Xu, J., Liu, L., Shen, H., Zeng, H., Shu, Y., 2012. A systematic-analysis of
against the H(2)O(2)-induced injury on cardiac myocytes via its target gene predicted miR-21 targets identifies a signature for lung cancer. Biomed. Phar-
PDCD4. J. Mol. Cell. Cardiol. 47 (1), 5–14. macother. 66 (1), 21–28.
Choi, J.S., Oh, J.H., Park, H.J., Choi, M.S., Park, S.M., Kang, S.J., Oh, M.J., Kim, S.J., Hwang, Ghosh, G., Subramanian, I.V., Adhikari, N., Zhang, X., Joshi, H.P., Basi, D.,
S.Y., Yoon, S., 2011. miRNA regulation of cytotoxic effects in mouse Sertoli cells Chandrashekhar, Y.S., Hall, J.L., Roy, S., Zeng, Y., Ramakrishnan, S., 2010.
exposed to nonylphenol. Reprod. Biol. Endocrinol. 9, 126. Hypoxia-induced microRNA-424 expression in human endothelial cells reg-
Chu, T.H., Yang, C.C., Liu, C.J., Lui, M.T., Lin, S.C., Chang, K.W., 2013. miR-211 promotes ulates HIF-␣ isoforms and promotes angiogenesis. J. Clin. Invest. 120 (11),
the progression of head and neck carcinomas by targeting TGF␤RII. Cancer Lett. 4141–4150.
337 (1), 115–124. Giraldez, A.J., Mishima, Y., Rihel, J., Grocock, R.J., Van Dongen, S., Inoue, K., Enright,
Chu, Y.H., Tzeng, S.L., Lin, C.W., Chien, M.H., Chen, M.K., Yang, S.F., 2012. Impacts of A.J., Schier, A.F., 2006. Zebrafish MiR-430 promotes deadenylation and clearance
microRNA gene polymorphisms on the susceptibility of environmental factors of maternal mRNAs. Science 312 (5770), 75–79.
leading to carcinogenesis in oral cancer. PLoS ONE 7 (6), e39777. Gironella, M., Seux, M., Xie, M.J., Cano, C., Tomasini, R., Gommeaux, J., Garcia, S.,
Ciencewicki, J., Brighton, L., Wu, W.D., Madden, M., Jaspers, I., 2006. Diesel exhaust Nowak, J., Yeung, M.L., Jeang, K.T., Chaix, A., Fazli, L., Motoo, Y., Wang, Q., Roc-
enhances virus- and poly(I:C)-induced Toll-like receptor 3 expression and chi, P., Russo, A., Gleave, M., Dagorn, J.C., Iovanna, J.L., Carrier, A., Pébusque, M.J.,
signaling in respiratory epithelial cells. Am. J. Physiol. Lung Cell Mol. Physiol. Dusetti, N.J., 2007. Tumor protein 53-induced nuclear protein 1 expression is
290 (6), L1154–L1160. repressed by miR-155, and its restoration inhibits pancreatic tumor develop-
Cimmino, A., Calin, G.A., Fabbri, M., Iorio, V., Ferracin, M., Shimizu, M., Wojcik, S.E., ment. Proc. Natl. Acad. Sci. U.S.A. 104, 16170–16180.
Aqeilan, R.I., Zupo, S., Dono, M., Rassenti, L., Alder, H., Volinia, S., Liu, C., Kipps, T.J., Glatt, H., Davis, W., Meinl, W., Hermersdarfer, H., Venitt, S., Phillips, D.H., 1998. Rat,
Negrini, M., Croce, C.M., 2005. miR-15 and miR-16 induce apoptosis by targeting but not human, sulfotransferase activates a tamoxifen metabolite to produce
BCL2. Proc. Natl. Acad. Sci. U.S.A. 102 (39), 13944–13950. DNA adducts and gene mutations in bacteria and mammalian cells in culture.
Corney, D.C., Flesken-Nikitin, A., Godwin, A.K., Wang, W., Nikitin, A.Y., 2007. Carcinogenesis 19 (10), 1709–1710.
MicroRNA-34b and MicroRNA-34c are targets of p53 and cooperate in con- Gong, A.Y., Zhou, R., Hu, G., Li, X., Splinter, P.L., O’Hara, S.P., LaRusso, N.F., Soukup,
trol of cell proliferation and adhesion-independent growth. Cancer Res. 67 (18), G.A., Dong, H., Chen, X.M., 2009. MicroRNA-513 regulates B7-H1 translation
8433–8440. and is involved in IFN-gamma-induced B7-H1 expression in cholangiocytes. J.
Cui, F.M., Li, J.X., Chen, Q., Du, H.B., Zhang, S.Y., Nie, J.H., Cao, J.P., Zhou, P.K., Immunol. 182 (3), 1325–1330.
Hei, T.K., Tong, J., 2013. Radon-induced alterations in micro-RNA expression Gottlicher, M., 1999. Receptor toxicology. In: Marquardt, H., Schafer, S., McClel-
profiles in transformed BEAS2B cells. J. Toxicol. Environ. Health A 76 (2), lan, R., Welsch, R. (Eds.), Toxicology. Academic Press, San Diego, CA,
107–119. pp. 231–243.
Das, N., Paul, S., Chatterjee, D., Banerjee, N., Majumder, N.S., Sarma, N., Sau, T.J., Basu, Gueta, K., Molotski, N., Gerchikov, N., Mor, E., Savion, S., Fein, A., Toder, V., Shom-
S., Banerjee, S., Majumder, P., Bandyopadhyay, A.K., States, J.C., Giri, A.K., 2012. ron, N., Torchinsky, A., 2010. Teratogen-induced alterations in microRNA-34,
Arsenic exposure through drinking water increases the risk of liver and cardio- microRNA-125b and microRNA-155 expression: correlation with embryonic
vascular diseases in the population of West Bengal, India. BMC Public Health. 12 p53 genotype and limb phenotype. BMC Dev. Biol. 10, 20.
(1), 639. Halappanavar, S., Jackson, P., Williams, A., Jensen, K.A., Hougaard, K.S., Vogel, U.,
Davidson, L.A., Wang, N., Shah, M.S., Lupton, J.R., Ivanov, I., Chapkin, R.S., 2009. Yauk, C.L., Wallin, H., 2011a. Pulmonary response to surface-coated nanoti-
N-3 polyunsaturated fatty acids modulate carcinogen-directed non-coding tanium dioxide particles includes induction of acute phase response genes,
microRNA signatures in rat colon. Carcinogenesis 30 (12), 2077–2080. inflammatory cascades, and changes in microRNAs: a toxicogenomic study.
Debernardi, S., Skoulakis, S., Molloy, G., Chaplin, T., Dixon-McIver, A., Young, B.D., Environ. Mol. Mutagen. 52 (6), 425–439.
2007. MicroRNA miR-181a correlates with morphological sub-class of acute Halappanavar, S., Wu, D., Williams, A., Kuo, B., Godschalk, R.W., Van Schooten, F.J.,
myeloid leukaemia and the expression of its target genes in global genome-wide Yauk, C.L., 2011b. Pulmonary gene and microRNA expression changes in mice
analysis. Leukemia 21 (5), 912–916. exposed to benzo(a)pyrene by oral gavage. Toxicology 285 (3), 133–141.
Dey, B.K., Gagan, J., Dutta, A., 2011. miR-206 and miR-486 induce myoblast differ- He, L., He, X., Lim, L.P., de Stanchina, E., Xuan, Z., Liang, Y., Xue, W., Zender, L., Magnus,
entiation by downregulating Pax7. Mol. Cell. Biol. 31 (1), 203–214. J., Ridzon, D., Jackson, A.L., Linsley, P.S., Chen, C., Lowe, S.W., Cleary, M.A., Hannon,
Dippold, R.P., Vadigepalli, R., Gonye, G.E., Hoek, J.B., 2012. Chronic ethanol feeding G.J., 2007a. A microRNA component of the p53 tumour suppressor network.
enhances miR-21 induction during liver regeneration while inhibiting prolifer- Nature 447 (7148), 1130–1140.
ation in rats. Am. J. Physiol. Gastrointest. Liver Physiol. 303 (6), G733–G740. He, X., He, L., Hannon, G.J., 2007b. The guardian’s little helper: microRNAs in the p53
Divakaran, V., Mann, D.L., 2008. The emerging role of microRNAs in cardiac remod- tumor suppressor network. Cancer Res. 67 (23), 11099–11100.
eling and heart failure. Circ. Res. 103, 1072–1080. He, X.Y., Chen, J.X., Zhang, Z., Li, C.L., Peng, Q.L., Peng, H.M., 2010. The let-7a microRNA
Dolganiuc, A., Petrasek, J., Kodys, K., Catalano, D., Mandrekar, P., Velayudham, A., protects from growth of lung carcinoma by suppression of k-Ras and c-Myc in
Szabo, G., 2009. MicroRNA expression profile in Lieber-DeCarli diet-induced nude mice. J. Cancer Res. Clin. Oncol. 136 (7), 1023–1030.
alcoholic and methionine choline deficient diet-induced nonalcoholic steato- He, Y.J., Wu, J.Z., Ji, M.H., Ma, T., Qiao, E.Q., Ma, R., Tang, J.H., 2013. miR-342 is associ-
hepatitis models in mice. Alcohol. Clin. Exp. Res. 33 (10), 1704–1710. ated with estrogen receptor-␣ expression and response to tamoxifen in breast
Dong, X., Liu, H., Chen, F., Li, D., Zhao, Y., 2013. MiR-214 promotes the alcohol- cancer. Exp. Ther. Med. 5 (3), 813–818.
induced oxidative stress via down-regulation of glutathione reductase and Herberth, G., Bauer, M., Gasch, M., Hinz, D., Röder, S., Olek, S., Kohajda, T.,
cytochrome P450 oxidoreductase in liver cells. Alcohol. Clin. Exp. Res., Rolle-Kampczyk, U., von Bergen, M., Sack, U., Borte, M., Lehmann, I., 2013.
http://dx.doi.org/10.1111/acer.12209 [Epub ahead of print]. Maternal and cord blood miR-223 expression associates with prenatal tobacco
Duan, H., Jiang, Y., Zhang, H., Wu, Y., 2010. MiR-320 and miR-494 affect cell cycles of smoke exposure and low regulatory T-cell numbers. J. Allergy Clin. Immunol.,
primary murine bronchial epithelial cells exposed to benzo[a]pyrene. Toxicol. http://dx.doi.org/10.1016/j.jaci.2013.06.036 [Epub ahead of print].
In Vitro 24 (3), 928–935. Heyn, J., Ledderose, C., Hinske, L.C., Limbeck, E., Möhnle, P., Lindner, H.A., Kreth, S.,
Duan, Z., Choy, E., Harmon, D., Liu, X., Susa, M., Mankin, H., Hornicek, F., 2011. 2012. Adenosine A2A receptor upregulation in human PMNs is controlled by
MicroRNA-199a-3p is downregulated in human osteosarcoma and regulates cell miRNA-214, miRNA-15, and miRNA-16. Shock 37 (2), 156–163.
proliferation and migration. Mol. Cancer Ther. 10 (8), 1337–1340. Hoppe, R., Achinger-Kawecka, J., Winter, S., Fritz, P., Lo, W.Y., Schroth, W., Brauch, H.,
Etheridge, A., Lee, I., Hood, L., Galas, D., Wang, K., 2011. Extracellular microRNA: a 2013. Increased expression of miR-126 and miR-10a predict prolonged relapse-
new source of biomarkers. Mutat. Res. 717 (1–2), 85–90. free time of primary oestrogen receptor-positive breast cancer following tamox-
Etnier, E.L., 1989. Water quality criteria for hexahydro-1,3,5-trinitro-1,3,5-triazine ifen treatment. Eur. J. Cancer, http://dx.doi.org/10.1016/j.ejca.2013.07.145
(RDX). Regul. Toxicol. Pharmacol. 9 (2), 147–157. [Epub ahead of print].
Fang, L., Deng, Z., Shatseva, T., Yang, J., Peng, C., Du, W.W., Yee, A.J., Ang, L.C., He, Hou, W., Tian, Q., Steuerwald, N.M., Schrum, L.W., Bonkovsky, H.L., 2012. The let-7
C., Shan, S.W., Yang, B.B., 2011. MicroRNA miR-93 promotes tumor growth and microRNA enhances heme oxygenase-1 by suppressing Bach1 and attenuates
angiogenesis by targeting integrin-␤8. Oncogene 30 (7), 806–821. oxidant injury in human hepatocytes. Biochim. Biophys. Acta 1819 (11–12),
Faraoni, I., Antonetti, F.R., Cardone, J., Bonmassar, E., 2009. miR-155 gene: a typical 1113–1120.
multifunctional microRNA. Biochim. Biophys. Acta 1792, 497–505. Hsu, P.Y., Deatherage, D.E., Rodriguez, B.A., Liyanarachchi, S., Weng, Y.I., Zuo, T., Liu,
Farraj, A.K., Hazari, M.S., Haykal-Coates, N., Lamb, C., Winsett, D.W., Ge, Y., Ledbetter, J., Cheng, A.S., Huang, T.H., 2009. Xenoestrogen-induced epigenetic repression
A.D., Carll, A.P., Bruno, M., Ghio, A., Costa, D.L., 2011. ST depression, arrhythmia, of microRNA-9-3 in breast epithelial cells. Cancer Res. 69 (14), 5936–5940.
vagal dominance, and reduced cardiac micro-RNA in particulate-exposed rats. Hu, H., Gatti, R.A., 2011. MicroRNAs: new players in the DNA damage response. J.
Am. J. Respir. Cell Mol. Biol. 44 (2), 185–196. Mol. Cell Biol. 3 (3), 151–158.
Faxuan, W., Qin, Z., Dinglun, Z., Tao, Z., Xiaohui, R., Liqiang, Z., Yajia, L., 2012. Altered Hu, H., Li, S., Cui, X., Lv, X., Jiao, Y., Yu, F., Yao, H., Song, E., Chen, Y., Wang, M., Lin, L.,
microRNAs expression profiling in experimental silicosis rats. J. Toxicol. Sci. 2037 2013. The overexpression of hypomethylated miR-663 induces chemotherapy
(6), 1207–1210. resistance in human breast cancer cells by targeting heparin sulfate proteogly-
Fujimoto, N., Wislez, M., Zhang, J., Iwanaga, K., Dackor, J., Hanna, A.E., Kalyankrishna, can 2 (HSPG2). J. Biol. Chem. 288 (16), 10973–10980.
S., Cody, D.D., Price, R.E., Sato, M., Shay, J.W., Minna, J.D., Peyton, M., Tang, X., Hwang, H.W., Mendell, J.T., 2006. MicroRNAs in cell proliferation, cell death, and
Massarelli, E., Herbst, R., Threadgill, D.W., Wistuba, I.I., Kurie, J.M., 2005. High tumorigenesis. Br. J. Cancer 94 (6), 776–780.
expression of ErbB family members and their ligands in lung adenocarcinomas IARC, 1999. Monographs on the Evaluation of Carcinogenic Risks to Humans. Inter-
that are sensitive to inhibition of epidermal growth factor receptor. Cancer Res. national Agency for Research on Cancer, Lyon, ISBN 978-92-832-1297-3.
65 (24), 11478–11480. Izzotti, A., Bagnasco, M., D’Agostini, F., Cartiglia, C., Lubet, R.A., Kelloff, G.J., De
Gabriely, G., Wurdinger, T., Kesari, S., Esau, C.C., Burchard, J., Linsley, P.S., Krichevsky, Flora, S., 1999. Formation and persistence of nucleotide alterations in rats
A.M., 2008. MicroRNA 21 promotes glioma invasion by targeting matrix metal- exposed whole-body to environmental cigarette smoke. Carcinogenesis 20 (8),
loproteinase regulator. Mol. Cell. Biol. 28, 5369–5370. 1499–1500.
G Model
Izzotti, A., Calin, G.A., Arrigo, P., Steele, V.E., Croce, C.M., De Flora, S., 2009a. Downreg- Ladeiro, Y., Couchy, G., Balabaud, C., Bioulac-Sage, P., Pelletier, L., Rebouissou, S.,
ulation of microRNA expression in the lungs of rats exposed to cigarette smoke. Zucman-Rossi, J., 2008. MicroRNA profiling in hepatocellular tumors is asso-
FASEB J. 23 (3), 806–812. ciated with clinical features and oncogene/tumor suppressor gene mutations.
Izzotti, A., Calin, G.A., Steele, V.E., Croce, C.M., De Flora, S., 2009b. Relationships of Hepatology 47 (6), 1955–1960.
microRNA expression in mouse lung with age and exposure to cigarette smoke Le, M.T., Teh, C., Shyh-Chang, N., Xie, H., Zhou, B., Korzh, V., Lodish, H.F., Lim, B.,
and light. FASEB J. 23 (9), 3243–3250. 2009. MicroRNA-125b is a novel negative regulator of p53. Genes Dev. 23 (7),
Izzotti, A., Kanitz, S., D’Agostini, F., Camoirano, A., De Flora, S., 2009c. Formation of 862–876.
adducts by bisphenol A, an endocrine disruptor, in DNA in vitro and in liver and Li, D., Wang, Q., Liu, C., Duan, H., Zeng, X., Zhang, B., Li, X., Zhao, J., Tang, S., Li, Z.,
mammary tissue of mice. Mutat. Res. 679 (1–2), 28–32. Xing, X., Yang, P., Chen, L., Zeng, J., Zhu, X., Zhang, S., Zhang, Z., Ma, L., He, Z.,
Izzotti, A., Cartiglia, C., Longobardi, M., Larghero, P., De Flora, S., 2011. Dose respon- Wang, E., Xiao, Y., Zheng, Y., Chen, W., 2012a. Aberrant expression of miR-638
siveness and persistence of microRNA alterations induced by cigarette smoke in contributes to benzo(a)pyrene-induced human cell transformation. Toxicol. Sci.
mice. Mutat. Res. Fund. Mech. 717, 9–16. 125 (2), 382–391.
Izzotti, A., Cartiglia, C., Steele, V.E., De Flora, S., 2012a. MicroRNAs as targets for Li, J., Zhang, Y., Zhao, J., Kong, F., Chen, Y., 2011a. Overexpression of miR-22 reverses
dietary and pharmacological inhibitors of mutagenesis and carcinogenesis. paclitaxel-induced chemoresistance through activation of PTEN signaling in
Mutat. Res. 751 (2), 287–303. p53-mutated colon cancer cells. Mol. Cell. Biochem. 357 (1–2), 31–38.
Izzotti, A., 2012b. Molecular medicine and the development of cancer chemo- Li, X., Lin, R., Li, J., 2011b. Epigenetic silencing of microRNA-375 regulates PDK1
preventive agents. Ann. N. Y. Acad. Sci. 1259, 26–32. expression in esophageal cancer. Dig. Dis. Sci. 56 (10), 2849–2850.
Jalas, J.R., Hecht, S.S., Murphy, S.E., 2005. Cytochrome P450 enzymes as catalysts Li, X., Shi, Y., Wei, Y., Ma, X., Li, Y., Li, R., 2012b. Altered expression profiles of microR-
of metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a tobacco NAs upon arsenic exposure of human umbilical vein endothelial cells. Environ.
specific carcinogen. Chem. Res. Toxicol. 18 (2), 95–110. Toxicol. Pharmacol. 34 (2), 381–387.
Jardim, M.J., Fry, R.C., Jasper, I., Dailey, L., Diaz-Sanchez, D., 2009. Disruption of Li, X., Wu, J., Zheng, J., Li, Y., Yang, T., Hu, G., Dai, J., Yang, Q., Dai, L., Jiang, Y.,
microRNA expression in human airway cells by diesel exhaust particles is 2013. Altered miRNA expression profiles and miR-1a associated with urethane-
linked to tumorigenesis-associated pathways. Environ. Health Perspect. 117 induced pulmonary carcinogenesis. Toxicol. Sci. 135 (1), 63–71.
(11), 1745–1750. Li, Y., Zhang, D., Chen, C., Ruan, Z., Li, Y., Huang, Y., 2012c. MicroRNA-212 displays
Jaspers, I., Ciencewicki, J.M., Zhang, W., Brighton, L.E., Carson, J.L., Beck, M.A., Madden, tumor-promoting properties in non-small cell lung cancer cells and targets the
M.C., 2005. Diesel exhaust enhances influenza virus infections in respiratory hedgehog pathway receptor PTCH1. Mol. Biol. Cell 23 (8), 1423–1430.
epithelial cells. Toxicol. Sci. 85 (2), 990–1000. Ligorio, M., Izzotti, A., Pulliero, A., Arrigo, P., 2011. Mutagens interfere with microRNA
Ji, Q., Hao, X., Meng, Y., Zhang, M., Desano, J., Fan, D., Xu, L., 2008. Restoration of tumor maturation by inhibiting DICER. An in silico biology analysis. Mutat. Res. 717
suppressor miR-34 inhibits human p53-mutant gastric cancer tumorspheres. (1–2), 116–128.
BMC Cancer 8, 266. Lin, J.S., Lin, C.C., Lin, H.H., Chen, Y.C., Jeng, S.T., 2012. MicroR828 regulates lignin and
Jiang, Y., Wu, Y., Greenlee, A.R., Wu, J., Han, Z., Li, X., Zhao, Y., 2011. miR-106a- H2 O2 accumulation in sweet potato on wounding. New Phytol. 196 (2), 427–440.
mediated malignant transformation of cells induced by anti-benzo[a]pyrene- Lippai, D., Bala, S., Csak, T., Kurt-Jones, E.A., Szabo, G., 2013. Chronic alcohol-induced
trans-7,8-diol-9,10-epoxide. Toxicol. Sci. 119, 50–60. microRNA-155 contributes to neuroinflammation in a TLR4-dependent manner
Juhász, K., Gombos, K., Szirmai, M., Révész, P., Magda, I., Gocze, K., Ember, I., 2012. in mice. PLoS ONE 8 (8), e70945.
DMBA induces deregulation of miRNA expression of let-7, miR-21 and miR-146a Liu, J., Luo, X.J., Xiong, A.W., Zhang, Z.D., Yue, S., Zhu, M.S., Cheng, S.Y., 2010a.
in CBA/CA mice. In Vivo 26 (1), 113–117. MicroRNA-214 promotes myogenic differentiation by facilitating exit from
Juhász, K., Gombos, K., Szirmai, M., Gőcze, K., Wolher, V., Révész, P., Magda, I., mitosis via down-regulation of proto-oncogene N-ras. J. Biol. Chem. 285 (34),
Sebestyén, A., Németh, A., Ember, I., 2013. Very early effect of DMBA and MNU 26599–26600.
on microRNA expression. In Vivo 27 (1), 113–117. Liu, L., Jiang, Y., Zhang, H., Greenlee, A.R., Yu, R., Yang, Q., 2010b. miR-22 functions as
Kalscheuer, S., Zhang, X., Zeng, Y., Upadhyaya, P., 2008. Differential expression of a micro-oncogene in transformed human bronchial epithelial cells induced by
microRNAs in early-stage neoplastic transformation in the lungs of F344 rats anti-benzo[a]pyrene-7,8-diol-9,10-epoxide. Toxicol. In Vitro 24, 1168–1170.
chronically treated with the tobacco carcinogen 4-(methylnitrosamino)-1-(3- Lizarraga, D., Gaj, S., Brauers, K.J., Timmermans, L., Kleinjans, J.C., van Delft, J.H.,
pyridyl)-1-butanone. Carcinogenesis 29 (12), 2394–2400. 2012. Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem.
Kang, H.W., Wang, F., Wei, Q., Zhao, Y.F., Liu, M., Li, X., Tang, H., 2012. miR-20a Res. Toxicol. 25 (4), 838–849.
promotes migration and invasion by regulating TNKS2 in human cervical cancer Lowery, A.J., Miller, N., Dwyer, R.M., Kerin, M.J., 2010. Dysregulated miR-183 inhibits
cells. FEBS Lett. 586 (6), 897–904. migration in breast cancer cells. BMC Cancer 10, 502.
Kasahara, T., Kuwayama, C., Hashiba, M., Harada, T., Kakinuma, C., Miyauchi, M., Lu, T.X., Munitz, A., Rothenberg, M.E., 2009. MicroRNA-21 is up-regulated in allergic
Degawa, M., 2003. The gene expression of hepatic proteins responsible for DNA airway inflammation and regulates IL-12p35 expression. J. Immunol. 182 (8),
repair and cell proliferation in tamoxifen-induced hepatocarcinogenesis. Cancer 4994–5000.
Sci. 94 (7), 582–588. Lum, A.M., Wang, B.B., Li, L., Channa, N., Bartha, G., Wabl, M., 2007. Retroviral acti-
Kasashima, K., Nakamura, Y., Kozu, T., 2004. Altered expression profiles of microR- vation of the mir-106a microRNA cistron in T lymphoma. Retrovirology 4, 5.
NAs during TPA-induced differentiation of HL-60 cells. Biochem. Biophys. Res. Luo, X.J., Liu, B., Dai, Z., Li, T.B., Li, N.S., Zhang, X.J., Yang, Z.C., Li, Y.J., Peng, J., 2013.
Commun. 322 (2), 403–410. Expression of apoptosis-associated microRNAs in ethanol-induced acute gastric
Kida, K., Nakajima, M., Mohri, T., Oda, Y., Takagi, S., Fukami, T., Yokoi, T., 2011. mucosal injury via JNK pathway. Alcohol 47 (6), 481–493.
PPAR␣ is regulated by miR-21 and miR-27b in human liver. Pharm. Res. 28 (10), Maccani, M.A., Avissar-Whiting, M., Banister, C.E., McGonnigal, B., Padbury, J.F., Mar-
2467–2470. sit, C.J., 2010. Maternal cigarette smoking during pregnancy is associated with
Kim, W.K., Park, M., Kim, Y.K., Tae, Y.K., Yang, H.K., Lee, J.M., Kim, H., 2011. downregulation of miR-16, miR-21, and miR-146a in the placenta. Epigenetics
MicroRNA-494 downregulates KIT and inhibits gastrointestinal stromal tumor 5 (7), 583–589.
cell proliferation. Clin. Cancer Res. 17 (24), 7584–7590. Malik, A.I., Williams, A., Lemieux, C.L., White, P.A., Yauk, C.L., 2012. Hepatic mRNA,
Esquela-Kerscher, A., Slack, F.J., 2006. Oncomirs – microRNAs with a role in cancer. microRNA, and miR-34a-target responses in mice after 28 days exposure to
Nat. Rev. Cancer 6, 259–269. doses of benzo(a)pyrene that elicit DNA damage and mutation. Environ. Mol.
Klaassen, C.D., Watkins, J.B., 2003. Casarett and Doull’s Essentials of Toxicology. Mutagen. 53 (1), 10–21.
McGraw-Hill, pp. 512. Marsit, C.J., Eddy, K., Kelsey, K.T., 2006. MicroRNA responses to cellular stress. Cancer
Kong, A.P., Xiao, K., Choi, K.C., Wang, G., Chan, M.H., Ho, C.S., Chan, I., Wong, C.K., Res. 66 (22), 10843–10850.
Chan, J.C., Szeto, C.C., 2012a. Associations between microRNA (miR-21, 126, 155 Mascaux, C., Laes, J.F., Anthoine, G., Haller, A., Ninane, V., Burny, A., Sculier, J.P.,
and 221), albuminuria and heavy metals in Hong Kong Chinese adolescents. Clin. 2009. Evolution of microRNA expression during human bronchial squamous
Chim. Acta 413 (13–14), 1053–1060. carcinogenesis. Eur. Respir. J. 33, 352–359.
Kong, K.L., Kwong, D.L., Chan, T.H., Law, S.Y., Chen, L., Li, Y., Qin, Y.R., Guan, X.Y., 2012b. Mateescu, B., Batista, L., Cardon, M., Gruosso, T., de Feraudy, Y., Mariani, O., Nicolas, A.,
MicroRNA-375 inhibits tumour growth and metastasis in oesophageal squa- Meyniel, J.P., Cottu, P., Sastre-Garau, X., Mechta-Grigoriou, F., 2011. miR-141 and
mous cell carcinoma through repressing insulin-like growth factor 1 receptor. miR-200a act on ovarian tumorigenesis by controlling oxidative stress response.
Gut 61 (1), 33–42. Nat. Med. 17 (12), 1627–1630.
Kong, W.Q., Bai, R., Liu, T., Cai, C.L., Liu, M., Li, X., Tang, H., 2012c. Mattiske, S., Suetani, R.J., Neilsen, P.M., Callen, D.F., 2012. The oncogenic role of miR-
MicroRNA-182 targets cAMP-responsive element-binding protein 1 and sup- 155 in breast cancer. Cancer Epidemiol. Biomarkers Prev. 21 (8), 1236–1240.
presses cell growth in human gastric adenocarcinoma. FEBS J. 279 (7), Mees, S.T., Mardin, W.A., Sielker, S., Willscher, E., Senninger, N., Schleicher, C.,
1252–1260. Colombo-Benkmann, M., Haier, J., 2009. Involvement of CD40 targeting miR-
Koturbash, I., Melnyk, S., James, S.J., Beland, F.A., Pogribny, I.P., 2013. Role of 224 and miR-486 on the progression of pancreatic ductal adenocarcinomas. Ann.
epigenetic and miR-22 and miR-29b alterations in the downregulation of Surg. Oncol. 16 (8), 2339–2340.
Mat1a and Mthfr genes in early preneoplastic livers in rats induced by 2- Meister, J., Schmidt, M.H., 2010. miR-126 and miR-126*: new players in cancer. Sci
acetylaminofluorene. Mol. Carcinog. 52 (4), 318–327. World J 10, 2090–2100.
Koufaris, C., Wright, J., Currie, R.A., Gooderham, N.J., 2012. Hepatic microRNA pro- Melkamu, T., Zhang, X., Tan, J., Zeng, Y., Kassie, F., 2010. Alteration of microRNA
files offer predictive and mechanistic insights after exposure to genotoxic and expression in vinyl carbamate-induced mouse lung tumors and modula-
epigenetic hepatocarcinogens. Toxicol. Sci. 128 (2), 532–543. tion by the chemopreventive agent indole-3-carbinol. Carcinogenesis 31 (2),
Krell, J., Frampton, A.E., Jacob, J., Pellegrino, L., Roca-Alonso, L., Zeloof, D., Alifrangis, 252–258.
C., Lewis, J.S., Jiao, L.R., Stebbing, J., Castellano, L., 2012. The clinico-pathologic Meng, F., Henson, R., Wehbe-Janek, H., Ghoshal, K., Jacob, S.T., Patel, T., 2007.
role of microRNAs miR-9 and miR-151-5p in breast cancer metastasis. Mol. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human
Diagn. Ther. 16 (3), 167–172. hepatocellular cancer. Gastroenterology 133, 647–658.
G Model
Meng, F., Glaser, S.S., Francis, H., Yang, F., Han, Y., Stokes, A., Staloch, D., McCarra, J., Pulliero, A., Fazzi, E., Cartiglia, C., Orcesi, S., Balottin, U., Uggetti, C., La Piana, R.,
Liu, J., Venter, J., Zhao, H., Liu, X., Francis, T., Swendsen, S., Liu, C.G., Tsukamoto, H., Olivieri, I., Galli, J., Izzotti, A., 2011. The Aicardi-Goutières syndrome. Molecular
Alpini, G., 2012. Epigenetic regulation of miR-34a expression in alcoholic liver and clinical features of RNAse deficiency and microRNA overload. Mutat. Res.
injury. Am. J. Pathol. 181 (3), 804–817. 717 (1–2), 99–108.
Moschos, S.A., Williams, A.E., Perry, M.M., Birrell, M.A., Belvisi, M.G., Lind- Qian, B., Katsaros, D., Lu, L., Preti, M., Durando, A., Arisio, R., Mu, L., Yu, H., 2009. High
say, M.A., 2007. Expression profiling in vivo demonstrates rapid changes in miR-21 expression in breast cancer associated with poor disease-free survival
lung microRNA levels following lipopolysaccharide-induced inflammation but in early stage disease and high TGF-beta1. Breast Cancer Res. Treat. 117 (1),
not in the anti-inflammatory action of glucocorticoids. BMC Genomics 8, 131–140.
240. Qiang, R., Wang, F., Shi, L.Y., Liu, M., Chen, S., Wan, H.Y., Li, Y.X., Li, X., Gao, S.Y.,
Motta, V., Angelici, L., Nordio, F., Bollati, V., Fossati, S., Frascati, F., Tinaglia, V., Bertazzi, Sun, B.C., Tang, H., 2011. Plexin-B1 is a target of miR-214 in cervical cancer and
P.A., Battaglia, C., Baccarelli, A.A., 2013. Integrative analysis of miRNA and inflam- promotes the growth and invasion of HeLa cells. Int. J. Biochem. Cell Biol. 43 (4),
matory gene expression after acute particulate matter exposure. Toxicol. Sci. 132 632–641.
(2), 307–316. Rager, J.E., Smeester, L., Jaspers, I., Sexton, K.G., Fry, R.C., 2011. Epigenetic changes
Nautiyal, J., Du, J., Yu, Y., Kanwar, S.S., Levi, E., Majumdar, A.P., 2012. EGFR regulation induced by air toxics: formaldehyde exposure alters miRNA expression profiles
of colon cancer stem-like cells during aging and in response to the colonic car- in human lung cells. Environ. Health Perspect. 119 (4), 494–500.
cinogen dimethylhydrazine. Am. J. Physiol. Gastrointest. Liver Physiol. 302 (7), Rager, J.E., Moeller, B.C., Doyle-Eisele, M., Kracko, D., Swenberg, J.A., Fry, R.C.,
G655–G660. 2013. Formaldehyde and epigenetic alterations: microRNA changes in the nasal
Ng, C.T., Dheen, S.T., Yip, W.C., Ong, C.N., Bay, B.H., Lanry Yung, L.Y., 2011. The epithelium of nonhuman primates. Environ. Health Perspect. 121 (3), 339–344.
induction of epigenetic regulation of PROS1 gene in lung fibroblasts by gold Rao, X., Di Leva, G., Li, M., Fang, F., Devlin, C., Hartman-Frey, C., Burow, M.E., Ivan,
nanoparticles and implications for potential lung injury. Biomaterials 32 (30), M., Croce, C.M., Nephew, K.P., 2011. MicroRNA-221/222 confers breast cancer
7609–7610. fulvestrant resistance by regulating multiple signaling pathways. Oncogene 30
Ng, T.K., Carballosa, C.M., Pelaez, D., Wong, H.K., Choy, K.W., Pang, C.P., Cheung, H.S., (9), 1082–1090.
2013. Nicotine alters MicroRNA expression and hinders human adult stem cell Raver-Shapira, N., Marciano, E., Meiri, E., Spector, Y., Rosenfeld, N., Moskovits, N.,
regenerative potential. Stem Cell Dev. 22 (5), 781–790. Bentwich, Z., Oren, M., 2007. Transcriptional activation of miR-34a contributes
Niu, Y., Mo, D., Qin, L., Wang, C., Li, A., Zhao, X., Wang, X., Xiao, S., Wang, Q., Xie, to p53-mediated apoptosis. Mol. Cell 26 (5), 731–743.
Y., He, Z., Cong, P., Chen, Y., 2011. Lipopolysaccharide-induced miR-1224 nega- Ren, X.P., Wu, J., Wang, X., Sartor, M.A., Qian, J., Jones, K., Nicolaou, P., Pritchard,
tively regulates tumour necrosis factor-␣ gene expression by modulating Sp1. T.J., Fan, G.C., 2009. MicroRNA-320 is involved in the regulation of cardiac
Immunology 133 (1), 8–20. ischemia/reperfusion injury by targeting heat-shock protein 20. Circulation 119
Noguchi, S., Iwasaki, J., Kumazaki, M., Mori, T., Maruo, K., Sakai, H., Yamada, N., (17), 2357–2360.
Shimada, K., Naoe, T., Kitade, Y., Akao, Y., 2013. Chemically modified synthetic Río, P., Agirre, X., Garate, L., Baños, R., Álvarez, L., San José-Enériz, E., Badell, I.,
microRNA-205 inhibits the growth of melanoma cells in vitro and in vivo. Mol. Casado, J.A., Garín, M., Prósper, F., Bueren, J.A., 2012. Down-regulated expression
Ther. 21 (6), 1204–1210. of hsa-miR-181c in Fanconi anemia patients: implications in TNF␣ regu-
Nohata, N., Hanazawa, T., Kikkawa, N., Mutallip, M., Sakurai, D., Fujimura, L., lation and proliferation of hematopoietic progenitor cells. Blood 119 (13),
Kawakami, K., Chiyomaru, T., Yoshino, H., Enokida, H., Nakagawa, M., Okamoto, 3042–3050.
Y., Seki, N., 2011. Tumor suppressive microRNA-375 regulates oncogene AEG- Riva, C., Donadieu, E., Magnan, J., Lavieille, J.P., 2007. Age-related hearing loss in CD/1
1/MTDH in head and neck squamous cell carcinoma (HNSCC). J. Hum. Genet. 56 mice is associated to ROS formation and HIF target proteins up-regulation in the
(8), 595–601. cochlea. Exp. Gerontol. 42 (4), 327–336.
Nymark, P., Guled, M., Borze, I., Faisal, A., Lahti, L., Salmenkivi, K., Kettunen, E., Anttila, Rokhlin, O.W., Scheinker, V.S., Taghiyev, A.F., Bumcrot, D., Glover, R.A., Cohen, M.B.,
S., Knuutila, S., 2011. Integrative analysis of microRNA, mRNA and aCGH data 2008. MicroRNA-34 mediates AR-dependent p53-induced apoptosis in prostate
reveals asbestos- and histology-related changes in lung cancer. Genes. Chromo- cancer. Cancer Biol. Ther. 7, 1288–1290.
somes Cancer 50 (8), 585–597. Ross, J.A., Blackman, C.F., Thai, S.F., Li, Z., Kohan, M., Jones, C.P., Chen, T., 2010. A
O’Donnell, K.A., Wentzel, E.A., Zeller, K.I., Dang, C.I., Mendell, J.T., 2005. c-Myc- potential microRNA signature for tumorigenic conazoles in mouse liver. Mol.
regulated microRNAs modulate E2F1 expression. Nature 435, 839–843. Carcinog. 49 (4), 320–323.
Ohdaira, H., Sekiguchi, M., Miyata, K., Yoshida, K., 2012. MicroRNA-494 suppresses Sander, S., Bullinger, L., Klapproth, K., Fiedler, K., Kestler, H.A., Barth, T.F., Möller, P.,
cell proliferation and induces senescence in A549 lung cancer cells. Cell. Prolif. Stilgenbauer, S., Pollack, J.R., Wirth, T., 2008. MYC stimulates EZH2 expression
45 (1), 32–38. by repression of its negative regulator miR-26a. Blood 112, 4202–4210.
Pal, A., Melling, G., Hinsley, E.E., Kabir, T.D., Colley, H.E., Murdoch, C., Lambert, Santarelli, L., Strafella, E., Staffolani, S., Amati, M., Emanuelli, M., Sartini, D., Pozzi,
D.W., 2013. Cigarette smoke condensate promotes pro-tumourigenic stromal- V., Carbonari, D., Bracci, M., Pignotti, E., Mazzanti, P., Sabbatini, A., Ranaldi, R.,
epithelial interactions by suppressing miR-145. J. Oral Pathol. Med. 42 (4), Gasparini, S., Neuzil, J., Tomasetti, M., 2011. Association of MiR-126 with soluble
309–314. mesothelin-related peptides, a marker for malignant mesothelioma. PLoS ONE
Pal, S., Baiocchi, R.A., Byrd, J.C., Grever, M.R., Jacob, S.T., Sif, S., 2007. Low levels of 6 (4), e18232.
miR-92b/96 induce PRMT5 translation and H3R8/H4R3 methylation in mantle Sarkar, S., Dey, B.K., Dutta, A., 2010. MiR-322/424 and -503 are induced during
cell lymphoma. EMBO J. 26 (15), 3558–3560. muscle differentiation and promote cell cycle quiescence and differentiation
Papagiannakopoulos, T., Shapiro, A., Kosik, K.S., 2007. MicroRNA-21 targets a net- by down-regulation of Cdc25A. Mol. Biol. Cell 21 (13), 2138–2140.
work of key tumor suppressive pathways in glioblastoma cells. Cancer Res. 68 Sarver, A.L., Li, L., Subramanian, S., 2010. MicroRNA miR-183 functions as an onco-
(19), 8164–8170. gene by targeting the transcription factor EGR1 and promoting tumor cell
Parasramka, M.A., Dashwood, W.M., Wang, R., Abdelli, A., Bailey, G.S., Williams, migration. Cancer Res. 70 (23), 9570–9580.
D.E., Ho, E., Dashwood, R.H., 2012. MicroRNA profiling of carcinogen-induced Sax, N.I., Lewis, R.J., 1987. Hawley’s Condensed Chemical Dictionary, 11th ed. Van
rat colon tumors and the influence of dietary spinach. Mol. Nutr. Food Res. 56 Nostrand Reinhold Co., New York, NY, pp. 338.
(8), 1259–1260. Schaar, D.G., Medina, D.J., Moore, D.F., Strair, R.K., Ting, Y., 2009. MiR-320 targets
Paul, S., Kim, S., Park, H., Lee, S., An, Y., Oh, M., Jung, J., Hwang, S., 2009. Alteration in transferrin receptor 1 (CD71) and inhibits cell proliferation. Exp. Hematol. 37,
miRNA expression profiling with response to nonylphenol in human cell lines. 245–255.
Mol. Cell. Toxicol. 5, 67–74. Schembri, F., Sridhar, S., Perdomo, C., Gustafson, A.M., Zhang, X., Ergun, A., Lu, J., Liu,
Pedrioli, D.M., Karpanen, T., Dabouras, V., Jurisic, G., van de Hoek, G., Shin, J.W., G., Zhang, X., Bowers, J., Vaziri, C., Ott, K., Sensinger, K., Collins, J.J., Brody, J.S.,
Marino, D., Kälin, R.E., Leidel, S., Cinelli, P., Schulte-Merker, S., Brändli, A.W., Getts, R., Lenburg, M.E., Spira, A., 2009. MicroRNAs as modulators of smoking-
Detmar, M., 2010. miR-31 functions as a negative regulator of lymphatic vascular induced gene expression changes in human airway epithelium. Proc. Natl. Acad.
lineage-specific differentiation in vitro and vascular development in vivo. Mol. Sci. U. S. A. 106 (7), 2319–2320.
Cell. Biol. 30 (14), 3620–3630. Schliekelman, M.J., Gibbons, D.L., Faca, V.M., Creighton, C.J., Rizvi, Z.H., Zhang,
Penna, E., Orso, F., Cimino, D., Tenaglia, E., Lembo, A., Quaglino, E., Poliseno, L., Q., Wong, C.H., Wang, H., Ungewiss, C., Ahn, Y.H., Shin, D.H., Kurie, J.M.,
Haimovic, A., Osella-Abate, S., De Pittà, C., Pinatel, E., Stadler, M.B., Provero, Hanash, S.M., 2011. Targets of the tumor suppressor miR-200 in regula-
P., Bernengo, M.G., Osman, I., Taverna, D., 2011. microRNA-214 contributes to tion of the epithelial–mesenchymal transition in cancer. Cancer Res. 71 (24),
melanoma tumour progression through suppression of TFAP2C. EMBO J. 30 (10), 7670–7680.
1990–2000. Schmeltz, I., Chiong, K.G., Hoffmann, D., 1978. Formation and determination of ethyl
Perdomo, C., Spira, A., Schembri, F., 2011. MiRNAs as regulators of the response to carbamate in tobacco and tobacco smoke. J. Anal. Toxicol. 2, 265–268.
inhaled environmental toxins and airway carcinogenesis. Mutat. Res. 717 (1–2), Shackelford, R.E., Kaufmann, W.K., Paules, R.S., 1999. Cell cycle control, checkpoint
32–37. mechanisms, and genotoxic stress. Environ. Health Perspect. 107 (Suppl. 1),
Pogribny, I.P., Tryndyak, V.P., Boyko, A., Rodriguez-Juarez, R., Beland, F.A., Kovalchuk, 5–24.
O., 2007. Induction of microRNAome deregulation in rat liver by long-term Shan, H., Zhang, Y., Cai, B., Chen, X., Fan, Y., Yang, L., Chen, X., Liang, H., Zhang, Y.,
tamoxifen exposure. Mutat. Res. 619 (1–2), 30–37. Song, X., Xu, C., Lu, Y., Yang, B., Du, Z., 2013. Upregulation of microRNA-1 and
Pogribny, I.P., Muskhelishvili, L., Tryndyak, V.P., Beland, F.A., 2011. The role microRNA-133 contributes to arsenic-induced cardiac electrical remodeling. Int.
of epigenetic events in genotoxic hepatocarcinogenesis induced by 2- J. Cardiol. 167 (6), 2798–2800.
acetylaminofluorene. Mutat. Res. 722 (2), 106–113. Sharma, M., Sharma, S., Arora, M., Kaul, D., 2013. Regulation of cellular Cyclin D1
Pothof, J., Verkaik, N.S., Van IJcken, W., Wiemer, E.A., Ta, V.T., van der Horst, G.T., gene by arsenic is mediated through miR-2909. Gene 522 (1), 60–64.
Jaspers, N.G., Van Gent, D.C., Hoeijmakers, J.H., Persengiev, S.P., 2009. MicroRNA- Shatseva, T., Lee, D.Y., Deng, Z., Yang, B.B., 2011. MicroRNA miR-199a-3p regu-
mediated gene silencing modulates the UV-induced DNA-damage response. lates cell proliferation and survival by targeting caveolin-2. J. Cell Sci. 124 (16),
EMBO J. 28, 2090–2100. 2826–2830.
G Model
Shen, Y.L., Jiang, Y.G., Greenlee, A.R., Zhou, L.L., Liu, L.H., 2009. MicroRNA expression Wang, Z., Liu, Y., Han, N., Chen, X., Yu, W., Zhang, W., Zou, F., 2010b. Profiles of
profiles and miR-10a target in anti-benzo[a] pyrene-7, 8-diol-9, 10-epoxide- oxidative stress-related microRNA and mRNA expression in auditory cells. Brain
transformed human 16HBE cells. Biomed. Environ. Sci. 22, 14–21. Res. 1346, 14–25.
Sen, C.K., Gordillo, G.M., Khanna, S., Roy, S., 2009. Micromanaging vascular biology: Wang, Z., Zhao, Y., Smith, E., Goodall, G.J., Drew, P.A., Brabletz, T., Yang, C., 2011.
tiny microRNAs play big band. J. Vasc. Res. 46 (6), 527–540. Reversal and prevention of arsenic-induced human bronchial epithelial cell
Smith, A.H., Marshall, G., Liaw, J., Yuan, Y., Ferreccio, C., Steinmaus, C., 2012. Mortality malignant transformation by microRNA-200b. Toxicol. Sci. 121 (1), 110–122.
in young adults following in utero and childhood exposure to arsenic in drinking Ward, A., Balwierz, A., Zhang, J.D., Küblbeck, M., Pawitan, Y., Hielscher, T., Wiemann,
water. Environ. Health Perspect. 120 (11), 1527–1530. S., Sahin, Ö., 2013. Re-expression of microRNA-375 reverses both tamoxifen
Song, M.K., Park, Y.K., Ryu, J.C., 2013. Polycyclic aromatic hydrocarbon (PAH)- resistance and accompanying EMT-like properties in breast cancer. Oncogene
mediated upregulation of hepatic microRNA-181 family promotes cancer cell 32 (9), 1173–1180.
migration by targeting MAPK phosphatase-5, regulating the activation of p38 Weber, D.G., Johnen, G., Bryk, O., Jöckel, K.H., Brüning, T., 2012. Identification of
MAPK. Toxicol. Appl. Pharmacol. 273 (1), 130–139. miRNA-103 in the cellular fraction of human peripheral blood as a potential
Stephens, P., Hunter, C., Bignell, G., Edkins, S., Davies, H., Teague, J., Stevens, C., biomarker for malignant mesothelioma – a pilot study. PLoS ONE 7 (1), e30221.
O’Meara, S., Smith, R., Parker, A., Barthorpe, A., Blow, M., Brackenbury, L., Butler, Wei, Q., Li, Y.X., Liu, M., Li, X., Tang, H., 2012. MiR-17-5p targets TP53INP1 and regu-
A., Clarke, O., Cole, J., Dicks, E., Dike, A., Drozd, A., Edwards, K., Forbes, S., Foster, lates cell proliferation and apoptosis of cervical cancer cells. IUBMB Life 64 (8),
R., Gray, K., Greenman, C., Halliday, K., Hills, K., Kosmidou, V., Lugg, R., Menzies, 697–704.
A., Perry, J., Petty, R., Raine, K., Ratford, L., Shepherd, R., Small, A., Stephens, Y., Wiesen, J.L., Tomasi, T.B., 2009. Dicer is regulated by cellular stresses and interferons.
Tofts, C., Varian, J., West, S., Widaa, S., Yates, A., Brasseur, F., Cooper, C.S., Flana- Mol. Immunol. 46 (6), 1222–1230.
gan, A.M., Knowles, M., Leung, S.Y., Louis, D.N., Looijenga, L.H., Malkowicz, B., Wilker, E.H., Baccarelli, A., Suh, H., Vokonas, P., Wright, R.O., Schwartz, J., 2010. Black
Pierotti, M.A., Teh, B., Chenevix-Trench, G., Weber, B.L., Yuen, S.T., Harris, G., carbon exposures, blood pressure, and interactions with single nucleotide poly-
Goldstraw, P., Nicholson, A.G., Futreal, P.A., Wooster, R., Stratton, M.R., 2004. morphisms in MicroRNA processing genes. Environ. Health Perspect. 118 (7),
Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature 431 (7008), 943–948.
525–526. Wu, J., Yang, T., Li, X., Yang, Q., Liu, R., Huang, J., Li, Y., Yang, C., Jiang, Y., 2013.
Stringer, R.L., Laufer, B.I., Kleiber, M.L., Singh, S.M., 2013. Reduced expression of brain Alteration of serum miR-206 and miR-133b is associated with lung carcino-
cannabinoid receptor 1 (Cnr1) is coupled with an increased complementary genesis induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Toxicol.
micro-RNA (miR-26b) in a mouse model of fetal alcohol spectrum disorders. Appl. Pharmacol. 267 (3), 238–246.
Clin. Epigenet. 5 (1), 14. Xi, S., Xu, H., Shan, J., Tao, Y., Hong, J.A., Inchauste, S., Zhang, M., Kunst, T.F., Mercedes,
Suarez, Y., Fernandez-Hernando, C., Pober, J.S., Sessa, W.C., 2007. Dicer dependent L., Schrump, D.S., 2013. Cigarette smoke mediates epigenetic repression of miR-
microRNAs regulate gene expression and functions in human endothelial cells. 487b during pulmonary carcinogenesis. J. Clin. Invest. 123 (3), 1241–1250.
Circ. Res. 100 (8), 1164–1170. Xiao, C., Rajewsky, K., 2009. MicroRNA control in the immune system: basic princi-
Sun, Y., Bai, Y., Zhang, F., Wang, Y., Guo, Y., Guo, L., 2010. miR-126 inhibits non-small ples. Cell 136 (1), 26–36.
cell lung cancer cells proliferation by targeting EGFL7. Biochem. Biophys. Res. Xiao, J., Luo, X., Lin, H., Zhang, Y., Lu, Y., Wang, N., Zhang, Y., Yang, B., Wang, Z., 2007.
Commun. 391 (3), 1483–1490. MicroRNA miR-133 represses HERG K1 channel expression contributing to QT
Suzuki, H.I., Yamagata, K., Sugimoto, K., Iwamoto, T., Kato, S., Miyazono, K., 2009. prolongation in diabetic hearts. J. Biol. Chem. 282, 12363–12370.
Modulation of microRNA processing by p53. Nature 460, 529–533. Xu, D., Takeshita, F., Hino, Y., Fukunaga, S., Kudo, Y., Tamaki, A., Matsunaga, J.,
Suzuki, H.I., Miyazono, K., 2010. Dynamics of microRNA biogenesis: crosstalk Takahashi, R.U., Takata, T., Shimamoto, A., Ochiya, T., Tahara, H., 2011. miR-22
between p53 network and microRNA processing pathway. J. Mol. Med. (Berl.) represses cancer progression by inducing cellular senescence. J. Cell Biol. 193
88 (11), 1085–1090. (2), 409–424.
Takata, A., Otsuka, M., Kojima, K., Yoshikawa, T., Kishikawa, T., Yoshida, H., Koike, K., Xu, L., Qin, W., Zhang, H., Wang, Y., Dou, H., Yu, D., Ding, Y., Yang, L., Wang, Y.,
2011. MicroRNA-22 and microRNA-140 suppress NF-␬B activity by regulating 2012. Alterations in microRNA expression linked to microcystin-LR-induced
the expression of NF-␬B coactivators. Biochem. Biophys. Res. Commun. 411 (4), tumorigenicity in human WRL-68 cells. Mutat. Res. 743 (1–2), 75–82.
826–831. Xue, Q., Guo, Z.Y., Li, W., Wen, W.H., Meng, Y.L., Jia, L.T., Wang, J., Yao, L.B., Jin, B.Q.,
Tellez, C.S., Juri, D.E., Do, K., Bernauer, A.M., Thomas, C.L., Damiani, L.A., Tessema, Wang, T., Yang, A.G., 2011. Human activated CD4(+) T lymphocytes increase IL-2
M., Leng, S., Belinsky, S.A., 2011. EMT and stem cell-like properties associated expression by downregulating microRNA-181c. Mol. Immunol. 48 (4), 592–599.
with miR-205 and miR-200 epigenetic silencing are early manifestations during Yamakawa, K., Kuno, T., Hashimoto, N., Yokohira, M., Suzuki, S., Nakano, Y., Saoo, K.,
carcinogen-induced transformation of human lung epithelial cells. Cancer Res. Imaida, K., 2010. Molecular analysis of carcinogen-induced rodent lung tumors:
71 (8), 3087–3090. involvement of microRNA expression and K-ras or Egfr mutations. Mol. Med.
Thulasingam, S., Massilamany, C., Gangaplara, A., Dai, H., Yarbaeva, S., Subramaniam, Rep. 3 (1), 141–147.
S., Riethoven, J.J., Eudy, J., Lou, M., Reddy, J., 2011. miR-27b*, an oxidative stress- Yamakuchi, M., Lowenstein, C.J., 2009. MiR-34, SIRT1 and p53: the feedback loop.
responsive microRNA modulates nuclear factor-kB pathway in RAW 264.7 cells. Cell Cycle 8 (5), 712–715.
Mol. Cell. Biochem. 352 (1–2), 181–188. Yamakuchi, M., Yagi, S., Ito, T., Lowenstein, C.J., 2011. MicroRNA-22 regulates
Tilghman, S.L., Bratton, M.R., Segar, H.C., Martin, E.C., Rhodes, L.V., Li, M., McLach- hypoxia signaling in colon cancer cells. PLoS ONE 6 (5), e20291.
lan, J.A., Wiese, T.E., Nephew, K.P., Burow, M.E., 2012. Endocrine disruptor Yang, B., Lin, H., Xiao, J., Lu, Y., Luo, X., Li, B., Zhang, Y., Xu, C., Bai, Y., Wang, H.,
regulation of microRNA expression in breast carcinoma cells. PLoS ONE 7 (3), Chen, G., Wang, Z., 2007. The muscle-specific microRNA miR-1 regulates cardiac
e32754. arrhythmogenic potential by targeting GJA1 and KCNJ2. Nat. Med. 13, 486–491.
Tili, E., Michaille, J.J., Cimino, A., Costinean, S., Dumitru, C.D., Adair, B., Fabbri, M., Yang, W., Sun, T., Cao, J., Liu, F., Tian, Y., Zhu, W., 2012. Downregulation of miR-210
Alder, H., Liu, C.G., Calin, G.A., Croce, C.M., 2007. Modulation of miR-155 and expression inhibits proliferation, induces apoptosis and enhances radiosensiti-
miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their vity in hypoxic human hepatoma cells in vitro. Exp. Cell Res. 318 (8), 944–954.
possible roles in regulating the response to endotoxin shock. J. Immunol. 179 Yang, Z., Chen, S., Luan, X., Li, Y., Liu, M., Li, X., Liu, T., Tang, H., 2009. MicroRNA-214
(8), 5082–5090. is aberrantly expressed in cervical cancers and inhibits the growth of HeLa cells.
Tossavainen, A., 1976. Metal fumes in foundries. Scand. J. Work. Environ. Health 2 IUBMB Life 61 (11), 1075–1080.
(Suppl. 1), 42–49. Ying, Q., Liang, L., Guo, W., Zha, R., Tian, Q., Huang, S., Yao, J., Ding, J., Bao, M., Ge,
Totsuka, Y., Nishigaki, R., Takamura-Enya, T., Kawahara, N., Sugimura, T., C., Yao, M., Li, J., He, X., 2011. Hypoxia-inducible microRNA-210 augments the
Wakabayashi, K., 2007. Analysis of the major RNA adduct derived from metastatic potential of tumor cells by targeting vacuole membrane protein 1 in
aminophenylnorharman, a novel endogenous mutagen and carcinogen. Genes hepatocellular carcinoma. Hepatology 54 (6), 2064–2070.
Environ. 29, 54–62. Yu, T., Wang, X.Y., Gong, R.G., Li, A., Yang, S., Cao, Y.T., Wen, Y.M., Wang, C.M., Yi,
Tryndyak, V.P., Ross, S.A., Beland, F.A., Pogribny, I.P., 2009. Down-regulation of the X.Z., 2009. The expression profile of microRNAs in a model of 7,12-dimethyl-
microRNAs miR-34a, miR-127, and miR-200b in rat liver during hepatocarcino- benz[a]anthrance-induced oral carcinogenesis in Syrian hamster. J. Exp. Clin.
genesis induced by a methyl-deficient diet. Mol. Carcinog. 48 (6), 479–487. Cancer Res. 28 (1), 64.
Tsang, W.P., Kwok, T.T., 2009. The miR-18a* microRNA functions as a potential tumor Zeiher, A.M., 1996. Endothelial vasodilator dysfunction: pathogenetic link to
suppressor by targeting on K-Ras. Carcinogenesis 30 (6), 953–959. myocardial ischaemia or epiphenomenon? Lancet 348 (Suppl. 1), s10–s12.
Urbich, C., Kaluza, D., Frömel, T., Knau, A., Bennewitz, K., Boon, R.A., Bonauer, A., Zhang, B., Pan, X., Cobb, G.P., Anderson, T.A., 2007. microRNAs as oncogenes and
Doebele, C., Boeckel, J.N., Hergenreider, E., Zeiher, A.M., Kroll, J., Fleming, I., tumor suppressors. Dev. Biol. 302, 1–12.
Dimmeler, S., 2012. MicroRNA-27a/b controls endothelial cell repulsion and Zhang, B., Pan, X., 2009. RDX induces aberrant expression of microRNAs in mouse
angiogenesis by targeting semaphorin 6A. Blood 119 (6), 1607–1610. brain and liver. Environ. Health Perspect. 117 (2), 231–240.
Volinia, S., Calin, G.A., Liu, C.G., Ambs, S., Cimmino, A., Petrocca, F., Visone, R., Iorio, M., Zhang, L., Liu, T., Huang, Y., Liu, J., 2011. microRNA-182 inhibits the proliferation
Roldo, C., Ferracin, M., Prueitt, R.L., Yanaihara, N., Lanza, G., Scarpa, A., Vecchione, and invasion of human lung adenocarcinoma cells through its effect on human
A., Negrini, M., Harris, C.C., Croce, C.M., 2006. A microRNA expression signature cortical actin-associated protein. Int. J. Mol. Med. 28 (3), 381–388.
of human solid tumors defines cancer gene targets. Proc. Natl. Acad. Sci. U. S. A. Zhang, Y., Wu, J.H., Han, F., Huang, J.M., Shi, S.Y., Gu, R.D., Chen, X.L., He, B., 2013.
103, 2257–2260. Arsenic trioxide induced apoptosis in retinoblastoma cells by abnormal expres-
Wang, F., Li, C., Jim, Y., 2012. Modulation of microRNA expression by volatile sion of microRNA-376a. Neoplasma 60 (3), 247–253.
organic compounds in mouse lung. Environ. Toxicol., http://dx.doi.org/ Zhao, Y., Liu, H., Li, Y., Wu, J., Greenlee, A.R., Yang, C., Jiang, Y., 2011a. The role of
10.1002/tox.21795. miR-506 in transformed 16HBE cells induced by anti-benzo[a]pyrene-trans-7,8-
Wang, M., Ye, Y., Qian, H., Song, Z., Jia, X., Zhang, Z., Zhou, J., Ni, C., 2010a. Com- dihydrodiol-9,10-epoxide. Toxicol. Lett. 205, 320–326.
mon genetic variants in pre-microRNAs are associated with risk of coal workers’ Zhao, Y., Xiong, Q., Xie, P., 2011b. Analysis of microRNA expression in embryonic
pneumoconiosis. J. Hum. Genet. 55 (1), 13–17. developmental toxicity induced by MC-RR. PLoS ONE 6 (7), e22676.
G Model
Zhou, Q., Gallagher, R., Ufret-Vincenty, R., Li, X., Olson, E.N., Wang, S., 2011. Zhu, S., Si, M.L., Wu, H., Mo, Y.Y., 2007. MicroRNA-21 targets the tumor suppressor
Regulation of angiogenesis and choroidal neovascularization by members of gene tropomyosin 1 (TPM1). J. Biol. Chem. 282 (19), 14328–14330.
microRNA-23∼27∼24 clusters. Proc. Natl. Acad. Sci. U. S. A. 108 (20), 8287–8290. Zhu, S., Wu, H., Wu, F., Nie, D., Sheng, S., Mo, Y.Y., 2008b. MicroRNA-21 targets tumor
Zhu, H., Wu, H., Liu, X., Evans, B.R., Medina, D.J., Liu, C.G., Yang, J.M., 2008a. suppressor genes in invasion and metastasis. Cell Res. 18 (3), 350–359.
Role of MicroRNA miR-27a and miR-451 in the regulation of MDR1/P- Zimmerli, B., Schlatter, J., 1991. Ethyl carbamate: analytical methodology, occur-
glycoprotein expression in human cancer cells. Biochem. Pharmacol. 76 (5), rence, formation, biological activity and risk assessment. Mutat. Res. 259 (3–4),
582–588. 325–350.

The Effects of Environmental Chemical Carcinogens On The microRNA Machinery

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

The Effects of Environmental Chemical Carcinogens On The microRNA Machinery

Uploaded by

Copyright:

Available Formats

G Model

IJHEH-12752; No. of Pages 27 ARTICLE IN PRESS

Contents lists available at ScienceDirect

International Journal of Hygiene and

The effects of environmental chemical carcinogens on the

Introduction The early sensitivity of miRNA to environmental carcinogens

Environmental chemical carcinogens and miRNA.

IJHEH-12752; No. of Pages 27

Human Left ventriculum endocardium qRT-PCR miR-1↑ Yang et al., 2007

IJHEH-12752; No. of Pages 27

miR-124a↓, miR-125b↓, miR-126↓, miR-143↓,

Pesticides and endocrine disruptors

Food and water carcinogens

IJHEH-12752; No. of Pages 27

MeIQx Mice Liver qPCR let-7a↓, miR-125a↓ Yamakawa et al., 2010

Ethanol Human Liver (hepatocellular qPCR miR-126↓ Ladeiro et al., 2008

Halappanavar et al., 2011b

Kasashima et al., 2004

Balansky et al., 2013

Bourdon et al., 2012

Alencar et al., 2011

Wang et al., 2010b

Gueta et al., 2010

Chen et al., 2008

Hou et al., 2012

let-7a/f/g↑, miR-185↑, miR-297↑, miR-297a↑,

ciﬁc miRNA alteration signature found in experimental studies is

miR-27↑, miR-142↓, miR-142↓, miR-320↓

early markers of the biological effects of exposure to environmental

carcinogens in healthy organisms. The possibility of using miRNAs

miR-466↑, miR-467↑, miR-466↑

their analysis is feasible via noninvasive sampling (Etheridge et al.,

The ﬁrst evidence that miRNA expression is altered by exposure

were exposed to CS. Large alterations in miRNA expression, pri-

marily downregulation, occurred in the lungs of rats (Izzotti et al.,

2009a) and adult and post-weanling mice (Izzotti et al., 2009b).

aimed at counteracting the effects of CS. However, the persistence

of this downregulated expression in mice that were exposed to

CS for 4 months resulted in the irreversible loss-of-function of

ticularly applied to let-7, suppressing the expression of a mutated

k-ras oncogene, whose role in lung carcinogenesis is well estab-

HL-60 human leukocyte

HL-60 human leukocyte

lished (He et al., 2010). The CS-induced mutation of the k-ras

gene was initially devoid of functional consequences because of

the existence of let-7. However, in the case of the irreversible

downregulation of let-7 that was induced by long-term exposure

oncogenes or tumor suppressor genes in the case of exposure to

to play a role in the development of non-small cell lung cancer

lular responses to DNA damage. miR-125 regulates the activation

of ERBB2, which plays an important role in lung carcinogenesis

(Stephens et al., 2004). Maternal cigarette smoking during preg-

ular changes that occur in the placenta upon exposure to cigarette

Titanium dioxide nanoparticles

smoke. This study demonstrated that exposure to CS during preg-

and miR-146a expression in the human placenta (Maccani et al.,

MiRNA expression in the human bronchial epithelium was

ers through an analysis of the expression of 467 miRNAs using

Pesticides and endocrine disruptors Nonylphenol

Bisphenol A Nonylphenol is a family of closely related organic compounds,

2-AAF Research on Cancer (IARC) classiﬁes ethylene oxide into group 1,

You might also like