Environmental Science and Pollution Research

https://doi.org/10.1007/s11356-020-08991-y

ENVIRONMENTAL POLLUTANTS AND THE RISK OF NEUROLOGICAL DISORDERS

Ochratoxin A–induced genotoxic and epigenetic mechanisms lead

to Alzheimer disease: its modulation with strategies
Kamal Niaz 1 & Syed Zahid Ali Shah 2 & Fazlullah Khan 3,4 & Mohammed Bule 5

Received: 9 December 2019 / Accepted: 22 April 2020

# Springer-Verlag GmbH Germany, part of Springer Nature 2020

Abstract
Ochratoxin A (OTA) is a naturally occurring mycotoxin mostly found in food items including grains and coffee beans. It induces
DNA single-strand breaks and has been considered to be carcinogenic. It is recognized as a serious threat to reproductive health
both in males and females. OTA is highly nephrotoxic and carcinogenic, and its potency changes evidently between species and
sexes. There is a close association between OTA, mutagenicity, carcinogenicity, and genotoxicity, but the underlying mecha-
nisms are not clear. Reports regarding genotoxic effects in relation to OTA which leads to the induction of DNA adduct
formation, protein synthesis inhibition, perturbation of cellular energy production, initiation of oxidative stress, induction of
apoptosis, influences on mitosis, induction of cell cycle arrest, and interference with cytokine pathways. All these mechanisms
are associated with nephrotoxicity, hepatotoxicity, teratotoxicity, immunological toxicity, and neurotoxicity. OTA administration
activates various mechanisms such as p38 MAPK, JNKs, and ERKs dysfunctions, BDNF disruption, TH overexpression,
caspase-3 and 9 activation, and ERK-1/2 phosphorylation which ultimately lead to Alzheimer disease (AD) progression. The
current review will focus on OTA in terms of recent discoveries in the field of molecular biology. The main aim is to investigate
the underlying mechanisms of OTA in regard to genotoxicity and epigenetic modulations that lead to AD. Also, we will highlight
the strategies for the purpose of attenuating the hazards posed by OTA exposure.

Keywords Ochratoxin A . Genotoxicity . Epigenetics . DNA methylation . Histone modifications . Nephrotoxicity .

Therapeutics . Alzheimer disease

Introduction
Presently ochratoxin A (OTA) is a major threat to public
health. Various species of fungi from the Penicillium,
Alternaria, and Aspergillus genera produce the OTA myco-
toxin (Zhu et al. 2017). OTA occurs in nutritional products of
both vegetative and animal origin. In general, it affects
products that are stored for longer periods of time such as
cereals, coffee, cocoa, nuts, and peanuts (Zhu et al. 2017).
OTA is a mycotoxin that specifically targets kidneys and is
known for its ability to cross the placental barrier and expos-
ing a newly formed fetus to its harmful effects (Malir et al.
2013a). OTA exposure is recognized as a major risk factor in
reproductive health in males and females throughout the

Responsible Editor: Mohamed M. Abdel-Daim

* Kamal Niaz 2
Department of Pathology, Faculty of Veterinary Science, Cholistan
kamalniaz1989@gmail.com; kamalniaz1989@cuvas.edu.pk University of Veterinary and Animal Sciences, Bahawalpur 63100,
Pakistan
Syed Zahid Ali Shah 3
The Institute of Pharmaceutical Sciences (TIPS), School of
zahidvet@cuvas.edu.pk
Pharmacy, International Campus, Tehran University of Medical
Fazlullah Khan Sciences (IC-TUMS), Tehran 1417614411, Iran
f-khan@tums.ac.ir 4
Department of Toxicology and Pharmacology, Faculty of Pharmacy,
1
Tehran University of Medical Science, Tehran 1417614411, Iran
Department of Pharmacology and Toxicology, Faculty of
5
Bio-Sciences, Cholistan University of Veterinary and Animal Department of Pharmacy, College of Medicine and Health Sciences,
Sciences, Bahawalpur 63100, Pakistan Ambo University, Ambo, Oromia, Ethiopia

world. Besides reproductive and renal damage, its association
with developmental malformations, neurotoxicity, hepatotox-
icity, and immunological toxicity has been shown in the lab-
oratory as well as in dairy farm animals and human beings
(Vettorazzi et al. 2013). It has also been observed that organ-
isms with a predisposed susceptibility may develop cancer
due to OTA exposure depending on species, sex, and age of
the organisms (Vettorazzi et al. 2013). Humans and animals
that consume foods and feedstuffs contaminated with OTA
adversely affect cells, tissues, organs, and fluids along with
blood which is considered an essential indicator of OTA ex-
posure. OTA contamination in laboratory and farm animals is
best observed in blood samples due to the difficulty of the
body to excrete it (Malir et al. 2013a, 2013b). The mecha-
nisms responsible for the adverse effects of OTA are mostly
still under discussion throughout the scientific community. A
variety of toxic effects has been attributed to OTA including
DNA damage, perturbation of protein synthesis, cell cycle
arrest, induction of programmed cell death, necrosis, chromo-
somal degradation, and protein damage. All these perturba-
tions are caused due to the reactive oxygen species (ROS)–
induced oxidative stress (Costa et al. 2016; Marin-Kuan et al.
2011; Zhu et al. 2017). In the year 1965, OTA was isolated by
a chemical process and defined structurally for the first time in
South Africa (Van Der Merwe et al. 1965). The name of OTA
was assigned according to the standard naming system and the
Chemical Abstracts Service (CAS) guidelines with a number
303-47-9. Structurally speaking, OTA is a dihydro-
isocoumarin derivative linked to L-phenylalanine N-[(5-
chloro-3, 4-dihydro-8-hydroxy-3-methyl-1-oxo-1-H-2-
benzopyran-7-yl) carbonyl]-(R) via an amide bond.
According to the IUPAC nomenclature, OTA is indicated as
(N-[[(3R)-5-chloro-8-hydroxy-3-methyl-1-oxo-7-
isochromanyl] carbonyl]-3-phenylL-alanine). Alternatively,
OTA is sometimes known as -N-[(5-chloro-8-hydroxy-3-
methyl-1-oxo-7-isochromanyl) carbonyl]-3-phenylalanine
along with the molecular formula C20H18O6ClN (Malir et al.
2016).
Before one can grasp the implications of OTA on the health
of humans and animals, a basic understanding of the biochem-
ical mechanisms of action by which OTA works is necessary.
OTA binds to protein moieties in the plasma membrane of
cells (80–90%). It forms a strong and persistent attachment
that results in protein synthesis inhibition and cellular and
mitotic degradations as well as arrest and urinary tract carci-
nogenicity (Kőszegi and Poór 2016; Malir et al. 2016).
The target site for the action of OTA is albumin in animals
and human beings. In the active site of the target protein,
OTAs’ isocoumarin structure is mainly situated among amino
acids composed of amino acids A291, L238, I260, I264, I290,
R257, and S287, whereas the phenyl group is surrounded by
K199, H242, Y211, L238, and W214 amino acids (Perry et al.
2004). The carbonyl and phenolic hydroxyl groups contain
Environ Sci Pollut Res
the oxygen that interacts with R257, although the carboxylic
acid interacts with the amino acids R218 and/or R222; the
customized albumin according to data robustly support the
interaction of the essential functions of R257 and R218 argi-
nines (Perry et al. 2004). As a result of the deprotonation of
R257 arginine, a stable ion pair is formed between the pheno-
lic hydroxyl group of OTA and the human serum albumin
(HSA).
Few other proteins besides albumin are also the targeted
sites of OTA; those protein structures with a molecular weight
of around 20 kDa have the potential to provide more affinity
to attract OTA rather than albumin. These proteins and their
mechanism of action are not clearly known as albumin, but
they could play a major role in the pathogenesis free filtration
through the glomeruli (Kőszegi and Poór 2016). The actions
of phenylalanine-tRNA synthase can be inhibited by OTA, as
the fact is well known that the OTA is protein synthesis in-
hibitor both in vitro and in vivo. It has been considered that
according to biochemistry, the phenylalanine portion of OTA
plays an important role in the competition between phenylal-
anine and the toxin (Alshannaq and Yu 2017; Creppy et al.
1984; Zanicgrubisic et al. 2000). Despite this, a recent study
revealed that isocoumarin itself is responsible for such inter-
actions than the phenylalanine since the modifications on the
isocoumarin moiety have resulted in a considerable effect on
its action (Kőszegi and Poór 2016). Additional studies need to
be conducted in order to emphasize the fact that the phenylal-
anine part is a major part contributing to mycotoxin toxicity
(Alshannaq and Yu 2017; Zanicgrubisic et al. 2000).
Moreover, OTA inhibits phenylalanine hydroxylase and also
acts as a false substrate of the catalytic reaction. The hydrox-
ylation of its phenylalanine moiety brings about tyrosine-
containing OTA that has been distinguished considerably dur-
ing in vivo examinations. However, we must underscore the
impact of OTA with respect to phenylalanine-tRNA synthase,
which is more toxic than phenylalanine hydroxylase. The cel-
lular production of ATP is influenced negatively by OTA.
Protein synthesis is reduced due to the improper functioning
of mitochondria (Kőszegi and Poór 2016). OTA plays a vital
role in energy metabolism due to its binding with protein
moieties found in the building of mitochondrial membranes,
blocking and interfering with the phosphate and electron
movement across the membrane.
Benzoquinone and its radicals play an important part in the
formation of DNA adduct as it is properly known that DNA
adduct is the causative agent of gene mutations and conse-
quently results in tumorigenesis, particularly the cancer of
urinary tract (Pfohl-Leszkowicz and Manderville 2007).
DNA adducts are the byproducts of the covalent interaction
of OTA generated via radical and benzoquinone intermedi-
ates. OTAs’ metabolite named as OTA hydroquinone
(OTHQ) undergoes autoxidation to produce the quinone elec-
trophile OTA quinine (OTQ) that undergoes the reaction with
Environ Sci Pollut Res
DNA. Production of ROS is initially enhanced by the input of
OTQ or phenoxy and aryl radicals and its eventually respon-
sible for cytotoxicity (Pfohl-Leszkowicz and Manderville
2011). C-bound C8-dG adduct is produced by aryl free radical
species while benzoquinone and quinone electrophile forms
benzetheno-type DNA adducts.
The C-bound C8-OTA adducts play their role in cytotox-
icity at a lower rate. Reductive dehalogenation of OTA also
shows in this manner (via cyclo-oxygenase alternately
lipoxygenase). Those C5-Cl particles are essential to DNA
adduction (genotoxicity), yet not for cytotoxicity (OTB
[Ochratoxin B] is cytotoxic yet all are not genotoxic); a few
quinone subsidiaries have been isolated from blood and urine
exposed to OTA. The carcinogenic effects while co-contact
with fumonisin (FB), citrinin (CIT), or both are clear and
understandable (Mantle et al. 2009). Although both carcino-
genic and genotoxic effects can be explained by the coopera-
tion of both factors as they are a major culprit for the induction
of COX2 leading to genotoxic compounds (Malir et al. 2013a,
2013b; Ringot et al. 2006). The professional community
agreed with the carcinogenic effect of OTA, and they realized
that OTA is one of the major mycotoxins that is a great threat
as a nephrotoxic, neurotoxic, reprotoxic, teratotoxic, and
embryotoxic (Huang and Chan 2016; Lühe et al. 2003;
Malir et al. 2013a, 2013b; Paradells et al. 2015). It is a threat
to the embryo/fetal development and all other aspects of the
development.
OTA is already an important topic for research and discus-
sion amongst the scientific community; major milestones have
been achieved in order to understand the molecular mecha-
nisms and epigenetics of OTA. The unique aspect of this
review is to cover those studies which took place recently.
The latest studies about OTA have been summarized in the
articles that are involved in the molecular mechanisms and
epigenetic alterations that cause Alzheimer’s disease (AD).
The article focuses on the key aspects according to molecular
and epigenetic alteration caused by OTA which ultimately
leads to AD that had not been reported previously in a single
article along with various strategies to lessen OTA toxicity.
Molecular mechanisms of OTA
Inhibition of protein synthesis
The major toxicities of OTA have been demonstrated in cell
culture models including bacteria, yeasts as well as mamma-
lian models. The modulation of transcription factors of differ-
ent proteins resulting in the inhibition of their synthesis and
leading to alterations in many specific cell functions. Protein
synthesis repression brings about the blocking of RNA syn-
thesis and peptide elongation inhibition due to the competition
with phenylalanine-tRNA synthetase (PheRS), considering
that protein synthesis inhibition results from RNA predomi-
nant downregulation and protein expression. Differentially
expressed genes which are directly related to protein inhibi-
tion have been observed due to OTA treatments such as up-
regulation of prostaglandin F2 receptor negative regulator
(PTGFRN), the eukaryotic translation initiation factor 4E
binding protein-1 (EIF4EBP1), and downregulation of the
elongation factor 1-alpha 1 (EEF1A1), which promotes the
guanosine triphosphate (GTP)–dependent binding of
aminoacyl-tRNA to the A-site of ribosomes during protein
biosynthesis (Fig. 1). Other related genes to protein synthesis
and proteolysis namely EIF2S1, EIF4E, EIF4G2, and
EEF1A1 as well as phosphatases, ligases, transferases, and
hydrolases are also observed to be differentially expressed
and downregulated while involving the protein synthesis, pro-
teolysis, and post-translational modification explaining that
the metabolism of proteins is the utmost altered process by
OTA as shown in Fig. 1 (Vettorazzi et al. 2013).
Mainly produced by different fungi species, the toxin curbs
the polyuridylic acid (poly-U)–dependent peptide synthesis
system leading to the accumulation of the MS-nucleotides
ppGpp and pppGpp resulting in phenylalanine inhibition in
the aminoacylation reaction, which is strongly dependent on
the Mg2+ concentration. This observation has concluded that
OTA stands out in non-specific protein synthesis inhibition
such as prohibiting the phenylalanine-tRNA synthase activity
by significantly contributing the isocoumarin structure as well
as preventing the phenylalanine hydroxylase (Kőszegi and
Poór 2016). The toxin could also influence other protein tran-
scription showing accurate effects inside the cells. For in-
stance, it has been reported that OTA induces specific degra-
dation of the mRNA that codes for gluconeogenesis key en-
zyme (phosphoenolpyruvate carboxykinase) resulting in de-
creasing the degree of its synthesis. Moreover, upregulation of
P21 in proximal tubule cells and in mouse skin and downreg-
ulation in hepatocarcinoma cells were recorded resulting in
blocking of the cyclin-dependent kinase activity and thereby
obstruction of the cell cycle and transcription regulation, DNA
repair as well as cell motility (Dutto et al. 2015). Studies have
shown that deoxynivalenol (DON) and OTA have toxicolog-
ical effects on the intestinal epithelial protein synthesis and
barrier integrity as their presence has been revealed in dog
foods, beer, and wines. In fact, the toxin affects Caco-2 cell
permeability by eliminating especial claudin isoforms out of
the tight junctions and the membrane microdomains (Van De
Walle et al. 2010; Arrúa et al. 2019; Songsermsakul et al.
2007). Furthermore, in vitro and in vivo lipid peroxidation
improvements following permissible OTA exposure were no-
ticed due to the expression of important cell or mitochondrial
membrane–related effects. These observations have been no-
ticed within in vivo mouse liver and cultured hepatoma cells
and Madin-Darby canine kidney cells and more accentuated
within the kidney and spleen. For instance, lon peptidase 1

Fig. 1 Mechanisms underlying OTA-induced genotoxicity
(Lonp1) has an essential function in protein metabolism and
modification. Assuming that OTA inhibits the synthesis and
the metabolism of protein and in order to investigate Lonp1
functions in OTA-induced renal cytotoxicity, an approach of
iTRAQ-based proteomics combined with RNAi was used to
analyze protein expression changes in HEK293 cell. Results
have demonstrated that OTA decreases Lonp1 within cells
and induces proteomic changes in Lonp1-deficient cells which
improved further knowledge in OTA cytotoxicity and indicat-
ed that OTA disturbs protein synthesis and modification
(Zhang et al. 2014).
Inhibition of cellular energy production
Adenosine triphosphate (ATP) provides the required energy
for chemical reactions, locomotion, and cell division within
metabolism or for active transport of chemical species across
biological membranes (Poór et al. 2014). It has been found
that OTA represses the phosphate carrier proteins of the inner
mitochondrial membrane resulting in the braking of the elec-
tron transit inside the mitochondria and preventing the
succinate-supported electron-dependent activities. The mito-
chondrial respiration chain was found to be blocked and the
Environ Sci Pollut Res
ATP emission was severely affected, which was noticed as the
first deleterious effect of OTA, followed by morphological
alteration of the organelle (Poór et al. 2014). Studies have
demonstrated that this oxidative status of the cells has affected
respiratory control and oxidative phosphorylation of the iso-
lated mitochondria resulting in an alteration within the mem-
brane structure and the bioenergetics functions as well as ATP
depletion in isolated mitochondria from rat liver (Poór et al.
2014).
Lonp1 is an ATP-dependent serine protease that facilitates
some transitory regulatory proteins in the mitochondrial ma-
trix, and it is also a mitochondrial DNA–binding protein
which is mandatory for maintaining mtDNA. By studying
the possible metabolic pathways of Lonp1, which is involved
in OTA-induced renal cytotoxicity, Lonp1 expression in
HEK293 cells was downregulated via RNA interference. It
has been shown that the OTA-subjected cells have expressed
Lonp1 deficiency and have demonstrated an undesirable ef-
fect on the mitochondrial protein metabolism resulting in high
oxidative damaged proteins and a significant impact on the
mitochondrial functions (Zhang et al. 2014). Genes that are
associated with the mitochondrial electron transport chain
were upregulated within in vitro HK-2 cells culture.
Environ Sci Pollut Res
Moreover, it has been found that at the mitochondrial and
cytosolic levels, genes that are responsible for carbohydrate
metabolism function were suppressed. These are genes which
are mainly associated with glycolysis (phosphofructokinase
(PFK) and phosphoglycerate kinase (PGK1)), tricarboxylic
acid cycle (isocitrate dehydrogenases IDH3B and IDH3G),
and gluconeogenesis (phosphoenolpyruvate carboxykinase 2
(PCK2) and C/EBP beta transcription factor) and have been
highlighted in HepG2 cells, suggesting that OTA significantly
impairs the cellular energy supply (Vettorazzi et al. 2013).
Other tests have indicated that exposure of human peripheral
blood lymphocytes to OTA has generated mitochondrial dys-
function, which in turn triggered apoptosis while decreasing
the pro-survival protein Bcl-xL (Fig. 1). In fact, the toxin
incidences on mitochondrial transmembrane potential have
been evaluated and results have explained that the toxin dam-
ages the mitochondria and induces disruption of the mitochon-
drial membrane due to loss of transmembrane potential in H9
cell (Darif et al. 2016).
Induction of oxidative/nitrosative stress
Appearance of ROS within the biological system shows the
rise of oxidative stress which can also trigger the reactive
nitrogen species and cause nitrosative stress, also referred to
as the ROS/RNS pathway (Marin-Kuan et al. 2011). OTA-
exposed cells, either in vivo or in vitro, have demonstrated
excessive expression of ROS resulting in high oxidative dam-
ages. It has been shown that the male Sprague-Dawley rats’
liver exposed to OTA has significantly decreased expression
in the activity of glutathione S-transferase and in the levels of
glutathione, as well as marked increases in the concentrations
of thiobarbituric acid reactive substances which had led to
oxidant and antioxidant imbalanced status and have
underlined that oxidative stress is OTA-dependent hepatic
toxicity (Palabiyik et al. 2012; Reverberi et al. 2012).
Furthermore, it was demonstrated that the expression of in-
ducible nitric oxide synthase (iNOs) and protein nitration are
marked by exposure to OTA that gives rise to ROS/RNS
production in normal rat kidney cell line and in rat hepatocyte
cultures (Fig. 1) (Marin-Kuan et al. 2011). In fact, OTA com-
prises an aryl-ring system that couples with direct redox cy-
cling reactions that decrease ROS. Besides, this phenol-
mediated oxidative stress mechanism was suggested for
OTA as futile thiol pumping, and then it causes oxidation of
thiols and depletion of antioxidants, as OTA reduces glutathi-
one reductase levels in mammalian cell lines (Marin-Kuan
et al. 2011). These reactions resulted in decreased antioxidant
defenses and increased levels of DNA, lipid, and protein ox-
idation. Furthermore, it has been noticed that oxidative stress
associated with OTA understates cell defensive ability to an-
tioxidant and induces cytotoxicity in cells leading to oxidative
DNA damages (Table 1) (Marin-Kuan et al. 2011). The
evidence was demonstrated through the repair enzyme
formamido-pyrimidine-DNA-glycosylase (Fpg) that was
shown to cause fragmentation of DNA at different oxidized
guanine adducts allowing the detection of oxidized DNA ba-
ses, namely 8-oxo-7, 8-dihydro-20-deoxyguanosine (dOG),
which is a biomarker for oxidative damage. Moreover, it has
been highlighted that the gene which encodes detoxification,
cytoprotective, and antioxidant enzymes was also affected by
OTA exposure which has been found to be engaged in
understating the expression of genes regulated by nuclear
factor-erythroid 2 p45-related factor (Nrf2) resulting in the
reduction of the Nrf2 pathway (Pfohl-Leszkowicz and
Manderville 2011). In the same context, it has been shown
that OTA-exposed rats have expressed affection for GCLC,
GCLM, glutathione synthetase (GSS), UGT3B5, and multiple
GST isoforms genes and that OTA exposure decreases the
GSTP and GCLC protein levels (Fig. 1). These findings have
shown an mRNA degradation of Nrf2-dependent genes in rat
liver and kidney as well as in human primary proximal tubule
cells proving that OTA behaves as an Nrf2 inhibitor
(Limonciel and Jennings 2014). Similarly, it has been reported
that OTA enhances malondialdehyde (MDA) development
which is a lipid peroxidation final product and a late stage of
oxidative stress biomarker and cellular damage (Marin-Kuan
et al. 2011). OTA supplementation to in vivo and in vitro rat
liver microsomes had increased levels of ethane exhaled and
boosts enzyme NADPH-dependent enzyme via chemical
ascorbate/FeS04-dependent pathway. Furthermore, it has
been reported that NADPH metabolizes OTA into two epi-
meric hydroxyl derivatives (4S)-4-0H-OA and (4R)-4-0H-
OA, as well as into an irreversible protein reactive species.
Thus, due to the availability of the NADPH-CYP450 reduc-
tase OTAFe3+ complex, the Fe3+ could be easily reduced to
develop the OTA-Fe2+ complex which gives rise to radical
species causing DNA damage and lipid peroxidation. Lipid
peroxidation by oxygen uptake has also been indicated as a
remarkable stimulator of OTA in a system involving of phos-
pholipid vesicles, the flavoprotein NADPH-cytochrome P450
reductase, Fe3+, EDTA, and NADPH. It has also been shown
that OTA generates protein carbonyl productions which are
markers of protein oxidation. In fact, protein carbonyl concen-
tration were measured in the plasma, kidney, and liver of
OTA-treated rats with the help of 2, 4 DNPH reagent
(Sorrenti et al. 2013). Significantly higher concentrations of
protein carbonyl due to lipid peroxidation of the kidney and
liver cells have been noticed confirming that the mechanism
of OTA-mediated toxicity involves oxidative stress and this is
not only by triggering lipid peroxidation but also by affecting
proteins (Sorrenti et al. 2013). Likewise, it has been demon-
strated that the production of ROS namely the superoxide
anion (O2), hydroxyl radical (OH), and peroxide (ROO) stim-
ulates the proximal tubule cell damage in response to OTA
exposure, inducing a wide range of lesions in the cell
 Environ Sci Pollut Res

Table 1 Different studies showed oxidative stress induced by OTA

Model Exposure Dosage Aim of the study Remarks References

time

Male Sprague-Dawley 3 weeks 3, 140, 280, and Protective role of chitosan COS-NPs enhance the antioxidant (Abdel-Wahhab et al.
rats 50 mg/kg b.w nanoparticles singly effect of quercetin and protect 2017)
(COS-NPs) or plus quercetin against the nephrotoxicity of
against OTA-induced oxida- OTA in high-endemic areas.
tive stress and renal
genotoxicity
Male Sprague-Dawley 21 days 3 and 250 mg/kg Determine total phenolics and Promising protective against OTA (El-Nekeety et al.
rats DPPH radical scavenging oxidative stress and 2017)
activity of papaya fruits and nephrotoxicity
evaluation of the protective
role of these extracts against
OTA-induced oxidative dam-
age and nephrotoxicity
Piglets 30 days 0.05 mg/kg Evaluate OTA oxidative stress Inflammation and chemokines (Marin et al. 2017b)
and immune response were higher in the gut than
those in the kidney.
Male Wistar rats 21 days 0.125 and 0.250 mg/kg Oxidative stress due to OTA OTA reduced GSH in the kidney (Rašić et al. 2018)
and increased MDA in the liver
and kidney.
Genotypes mice 21 days 2.5 mg/kg OTA nephrotoxicity mechanism Downregulation of Nrf2 factor, (Loboda et al. 2017)
during HO-1 deficiency miR-29c, influence in miRNA,
induce p53-regulated miR-34a
and pro-fibrotic miR-2
Broiler chicks 60 days 1.6, 3.2, and 6.4 mg/kg OTA oxidative stress in day-old ↓ SOD, GPx, and TAS indicate (Hameed et al. 2017)
of feed chicks oxidative stress
Pig and PK15 cells – – Evaluate porcine circovirus type In vivo trial illustrated that PCV2 (Gan et al. 2018)
2 (PCV2) infection on infection aggravated
OTA-induced nephrotoxicity OTA-mediated poor growth
performance, nephrotoxicity,
p38 phosphorylation, and au-
tophagy as demonstrated by
Atg5, LC3 II, and p62 protein
expressions in the kidney of
pigs, while in vitro trial elabo-
rated that PCV2 infection sig-
nificantly aggravated
OTA-induced nephrotoxicity
as demonstrated by cell
viabilities, annexin V/PI bind-
ing and caspase 3 activities, and
induced p38 phosphorylation
and autophagy in PK15 cells.
Pig sperm 24 h 10 and 100 μM OTA Evaluate OTA for boar OTA decreased sperm motility (Zhang et al. 2018)
spermatozoa motility and via AMPK and PTEN
pathways.
Piglets 30 day 0.05 mg/kg feed Investigate the low level of OTA OTA activates immune response (Marin et al. 2017a)
has a toxic effect pathways, oxidative stress, and
carcinogenicity.
3D4/21 cell lines 48 h Aflatoxin B1 (0, 0.01, Evaluate aflatoxin B1 and OTA Both induce degradation of IκBa, (Hou et al. 2018)
0.02, 0.04, 0.08, 0.16, induced immunotoxicity the phosphorylation of nuclear
0.32, and 0.64 μg/ml) factor kappa B (p65), and the
and OTA (0, 0.1, 0.5, translocation of activated
1, 1.5, 2, 4, and nuclear factor kappa B (NF-κB)
8 μg/ml) into the nuclei.
Human peripheral blood OTA induced oxidative stress- ROS accumulation–oxidative (Liu et al. 2012)
mononuclear cells DNA damage DNA damage–G1 arrest and
(hPBMC) in vitro apoptosis
Male Sprague-Dawley 14 days 5 mg/kg/day Protective effect of lycopene Lycopene overcomes OTA (Palabiyik et al. 2013)
rats against OTA oxidative stress and apoptosis,
protective against
nephrotoxicity
HepG2 cells Zinc supplementation inhibits Zinc reduces OTA-induced DNA (Zheng et al. 2013)
OTA-induced oxidative stress strand breaks, 8-hydroxy-2′--
and DNA damage deoxyguanosine (8-OHdG)
Environ Sci Pollut Res

Table 1 (continued)

Model Exposure Dosage Aim of the study Remarks References

time

formation, and DNA hypome-

thylation. OTA increased the
mRNA expression of
metallothionein1-A (MT1A),
metallothionein2-A (MT2A),
and Cu/Zn superoxide dismut-
ase (SOD1).
Rat 28 days OTA administrated with OTA facilitates karyomegaly, cell (Taniai et al. 2014)
enzymatically modified cycle aberrations, and
isoquercitrin or α-lipoic acid apoptosis.
HepG2 cells Quercetin modulates OTA-induced calcium, ROS (Ramyaa and Padma
OTA-induced oxidative stress production, activates NF-κB. 2014)
and redox signaling. While quercetin meliorated
ROS and calcium release as
well as NF-κB induction and
expression, Nrf-2 nuclear
translocation and expression.
Quercetin’s anti-inflammatory
COX-2, prevent DNA damage
and micronucleus formation.
Rats 4 or 70 or 210 μg/kg bw Oxidative stress and renal OTA induced mRNA level of (Qi et al. 2014b)
13 wee- carcinogenicity induced by clusterin, vimentin and
ks OTA lipocalin 2
Penicillium verrucosum Penicillium verrucosum produce Citrinin regulates cAMP/PKA (Schmidt-Heydt et al.
citrinin signal transduction pathway 2015)
and compete oxidative stress in
different environmental condi-
tions.
Lymphocytes 20 μM OTA-induced cytotoxicity, OTA-induced NO, TNF-α, IL-6, (Periasamy et al.
genotoxicity, and and IL-8 were significantly re- 2016)
inflammatory response duced in the quercetin, which
revealed quercetin exerts a
cytoprotective effect against
OTA-induced oxidative stress,
genotoxicity, and inflammation
in lymphocytes.
Wistar rat liver 6 mg/kg bw Lipid peroxidation induction by Play a role in the observed toxicity (Rahimtula et al.
microsomes, kidney OTA of OTA 1988)
microsomes
Wistar rat male Gastric Every 48 h/3 weeks Protective effect of superoxide SOD + catalase prevents the (Baudrimont et al.
intuba- 289 μg/kg body dismutase (SOD) and catalase nephrotoxicity induced by 1994)
tion weight OTA in rats.
Swiss mice 48 h 2 mg/kg bw Effects of vitamins on the Vitamins E, A, and C also reduced (Grosse et al. 1997)
genotoxicity of OTA OTA-DNA adduct formation in
mice kidney.
Bacillus brevis 10 min 1 mg/mL Study free radical generation in OTA induces free radical (Hoehler et al. 1996)
bacteria as a model system production, enhancing
permeability of the cellular
membrane to Ca2+.
Sprague-Dawley liver 2.5 mM Free radical generation by OTA Oxidative damage may be one of (Hoehler et al. 1997)
microsomes, liver in hepatocytes, mitochondria, the manifestations of cellular
mitochondria, and and microsomes using electron damage in the toxicity of OTA.
hepatocytes cells paramagnetic resonance (EPR)
Bronchial epithelial 4h 10 μM Roles of cyclooxygenase and OTA is biotransformed into (Pinelli et al. 1999)
cells incubated with lipoxygenase in OTA genotoxic metabolite via a
microsomes of genotoxicity in human lipoxygenase, whereas
seminal vesicles of epithelial lung cells prostaglandin H synthetase
pig (PGHS) decreases OTA
genotoxicity.
Fischer rats 4, 8, 24, 0–2.0 mg/kg bw Chemical and biological markers Oxidative stress may contribute to (Gautier et al. 2001)
48 h induced by OTA exposure the mechanism of OTA renal
associated with oxidative toxicity and carcinogenicity in
stress rats over long term exposure.
2 years
 Environ Sci Pollut Res

Table 1 (continued)

Model Exposure Dosage Aim of the study Remarks References

time

Dark Agouti (DA), 0.4 mg/kg Life-time study to evaluate the MESNA decreased karyomegalies (Pfohl-Leszkowicz
Lewis rats bw potential protective effect of 2 in the kidney, but had no et al. 2002)
mercaptoethane sulfonate beneficial effect on renal tumor
(MESNA) and N-acetyl cyste- incidence
ine (NAC)
Dark Agouti (DA), 0.4 mg/kg Life-time Life-time study to evaluate if Lack of effect of MESNA on (Son et al. 2003)
Lewis rats bw MESNA leads to a more OTA-induced urinary tract
effective reduction of damage or renal tumor devel-
OTA-induced tumor develop- opment
ment or urinary tract damage
Proximal tubular cells 24–72 h 5.0 μM, 12.5 μM In vivo and in vitro gene In vitro and in vivo gene (Lühe et al. 2003)
(PTC), Wistar rats (in vivo in vitro; 1 and expression comparative study expression data were
and 10 mg/kg bw comparable. Response to
in vitro) oxidative stress-related genes
hypoxia-inducible factor 1 and
catalase was observed.
Human hepatoma— 1 h, 24 h 0–50 μg/mL Genotoxicity of OTA No inductions of mutations in the (Ehrlich et al. 2002)
derived cell line Ames assay, a dose-dependent
(HepG2) induction of micronuclei in the
MN assay, and DNA migration
(comet assay) were detected.
Wistar rats 10, 30, 120 μg/kg bw Kidney low dose OTA response: Low dose induces oxidative stress, (Petrik et al. 2003)
60 days sequence of events leading to apoptosis in proximal, and
cell death distal tubule kidney cells.
Primary proximal 0–24 h 0–100 μM OTA mediated oxidative stress Oxidative stress contributes to (Schaaf et al. 2002)
tubules renal (PT) response in proximal tubular tubular toxicity. Antioxidants
cells, proximal tubu- cells, oxidative stress (α-tocopherol,
lar cell line protection N-acetyl-L-cysteine (NAC))
(LLC-PK1) treatment prevents OTA toxici-
ty.
Human 24 h 0–40 μg/mL Genotoxicity of OTA Dose-dependent induction of (Knasmuller et al.
hepatoma-derived DNA single-strand breaks 2004)
cell line (HepG2) (comet assay) and micronuclei
(MN)
Fetal rat telencephalon 24–48 h, 0–20 nM Adverse effect of OTA in the Brain inflammatory response (Zurich et al. 2005)
aggregating cells 9 days brain induction of HO-1, iNOs,
PPARγ, cytoskeletal damage
Human fibroblast cells 48–72 h 0–50 μM Oxidative stress protection study Reduction of free radical species (Russo et al. 2005)
production and DNA damage
prevention by cyanin
3-O-β-D-glucoside (C3G)
Sprague-Dawley 15 days 3 mg/kg Oxidative stress protection Preventive effect against (Abdel-Wahhab et al.
in vivo study OTA-induced oxidative stress 2005)
and lipid peroxidation by mel-
atonin
Human hepatoma— 48–72 h 35–10 mM Oxidative damage protection No cytotoxicity protection (Hundhausen et al.
derived cell line study observed with Vitamine E, 2005)
(HepG2) polyphenols
F344 Fischer rats 2 weeks 0–2000 μg/kg bw Genotoxicity of OTA DNA strand breaks in target and (Mally et al. 2005)
nontarget tissues probably
involving oxidative stress
mechanism.
Human 24, 48, 0–100 μM Oxidative stress protection study OTA-induced oxidative stress (Guerra et al. 2005)
hepatoma-derived 72 h damage. Protective effect by
cell lines (HepG2), Cyanidin-3-O-β
human colonic ade- glucopyranoside (C-3-G)
nocarcinoma cell line
(Caco-2)
Rat lymphoid cells 1h 0.5, 2, 20 μM OTA immune function Protein synthesis inhibition, (Alvarez-Erviti et al.
modification oxidative metabolism of OTA, 2005)
prostaglandin synthesis
implicated in NK cells toxicity
V79 (Chinese hamster 1–24 h 2.5, 100 μmol/L OTA Cytotoxicity and oxidative DNA (Kamp et al. 2005b)
lung fibroblasts) damage already at low doses
Environ Sci Pollut Res

Table 1 (continued)

Model Exposure Dosage Aim of the study Remarks References

time

cells, CV-1 (African Relevance of OTA-induced oxi- could be a relevant factor for
green monkey, kid- dative damage in nephrotoxi- the nephrocarcinogenicity
ney) cells, primary rat city and carcinogenicity
kidneycells
F344 rats 0.03, 0.10, 0.30 mg/kg Evaluate relevance of Tumors in rat kidney may be (Kamp et al. 2005a)
bw OTA-induced oxidative dam- attributable to oxidative DNA
age on nephrotoxicity and car- damage in combination with
cinogenicity cell-specific cytotoxic and
proliferation-stimulating effects
as cell-signaling response
Wistar rats 7, 14 and 0.5 mg/kg bw Effect of OTA on protein Increased protein carbonyls in the (Rudeš 2006)
21 days oxidation in kidney and liver kidney and liver
Pig kidney microsomes, Cells: 2, 7, 0.5, 1.0, 2.5 μM Genotoxicity of the hydroquinone OTQ-mediated adduct spots form (Tozlovanu et al.
human bronchial 24 h (OTHQ) metabolite of OTA in a dose- and-time-dependent 2006)
epithelial cells, manner
human kidney cells
Wistar rats 15 days 5 ng; 0.05 mg; Effect of OTA on DNA damage Oxidative stress responsible for (Domijan et al. 2006)
0.5 mg/bw OTA-DNA damage as shown
by Fpg modified comet assay
Wistar rats 7, 14, and 0.5 mg/kg bw/day Genotoxic potential of OTA OTA-induced DNA strand breaks (Zeljezic et al. 2006)
21 days measuring DNA strand breaks were detected, OTA
(comet assay) in the kidney concentration in the kidney and
duration of the treatment
correlated with severity of the
DNA damage.
Swiss mice 24 h 10 mg/kg Immune cell response after acute OTA-induced oxidative stress (Ferrante et al. 2006)
OTA exposure response responsible for its
own toxicity
F344 rats 7 and 300 mg/kg bw OTA mechanism of Oxidative stress and metabolic (Marin-Kuan et al.
21 day- action-microarrays study in response modulated involving 2005)
s; 4, 7, liver and kidney mainly Nrf2 and HNF4α
and pathway disruption
12 mo-
nths
Swiss mice 2 weeks Acute 3.5 mg/kg; Effect of chronic low dose OTA Low doses exposure caused global (Sava et al. 2006b)
chronic 4, 8,16 mg/kg exposure on regional brain oxidative stress.
oxidative stress and stratial DA
metabolism
Swiss ICR 6, 24, 72 h 0–6 mg/kg bw Oxidative stress and OTA Acute depletion of striate DA on a (Sava et al. 2006a)
neurotoxicity background of globally
increased oxidative stress and
transient inhibition of oxidative
DNA repair.
Wistar rats 90 days 289 μg/kg bw Early effects of chronic OTA Reduction in the ability to (Gagliano et al. 2006)
administration in liver counteract oxidative stress in
liver
Eker and wild-type rats 1–14 days 210 μg/kg bw Early carcinogen-specific gene Oxidative DNA damage response (Stemmer et al. 2007)
expression study genes, general stress response,
and cell proliferation
Male Fischer 344; Rats 300 μg–100/kg bw; Demonstration of cellular defense OTA induces depletion of (Cavin et al. 2006)
primary hepatocytes; 2 years; 1.5–6.0 μM reduction by OTA antioxidant defense by
adherent proximal in vitro inhibition of Nrf2 responsible
tubules epithelial culture for oxidative stress response.
NRK cells; rat liver 24–48
RL-34 h
Human renal proximal 50–800 μM Evaluate single-strand DNA Oxidative stress precedes (Arbillaga et al.
tubular epithelial cell breaks and oxidative damage cytotoxicity and genotoxicity. 2007a)
line HK-2 induction by OTA
Human renal cell line 6 and 24 h 50 μM Mechanism of action Significant increase in ROS level (Arbillaga et al.
HK-2 study-microarrays and oxidative DNA damage 2007b)
Rats 4 weeks 289 μg/kg Oxidative stress protection study Melatonin protection against (Sutken et al. 2007)
OTA-induced oxidative dam-
age in the liver and kidney.
CoQ protective in liver
 Environ Sci Pollut Res

Table 1 (continued)

Model Exposure Dosage Aim of the study Remarks References

time

Neural stem/progenitor 0.01–100 μg/mL Vulnerability of brains mouse Robust increased in total and (Sava et al. 2007)
cells (NSCs) cells to OTA mitochondrial SOD activity.
OTA impaired hippocampus
neurogenesis.
Human epithelial 100 μM Effect of OTA on barrier function Loss of microdomains associated (Lambert et al. 2007)
colorectal impairment with tight junctions maybe due
adenocarcinoma to oxidative events
Caco-2 cells
Pig kidney cell line 24 h 0, 10, 15, 20 μM Oxidative stress protection study OTA-induced ROS. Scavenging (Costa et al. 2007)
LLC-PK1 by catechins (epigallocatechin
gallate (EGCG) and epicatechin
gallate (ECG))
Rats Sprague-Dawley 4 weeks 200 ppb Oxidative stress protection study OTA-induced oxidative stress and (Di Giacomo et al.
DNA damage chemoprotection 2007)
by cyanidin 3-O-β-D-glucoside
Chinese Hamster lung 0–438 μM OTA mutagenicity OTA is mutagenic at cytotoxic (Palma et al. 2007)
V79 cells; doses in mammalian cells via
Lymphoma mouse oxidative DNA damage
LY5178 cells induction.
Rat Wistar 15 days 5 ng/g bw 50 ng/kg bw Oxidative damage study (proteins Malondialdehyde (MDA) and (Domijan et al. 2007)
and lipids) protein carbonylation (PC) in-
crease in kidney > liver
Human hepatocytes 0–100 μM Decrease GSH No induction of heat shock protein (Hassen et al. 2007)
HepG2; Monkey (HSP)
kidney Vero cells
Rat F344 7 and 0.5 mg/kg bw Mechanism of action Oxidative stress, calcium (Arbillaga et al.
21 days study-microarrays homeostasis, cytoskeleton 2007b)
structure
Rat Sprague-Dawley 15 days 3.0 mg/kg bw Oxidative stress protection study OTA-induced oxidative stress (Abdel-Wahhab et al.
chemoprotection by Inula 2008)
crithmoides
Porcine kidney tubule 24 h 1–100 μmol/L Impact of OTA on Nrf2, AP-1 Enhanced production of ROS, (Boesch-Saadatmandi
cells LL-PK1 activity, antioxidant enzymes, GST impairment. Nrf2 and et al. 2008)
and GST AP-1 disruption by OTA.
Impairment of the detoxifica-
tion machinery
Porcine kidney tubule 6–24 h 1–100 μmol/L Characterization effect of OTA Nrf2 potential signal transduction (Boesch-Saadatmandi
cells LL-PK1 on Nrf2 response pathway by which OTA et al. 2009)
impairs its own detoxification
BALB/c macrophage 24, 48, 30 nM–100 μM OTA immunotoxicity and Induction of iNOs, COX-2, and (Ferrante et al. 2008)
J774a cell line 72 h modulation inflammatory NF-κb expression by OTA.
process OTA is an immunotoxic
compound.

components. Other studies have suggested that OTA toxicity
could be also attributed to its isocoumarin moiety propriety
while involving the lactone carbonyl group and engaging Fe2+
and Ca2+ mobilization pathways which leads to uncoupling of
oxidative phosphorylation and raising the level of hydroxyl
radical through the Fenton-like reaction while describing a
pro-oxidant behavior of the cell (Sorrenti et al. 2013; Zheng
et al. 2013). The oxidation of OTA phenol by chemical, elec-
trochemical, and photochemical processes has been found to
generate an OTA hydroquinone/quinone couple.
Hydroquinone is formed through the quinone reductions
which leads to the creation of glutathione conjugate of OTA
and consequently causes redox cycling and production of
ROS in vitro as well as in vivo. In order to verify the correla-
tion between OTA and ROS-induced oxidative brain, liver,
and kidney cell damage of OTA-treated rats, they were eval-
uated for non-proteic thiol groups (RSH), lipid hydroperoxide
(LOOH) levels, and DNA fragmentation. Alterations in
LOOH and RSH were observed confirming the oxidative
pathway involvement in the OTA-induced damages in all
the examined tissues. It has been pointed out that OTA could
generate excess NO in kidney and liver inducing iNOS and
forming the pro-oxidant ONOO− causing an increased nitrite
and nitrate levels and consequently in nitrosative stress as
shown in Table 1 (Sorrenti et al. 2013). Other studies have
revealed that HepG2 cells exposed to OTA have
Environ Sci Pollut Res
modifications in the transcription of the zinc transporter, ZnT
(SLC30), and Zip (SLC39) genes which are implicated in the
control of the intra- and intercellular zinc translocation.
Furthermore, OTA can interact directly with Zn2+ and act on
the transporter proteins and on the expression of multiple
metallothioneins which results in the depletion of the intracel-
lular Zn2+ and it induces oxidative damage. Supplementation
with the zinc chelator N,N,N′,N′-tetrakis (2-pyridylmethyl)
ethylenediamine (TPEN) strongly lessened the OTA-
mediated oxidative stress (Zheng et al. 2013).
It is well-established that OTA activation is possible due to
the production of peroxidase enzymes that adduct C8-OTA
while cytochrome p450 adduct OTA-mediated DNA using
32
P-post labeling which shows the relationship of OTA struc-
ture (Manderville and Pfohl-Leszkowicz 2008). It has shown
that OTA causes oxidative DNA damage in the outer medulla
of male rat kidney that leads to mutagenicity. Therefore, it
gives structural evidence of DNA adduction caused by OTA
which is direct genotoxicity in OTA-mediated renal carcino-
genesis (Pfohl-Leszkowicz and Manderville 2011). Among
OTA, OTBr, and OTB toxins, the highest cytotoxicity was
exhibited by OTA due to the presence of C5-Cl atom toward
direct genotoxicity in OK and WI26 cell model. These find-
ings reveal that cytotoxicity occurs due to oxidative DNA
damage while mutagenicity stems from genotoxicity
(Hadjeba-Medjdoub et al. 2012).
On the other hand, there is no significant difference in the
metabolism of OTA in the male and female rat; however, the
extent of OTA metabolism was greater in male than that in
female rats which shows that male rats are highly sensitive to
the metabolism of OTA toxicity (Tozlovanu et al. 2012). It has
been reported that OTA genotoxicity can be lessened with the
pretreatment of the model with N-acetylcysteine and 2-
mercaptoethane sulfonate which act as free thiol diminisher
in the kidney (Pfohl-Leszkowicz et al. 2002).
Apoptosis
OTA toxicity, even with relatively low doses, was found to
cause either apoptotic or necrotic cell death in accordance with
the dose and duration of exposure. Lesions’ appearance in the
plasma membrane characterizes necrosis and apoptosis that
could be generated by heat, toxins, free radicals, growth fac-
tors, and cytokines (Zhang et al. 2009). Both processes can
occur within different biological systems leading to cell death;
however, apoptosis is known to be the predominant cell ad-
aptation system that varies biochemically and morphological-
ly from necrosis. It has been suggested that the apoptotic cel-
lular mechanism is mostly trigged by OTA which induces
diverse toxic effects on several organs and leads to cell death.
Therefore, OTA toxicity leads to oxidative damage and calci-
um entry which stimulates, in vivo and in vitro, DNA alter-
ation and thereby apoptosis (Kőszegi and Poór 2016). This
process has been observed in different cell types namely kid-
ney, liver, neuronal, intestinal, gastric, renal tubule cells, de-
veloping embryos, and lymphocytes and has been associated
with the pathogenesis of many diseases. In fact, notable mor-
phological modifications could distinguish the apoptotic cells
and have been recognized in different cell lines following
chromatin aggregation, DNA fragmentation, appearance of
apoptotic bodies, apoptosis protein development, proteolysis
of apoptosis specific substrates or exposure of
phosphatidylserine on the outer layer of the cell membrane,
or some enzyme activation as well as the development of
chronic tubulointerstitial kidney damage (Kumar et al.
2014). It has been demonstrated that renal tubular lesions,
nuclear effect, and DNA fragmentation observed in HL-60
human promyelotic leukemia cells and the activation of
caspase-3 and c-Jun amino-terminal kinase (JNK) in
MDCK-C7 cells result from apoptosis significantly stimulated
by OTA exposure. Likewise, intracellular apoptotic bodies
have been found in the livers of mice and within myc
transfected cell lines following OTA intoxication (Atroshi
et al. 2000). Nephrotoxicity of this mycotoxin was reported
in humans as well as in poultry, swine, mice, rats, and rabbits,
and increased apoptotic cell percentage was observed partic-
ularly over 60 days post-exposure (Kumar et al. 2014). It has
been identified that the inhibition of p53 activation, especially
the suppression of JNK activation as well as the downregula-
tion of Bcl-xL, enhances OTA ability to stimulate apoptosis in
MARC-145, Vero monkey kidney cells, and HEK293 human
kidney cells significantly (Li et al. 2011). Furthermore, in vivo
and in vitro apoptotic changes in rat and mouse livers have
been observed as OTA hepatotoxic effects which are mediated
by the released TNF-α from Kupffer cells. OTA physiological
pro-apoptotic stimuli of TNF-α essentially involve TNFR I
receptor as well as the ActD transcriptional inhibitor as a spe-
cific cytotoxic event, although it has been found that OTA
could mediate apoptosis even in the absence of Kupffer cells
and TNF-α following a direct binding to TNFR I, which
mimic cytokine-induced apoptosis. Apoptosis outbreak im-
plies binding of TNF-α to the extracellular domain in order
to activate the intracellular domain, referred to as adaptor pro-
tein which is the cell membrane receptor TNF-α receptor I
(TNFRI) related to the death domain (TRADD). TRADD
stimulation generates the recruitment and stimulation of the
initiator aspartate specific cysteine protease caspase-8, as a
stimulator of additional apoptotic actions (Essid et al. 2012).
The mitogen-activated protein kinase kinase kinase
(MAPKKK, MAP 3K) family member apoptotic signal-
regulating kinase 1 (ASK1), which is mainly involved in cell
apoptosis, is expressed during OTA-mediated renal cytotox-
icity and apoptosis. Investigation on the regulatory mecha-
nisms of ASK1 in OTA-induced renal cytotoxicity using
RNA interference of ASK1 in HEK293 cells has shown that
ASK1 significantly promotes OTA-induced apoptosis. It has

been found that ASK1 downregulates DHRS2 expression,
which has a protective role against apoptosis, which is due
to OTA results in partially cell apoptosis (Liang et al. 2015).
Moreover, it has been demonstrated that ASK1 inhibits Prx4,
which is an antioxidant enzyme, leading to cell apoptosis as a
response to increased free-radicals, via activation of JNK. In
addition, it has been reported that cell apoptosis might be
induced by OTA via regulation of CDK1 and DHRS2 pro-
teins, which are related to cell death due to ASK1 activation
by OTA, probably as a result a cascade of activation of JNK
(Table 1). This suggested that the OTA initiates apoptosis
through multiple pathways, including mitochondrial mem-
brane potential loss, nucleotide metabolism, cell cycle check-
points, DNA repair mechanisms, lipid and lipoprotein metab-
olism, and the blockade of RNA synthesis and ASK1 is im-
plied in these metabolic pathways (Liang et al. 2015). So as to
further distinguish the impact of OTA on cell viability, cyto-
toxic activity of OTA was evaluated separately and along with
citrinin (CTN) in HepG2 cells to induce hepatotoxicity. It has
been found that OTA and CTN act in harmony in mediating
the cytotoxic effects in the HepG2 cell line and that OTA was
found to be responsible for nuclear and morphological chang-
es of apoptosis while the interaction between CTN and OTA
was greatly found to lead to apoptotic death of hepatocytes.
Besides, OTA was shown to alter the mitochondrial trans-
membrane potential, whether tested individually or in combi-
nation with CTN, indicating that mitochondria undergo
changes in nuclei after which apoptosis becomes morpholog-
ically evident through caspase-8-associated death receptor
pathway or caspase-9-associated mitochondria-mediated in-
trinsic pathway. Therefore, in both pathways, caspase-3 is
activated, following the cleavage of procaspase-3, in order to
express the cleavage of PARP protein which takes part in the
mechanism of repair of DNA and therefore apoptosis is stim-
ulated. OTA and CTN, administered separately or combined,
have been found to enhance caspase-9 cleavage expression
while disadvantaging procaspase-8 expression and caspase-8
cleavage indicating that the mycotoxins initiate the
mitochondria-mediated intrinsic pathway, which includes cas-
pase-9. Furthermore, the mycotoxins have been found to re-
duce procaspase-3 expression and to increase caspase-3 ex-
pression cleavage while significantly enhancing the
proapoptotic protein Bax and PARP cleavage expressions.
These findings have confirmed the mitochondria involvement
in apoptotic cell death induced by OTA and CTN individually
as well as in combination (Gayathri et al. 2015).
Influence on mitosis
It has been reported that OTA toxicity mediates disruption of
mitosis and generates mitotic abnormalities or aberrant exit
from mitosis without nuclear division that could generate cell
death at the level of mitosis. In fact, exposure to OTA at
Environ Sci Pollut Res
different concentrations causes DNA damages like oxidation
and strand breakage of the DNA bases that give rise to differ-
ent DNA lesions which are permanent cellular alterations
causing ultimate genomic instability and thereby harmful
transformations within the cells (Arbillaga et al. 2007a, b).
OTA-treated kidney epithelial cells of rats have shown
degenerated cells after the use of mitosis marker phospho
H3 (Ser10). Gene expressions were analyzed after OTA treat-
ment at various dose levels that can initiate tumor formation in
the kidney. Many genes were found altered such as the genes
involved in G1/S, G2, and M stages of the cell cycle including
cyclins, cyclin-dependent kinase inhibitors, cyclin-dependent
kinases, and genes responsible for the proliferation and sur-
vival of cells known as oncogenes and tumor suppressor
(Gordon et al. 2018). Other genes associated with DNA dam-
age, chromosomal instability, spindle assembly checkpoints,
aneuploidy, and poor prognosis along with growth factor
encoding genes and their receptors were altered. It is well-
established that the alteration in expression of different mitosis
regulators that are important in centrosome function, G2/M
progression, chromosome condensation and segregation,
spindle checkpoint, and cytokinesis was observed indicating
that their overexpression in the renal cells of the animal could
be the main tumor caused by OTA. Furthermore, OTA-treated
immortalized human kidney epithelial cells (IHKE) have
shown nuclear enlargement and mitotic aberrations which
confirm that OTA toxicity generates mitotic disruption
(Mally 2012). Besides, analyzing the effects of OTA on cell
division in IHKE cells has confirmed that OTA generates
aberrant condensation in mitotic chromosomes and alters core
histones phosphorylation and acetylation of sister chromatid
separation which leads to sustain mitotic arrest and exit from
mitosis without nuclear or cellular division. OTAs’ ability to
affect the enzymatic activity of those important for regulating
the posttranslational histone modifications was tested, and
loss of histone H3 phosphorylation at threonine 3 was ob-
served as well as a significant blockage of histone acetyltrans-
ferase (HAT) activity was seen in a nuclear cell extract. These
findings suggest that OTA could inhibit histones acetylation
regulator and non-histone proteins at lysine residues and have
revealed the interference of OTA on the mitotic machinery
plus a mitotic level cell cycle inhibition due to the loss of
HAT function (Czakai et al. 2011; Liu et al. 2012). While
reviewing the mechanism of action of OTA toxicity for renal
carcinogenicity, a combination of genetic instability and in-
creased proliferative changes were found as consequences of
OTA-mediated disruption of mitosis due to active trans-
porters. In vitro studies conducted on OTA-treated monkey
kidney epithelial cells and IHKE cells have shown abortive
mitosis, cell degeneration, the formation of multiple nucleated
cells, and abnormal mitotic figures (Mally 2012). Besides,
asymmetric spindles, aberrant chromosome alignment, and
highly condensed metaphases with separated chromatids were
Environ Sci Pollut Res
observed proving further that OTA inhibits sister chromatid
separation and genetic material distribution towards the
daughter cell during mitosis (Mally 2012). Other studies have
shown that OTA treatment triggers breaking of the DNA after
FPG treatment in rat’s liver and kidney and treatment of IHKE
cells proposing that the toxin blocks the metaphase/anaphase
transition and induces disruption of mitosis by showing aber-
rant mitotic figures and giant cells as well as chromosomal
instability through inhibition of microtubule assembly
(Rached et al. 2006). These findings of both in vivo and
in vitro suggested that OTA involves instability and tumori-
genesis via counteract with mitosis process during cell divi-
sion. OTA treatment mediated nuclear aberrations which ex-
hibited that OTA could influence the functionality of some
mitosis key regulators which brings to block asymmetric cell
division and to increase aneuploidy probability and therefore
tumorigenesis and acquisition of a malignant phenotype.
However, the toxin is categorized as a non-mutagenic and
non-DNA-reactive carcinogen (Pfohl-Leszkowicz and
Manderville 2011). Similarly, it has been reported that OTA
intoxication leads to the observation of karyomegaly charac-
teristics and disruption of normal mitosis via cyclin-dependent
kinase inhibitor expression as well as topoisomerase II expres-
sion (Adler et al. 2009; Mally 2012).
Induction of cell cycle arrest
The processes involved in cell signaling like inhibition of gap
junction intercellular communication (GJIC) interfere with
microtubule dynamics, and mitotic spindle formation or in-
creased histone deacetylase (HDAC) enzymatic activity has
been noticed upon OTA treatment. Undesirable effects of
OTA treatment on cell cycle arrest were studied in kidney
cells and in lung fibroblasts, and these changes were assumed
to occur in order to repair the DNA and to minimize replica-
tion and segregation of the damaged DNA due to the obser-
vation of the phenomenon prior to DNA replication (through
G1 checkpoint to S), during DNA replication, or before mito-
sis (through G2 checkpoint to mitosis) (Wen et al. 2016). It has
been reported that OTA decreases CDK4 and cyclinD1 ex-
pression in hPBMC leading to arrest the G1 cell cycle phase
due to high coordination between the cell cycle and the acti-
vation of cyclin and cyclin-dependent kinase (CDK), especial-
ly cyclinD1/CDK4/6 kinase complex which are the initiation
points to mitogenic signals in G1 phase. Furthermore, it has
been found that OTA toxicity blocks the G2 phase in immor-
talized human gastric epithelial cells (GES-1) and in Chinese
hamster lung fibroblasts (Liu et al. 2012; Chen et al. 2018a, b).
It might affect proper regulation of the cell cycle and thereby
maintain the genomic integrity as well as chromosome insta-
bility. In fact, OTA reduces the cyclinB1–Cdc2 complex
which significantly influences Cdc25C, Cdc2, and cyclinB1
expression at messenger RNA (mRNA) and protein levels
(Cui et al. 2010). This is mandatory in the G2 phase to prog-
ress to mitosis, by dephosphorylating Cdc2 and inactivating
the binding between cyclinB1 and Cdc2 which very important
for activating cyclinB1–Cdc2 complexes. Hence, inappropri-
ate inactivation of Cdc2 during mitosis leads to polyploidy
and nuclear aberrations. These findings outline that OTA is
able to dramatically obstruct cell proliferation leading to cell
apoptosis (Liu et al. 2012). Moreover, studies have reported
that OTA toxicity results in the formation of DNA adducts and
subsequent induction of apurinic/apyrimidinic (AP) endonu-
clease formation, which itself is the enzyme responsible for
DNA base excision repair pathway. It also inhibits topoisom-
erase II activity leading to disorders of the normal DNA repair.
These findings have elaborated that OTA is causing DNA
strand breaks following alterations in Rad18, Brip1, Brcc3,
and chek1 gene expression. These are DNA double-strand
break repair (DSBRs) genes. Analysis of global gene expres-
sion similarities under OTA exposure has revealed the molec-
ular changes of the upregulation of the genes which are related
to cell cycle transition and or progression to G1/S (Ccne1),
associated to the cell cycle checkpoint at G2/M (Chek1), and
involved in cell cycle arrest at G2/M phase (Wee1). Besides,
results have supported that the cell proliferation at the S3
segment was enhanced and cycle progression was suppressed
as a consequence of the cell cycle arrest at the G2/M phase.
Another study that was performed in order to highlight
nephrotoxicity-promoting molecular mechanisms of OTA
has shown that OTA induces DNA damage and S phase arrest
in human embryonic kidney cells (HEK392) following the
formation of DNA comet tails. The important expression of
γ-H2AX and the critical lower expression of cyclin A2, cyclin
E1, and CDK2 are the key cell cycle regulatory factors. In the
same context, the presumed OTA-induced G2 arrest pathways
were evaluated while exploring the oxidative DNA damage
and the ataxia telangiectasia-mutated (ATM) functions in
GES-1 cells (Hibi et al. 2013; Yang et al. 2014a). Studies have
revealed that the intracellular ROS was highly increased due
to OTA exposure, leading to DNA damage as well as en-
hanced levels of 8-OHdG and DNA double-strand breaks.
Furthermore, it has been underlined that, in response to
DNA DSBs, the toxin generates ATM protein phosphoryla-
tion and molecules Chk2 and p53 (Cui et al. 2013). In addi-
tion, investigations on OTA-induced G2 arrest modulation
have involved the MAPK pathway in GES-1 cells, taking into
account the important role MAPK plays in cell cycle progress.
Results have demonstrated that cell exposure to OTA pro-
vokes ERK inhibitor PD98059 and p38 inhibitor SB203580
activation, which are MAPK family members and remarkably
permutes Cdc25C/p-Cdc25C, Cdc2/p-Cdc2, cyclinB1, and
cyclinB1–Cdc2 complex repression. Consequently, ERK
and p38 MAPK are recognized to have a major role in
OTA-induced G2 phase arrest in human gastric epithelium

cells and could induce human gastric carcinogenesis (Wang
et al. 2012).
Other mechanisms
The harmful effects of OTA have also been associated with
organogenesis, immunosuppression, organ immune decrease,
antibody response reduction, and immune cell activity distor-
tion (Ha 2015). The mechanism of toxicity of OTA in the
organisms has revealed that low or moderate OTA addition
decreases the level of lymphocytes and macrophages as well
as modulates cytokine secretion in order to intensively affect
the mucosal immunity, which is the first obstacle for pathogen
mucosal immunity and thereby could influence susceptibility
to infectious diseases (Darif et al. 2016). For instance, in
zebrafish embryos, OTA treatment has shown improper heart
looping and heart chambers narrowing as well as a damaged
renal morphology and a decreased rate of glomerular filtra-
tion. Diminished expression of prolactin receptor a gene
(PRLRa) has also been found within these embryos, which
is indeed involved in the organogenesis and osmoregulation
within vertebrates. Beside suppressed phosphorylation of the
transcription activators (STAT5), promoting cell growth and
differentiation during development was observed in addition
to phosphorylation of the AKT, an essential protein in mam-
malian cell signaling. Furthermore, microRNA profiling has
demonstrated the upregulation of microRNA-731 (miR-731).
All these observations together have suggested that OTA tox-
icity together with miR-731 and PRLR signaling cascade
modulation distorts normal renal development in order to ex-
press negatively impacted organogenesis within zebrafish
(Wu et al. 2016). Apart from that, scientific evidence has
shown that OTA exhibits immunotoxic properties and mech-
anisms that are underlying immunotoxicity and have indicated
that the toxin adjusts immune response, even at insignificant
ranges under the toxic threshold by reducing humoral and
cellular immunity. Thus, it has been suggested that the result
of the toxin interference with cellular metabolism could lead
to immunosuppressive effects, especially after chronic expo-
sure. For instance, it has been demonstrated that OTA plasma
levels and the number of CD4+T lymphocyte population in
the oral mucosa are positively correlated, explaining that OTA
stimulates mucosal inflammation which is believed to be pro-
moting the HIV transmission to neonates by up to 11-fold in
South Africa (Darif et al. 2016). Moreover, it has been found
that supplementation of food contaminated with OTA to ani-
mals has suppressed immunoglobulin-containing cells in all
the lymphoid tissues resulting in a remarkable reduction in the
total serum immunoglobulin levels and thereby an increased
infection frequency (Dwivedi and Burns 1984). Furthermore,
it has been proved that OTA suppresses the lymphocytes’
blastogenesis by decreasing IL-2 production impairment and
IL-2 receptor expression of activated T lymphocytes. It also
Environ Sci Pollut Res
reduces the cells’ responsiveness to mitogens which simulate
within human T cells and increases the Ca 2+ release from
intracellular stores and Ca 2+ influx across the plasma mem-
branes giving rise to Ca2+ levels. The toxin has also effects on
the phagocytic function of the reticuloendothelial system by
reducing macrophages number and phagocytic activity as well
as bacteriolytic capacity and delayed immune response to tu-
berculin (Marin and Taranu 2015). Inflammation is also an-
other consequence of the toxin following the increase of vas-
cular permeability and neutrophils (PMN) infiltrating in tis-
sues and stimulation of cytokine production by immune cells.
These small peptides are vital inducers of immune and inflam-
matory responses. It has been observed that OTA eliminates
bacterial lipopolysaccharides (LPS), which act as a stimulat-
ing agent for monocytes/macrophages, production of tissue
factor (TF), and suppression of plasminogen activator
inhibitor-2 (PAI-2) response resulting in the impairment of
blood clotting activation, fibrin formation, and cell activation
(Rossiello et al. 2008). Thereby, the monocyte/macrophage
role in fibrin accumulation has been found dysfunctional caus-
ing a decreased inflammatory response and weakened cell-
mediated immune response. Moreover, the toxin and its me-
tabolites diminish the metabolic activity, proliferation, differ-
entiation, and membrane integrity of the immune cells. It pro-
vokes migration of white blood cells and immune cells to bone
marrow and hypocellularity resulting in their repression while
minimizing bone marrow macrophage-granulocyte progeni-
tors and hematopoietic stem cell number as well as erythro-
poiesis. Furthermore, it has been noticed that OTA promotes
tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6),
which trigger the narrowing of thymus, spleen, bursa, and
lymph node cells resulting in their abnormal functioning and
depletion (Asrani et al. 2016; Marin and Taranu 2015).
Evidence has demonstrated that CD69 and CD25 markers
have been expressed on the cell surface as a response to low
OTA concentrations and IL-6 has been produced in lympho-
cytes after mitogenic stimulation; however, higher amounts
block the expression of CD69, CD25, CD71, and TNF-α
production (Darif et al. 2016). Moreover, it was pointed out
that MAPK signaling pathway is involved in the mechanism
of OTA toxicity while including p38 extracellular signal-
regulated kinases (ERK) and c-Jun N-terminal kinase (JNK),
which are proteins that participate in intracellular signaling
cascades at the time of proliferation, differentiation, cellular
stress responses, and apoptosis (Table 1). A study conducted
on PK15 cells and porcine primary splenocytes has demon-
strated that OTA induced p38 and ERK1/2 phosphorylation in
both types of cells, and the results have indicated that neph-
rotoxicity due to OTA was mediated by p38 signaling path-
way and immunotoxicity by ERK signaling pathway (Gan
et al. 2017). Other OTA toxicity features have been investi-
gated and have highlighted that OTA significantly enhanced
ornithine decarboxylase activity, DNA synthesis, hyperplasia,
Environ Sci Pollut Res
and the expression of cyclin-D1 and COX-2, which are short-
term markers of skin tumor promotion, explaining that the
toxin could promote skin tumor. In fact, it has been found that
OTA cytotoxicity decreases DNA synthesis and impacts
phosphorylation and the resulting activation of epidermal
growth factor receptor (EGFR) and its subsequent signaling
pathways via Akt, ERK1/2, p38, and JNK mitogen-activated
protein kinases (MAPKs) (Fig. 1). Besides, it causes suppres-
sion of c-Jun, c-Fos, cyclin-D1, and COX-2 as well as de-
creased binding of nuclear factor-kappa B (NF-κB) and AP-
1 transcription factors to the promoter region of cyclin-D1 and
COX-2 genes. Thus, it has been suggested that OTA is able to
proliferate cells and to promote skin tumors while involving
EGFR-mediated MAPKs and Akt pathways along with
NF-κB and AP-1 transcription factors and engaging cyclin-
D1 and COX-2 as target genes to promote OTA tumor activity
(Kumar et al. 2012). Alteration of intracellular calcium ho-
meostasis due to OTA exposure has also been investigated
in relation to genes involved in the calcium homeostasis such
as chemokine (c-c motif) ligand 14 (CCL1), CD24 antigen,
ATPase AT2A2, and the protein phosphatase PP3CB.
Possible calcium homeostasis deregulation has been noticed
through inhibition of regucalcin (RGN) gene and downregu-
lation of senescence marker protein 30 (smp30). Besides, de-
pletion of intracellular calcium stores has been reported in Hep
G2 cells which had a considerable decrease in calcium influx
indicating the OTA has an inhibitory action on store-operated
Ca+2 channels. Furthermore, biotransformation features and
involvement of different transporters have been associated
with OTA toxicity. Gene expression assays have associated
OTA exposure with transporter deregulation as well as genes
related to biotransformation and detoxification processes and
have been associated with necrotic lesions observed in the
histological examinations. Enzymes such as alcohol dehydro-
genase 1, argininosuccinate lyase, glutamine synthetase,
GST’s alpha, P1 and Ya, and sulfotransferase and K2 are
altered. In addition, downregulation of genes related to trans-
porters and xenobiotic metabolism was also observed such as
organic anion transporters (OAT) or relevant CYP450s, such
as CYP2C11 (Vettorazzi et al. 2013).
Epigenetic alterations caused by OTA
OTA and DNA methylation
The emerging field of epigenetics involving the modulation of
gene functions and/or its regulation without changing the pri-
mary DNA sequence has gained significant interest in recent
years as one of the most rapidly expanding fields of biology
with massive therapeutic potential. DNA methylation is the
most researched epigenetic mechanism that most commonly
occurs by the transfer of methyl group to the 5th position on
the cytosine ring of DNA catalyzed by DNA methyltransfer-
ases (DNMTs) as shown in Fig. 2. Zheng et al. (2013) dem-
onstrated DNA hypomethylation induced by OTA treatment
in HepG2 cells for the first time. Another study reported a
time- and dose-dependent alternation of global DNA methyl-
ation profile after long-term OTA exposure (Li et al. 2015).
High-dose (210 μg/kg·bw) OTA treatment induces DNA
hypermethylation in promoters of E-cadherin, N-cadherin,
and cell adhesion–related genes of rat kidneys treated with
OTA for 13 weeks. However, observed deleterious effects
disappeared after 26 weeks of OTA treatment. This suggests
alternate DNA hyper- and hypomethylation occurrence in var-
ious anatomical or genomic loci (Li et al. 2015). Furthermore,
the mentioned study confirmed observed changes in DNA
methylation levels by alterations of DNMT enzymes, where
the expression of DNMT1 and DNMT3b mRNAs consider-
ably raised at the end of the13-week OTA exposure (Li et al.
2015). Conversely, no alterations in global DNA methylation
status were exhibited in MDCK and BME-UV1 cells after
OTA treatment in an in vitro study by Giromini et al.
(2015). Different contradictory reports on OTA-related DNA
methylation levels in kidney cells may be explained by its
heterogeneity, as it consists of many cell types that may adopt
different DNA methylation levels (Zhu et al. 2017).
OTA and histone modifications
Histones are alkaline DNA-binding proteins that facilitate the
packing of DNA into nucleosomes, which are the fundamental
subunits of chromatin. They are highly conserved and can be
grouped into 5 classes: H2A, H2B, H3, and H4 which are core
histones and H1/H5 which serves as linkers (Bhasin et al.
2006). Histones are involved in the regulation of a number
of biological processes, such as gene expression, DNA repair,
mitosis, and meiosis (Alberts et al. 2002; Bannister and
Kouzarides 2011). The interaction of histone DNA and nucle-
ar proteins can be disrupted by post-translational modifica-
tions, resulting in altered gene expression. Mentioned modifi-
cations can be acetylation, phosphorylation, methylation,
ubiquitination, SUMOylation, citrullination, and ADP-
ribosylation (Zhu et al. 2017). A recent study on the relation-
ship between ochratoxin toxicity and mitosis in immortalized
human kidney epithelial cells showed that OTA treatment
caused aberrant condensation of mitotic chromosomes and
premature sister chromatid separation, which has been related
to altered acetylation and phosphorylation of core histones.
Moreover, phosphorylation of histone 3 at threonine 3 posi-
tion (H3T3ph) has been completely lost at OTA concentra-
tions ≥ 10 μM. This is particularly important since histone 3 is
essential in chromatid cohesion and normal chromosome
alignment (Czakai et al. 2011; Dai et al. 2006). Additionally,
OTA showed no effect on the activity of Haspin kinase, which
mediates H3T3 phosphorylation, suggesting an indirect

mechanism of action. This mechanism may involve inhibition
of HAT, as it has been shown in nuclear IHKE cell extract that
OTA considerably blocked HAT activity in a dose-dependent
fashion as shown in Fig. 2. Furthermore, since HATs also
regulate posttranslational modifications of non-histone pro-
teins, OTA blocks completely the lysine acetylation of nuclear
and cytosolic proteins in IHKE cells in a dose-dependent fash-
ion. Similarly, an in vivo study in rats treated with OTA at 0,
21, 70, and 210 μg/kg bodyweight for 90 days revealed a
trend towards a decrease of lysine acetylation levels in kidney
isolated proteins (Czakai et al. 2011).
OTA and miRNA (non-coding RNA)
MicroRNAs are a class of non-coding RNAs of nearly 22-
nucleotide long made of hairpin-shaped 70 to 100 base-
pair precursors. They are important regulatory elements
that serve via targeting mRNAs for cleavage or translation-
al repression (Bartel 2004). The first report on the relation-
ship between OTA toxicity and miRNAs comes from Dai
and his co-workers who analyzed miRNA profiling in rat
kidney treated with OTA (Dai et al. 2014). They have
identified 394 miRNAs that were differentially expressed
amongst control and OTA-treated groups. Furthermore,
expression levels of Drosha and Dicer, miRNA processing
enzymes, which are required for the maturation of
miRNAs, were reduced in the rats’ kidney upon treatment
with OTA. This indicates that miRNA dysregulation might
be due to renal carcinogenesis and nephrotoxicity of OTA.
Additionally, this research has also identified eight novel
miRNAs. A study by Qi et al. (2014a) first used multi-
omics methods in the investigation of OTA-induced early
hepatotoxicity. The miRNA profiling revealed enrichment
of the MAPK signaling pathway, metabolic pathways, and
pathways in cancer after OTA treatment. Together with
mRNA and protein profiling, five of the most common
pathways affected by OTA were identified to be cysteine
and methionine metabolism, PPAR signaling, primary bile
acid biosynthesis, arginine and proline metabolism, and
metabolism of xenobiotics by cytochrome P450 (Qi et al.
2014a). In an in vitro study in HEK293 cells and HepG2
cells, OTA-treated cell miRNA profiling revealed that the
same changing miRNAs were the ones of signal transduc-
tion pathways, while the different changing miRNAs were
encompassed in human cancer pathways (Zhao et al.
2017). OTA treatment also resulted in reduced expression
levels of DGCR8, Dicer1, and Drosha enzymes.
Hennemeier et al. (2014) reported increased collagen I,
III, and IV protein concentrations with no variation in
levels of collagen mRNA expression, suggesting post-
transcriptional regulated mechanisms that could potentially
involve miRNAs in OTA-exposed HEK293 cells. Apart
from that, OTA treatment affected the distribution of
Environ Sci Pollut Res
intracellular miR-29b with decreased miR-29b amounts
in the cytoplasm. Overall, these findings suggest that
OTA may facilitate the incidence of fibrotic kidney disor-
der through post-transcriptional regulations via miR-29b
(Hennemeier et al. 2014). A study conducted on porcine
renal proximal tubular cells by Stachurska et al. (2013)
demonstrated that OTA-induced increase in the total pool
of cellular microRNAs along with elevated expression of
miR-132 and miR-200c (Fig. 2). Also, these 2 miRNA spe-
cies reversed OTA-mediated reduction of HO-1 expression
and restored ROS production and TGFβ expression. The
inhibition of miR-132 by specific antagomir retrieved
OTA-mediated reduced Nrf2 expression. A recent study
(Zhu et al. 2016) on OTA-induced hepatotoxicity and
miR-122, the most abundant miRNA in the liver, reports
findings of both in vitro and in vivo studies. miR-122
levels were found to be raised in the OTA-treated HepG2
cells and reduced in the livers of OTA-exposed rats after
4 weeks but increased back after a 13-week period.
Additionally, the relationship with apoptosis has been
studied. Briefly, miR-122 was found as the primary effec-
tor of CCNG1/p53 and Bcl-w/caspase-3 pathway in OTA-
induced hepatocytic apoptosis both in vivo and in vitro.
OTA and acetylation
The relationship between OTA-induced toxicity and acetyla-
tion has already been discussed related to histone modifica-
tions. In addition to that, here we discuss a brief supplement
focused specifically on the HAT, a group of enzymes that
catalyze lysine acetylation of histone proteins (Fig. 2). A
dose-response trend has been demonstrated in OTA-induced
repression of acetyltransferase activity in IHKE cells. This
suggests that OTAs’ mechanism of carcinogenesis may in-
volve interfering in the mitotic machinery, with HATs as the
primary cellular targets of OTA (Czakai et al. 2011).
OTA and RNA interference
RNA interference (RNAi) is a mechanism of post-
transcriptional gene silencing in which double-stranded
RNA (dsRNA) molecules neutralize the actions of targeted
mRNAs in a sequence-specific manner. siRNAs are 21- to
23-base-pair-long dsRNA molecules that recognize their ho-
mologous RNA targets, and together with associated protein
partners, they cause mRNA cleavage (Ozcan et al. 2015).
Thomas et al. (2018) studied the effect of some designed
siRNAs on the OTA producing Aspergillus nigri to examine
if the biosynthesis of OTA could be affected by certain tran-
scriptional factors. For that purpose, in silico studies were
conducted for pks gene promoter sequences and the influence
of RNA interference on OTA silencing was evaluated. It has
been shown that the treatment of fungal protoplasts with
Environ Sci Pollut Res
Fig. 2 Various epigenetic mechanisms of OTA-induced toxicity
synthetically designed siRNAs directed toward pks gene ef-
fectively silenced the production of OTA. The designed
siRNA successfully inhibited OTA production, and no effect
on the transfection efficiency has been observed at concentra-
tions between 6.3 and 50 nM. On the contrary, this case was
different from OTA inhibition where concentration consider-
ably influenced the inhibitory action of OTA in Aspergillus
carbonarius, except for pks_Ia siRNA that showed a consid-
erable effect at the concentration of 25 nM. However, a study
by Abdel-Hadi et al. (Abdel-Hadi 2011) reported the concen-
tration of 25 nM as the most effective siRNA to inhibit AflD
and AflR/AflS genes in Aspergillus flavus and Aspergillus
parasiticus. In a study by Leite (2013), 10-nM concentration
was reported as the optimum for silencing the Otapks PV
gene, while 25 nM was reported for the Tri5 gene. The differ-
ences between the studies can be explained as the individual
features of single genes, since different target genes may re-
quire different optimal siRNA concentrations. To conclude
with, successful inhibition of pks gene by siRNAs gives prom-
ise to its use as a target gene in OTA control using RNA
interference technology.
Imprinting
Genomic imprinting or silencing refers to epigenetic marks
that result in the suppression of the transcriptional activity of
certain genes depending on the parental origin. It is achieved
mostly through adding DNA methylation tags at the alleles of
imprinted genes in the specific imprinting-controlled regions.
Such imprinted expression patterns are established in the pa-
rental germ-line and are further maintained in the offspring
throughout somatic development using histone modifications,
noncoding RNAs, insulators, and higher-order chromatin
structure. Therefore, the gender of the parental germ deter-
mines the expression levels of each allele (Ferguson-Smith
2011; Wood and Oakey 2006). There are not many studies
available on the subject area that draws a connection between
OTA and imprinting epigenetic mechanisms. Correlations are
usually referred to as genetic predisposition and the possible
role of genetic imprinting in mycotoxin sensitivity and subse-
quent nephropathy, as elaborated in the study on a population
from the rural environment of West Tunisia that has been
exposed to OTA in their diet (Creppy et al. 2005). This geo-
graphic area has been considered as the high OTA contami-
nation region and even reported as an area of endemic OTA-
related nephropathy. Blood and urine tests along with HLA
fingerprinting have been used as the relevant method for the
evaluation of OTA susceptibility. The results have shown
people with HLA haplotype A3, B27/35, DR7 as the most
sensitive to the onset of chronic interstitial nephropathy, under
similar or lower OTA exposure with respect to the other sub-
jects that appeared healthy (Fig. 2). Furthermore, two more
studies by Yang et al. (2017) and Spoendlin et al. (1995) also
reported siblings with similar HLA haplotype patterns related
to OTA renal tubulopathy. It is revealed that the role of OTA

in contributing to the onset of human nephropathy could be
associated with specific genetic imprinting in diseased
individuals.
Nucleosome positioning and modification
Eukaryotic chromatin structure has a flexible and dynamic
architecture maintained through the process of nucleosome
remodeling by helicase ATPase enzymes. These modifica-
tions involve partial disassembly and repeated assembly of
nucleosomes, the exchange of histones for variants, or the
movement of histone octamers on DNA. In this way, DNA
sequences are either left accessible to interacting proteins
or packed into tightly folded structures (Becker and
Workman 2013). There are very limited numbers of stud-
ies available about the correlation between OTA and nu-
cleosome remodeling. One study reported the upregulation
of nucleosome assembly protein, which has a major role in
unpacking chromatin for DNA replication or repair. The
observed upregulation could be explained because of the
repair processes subsequent to OTA-induced DNA dam-
age (Lühe et al. 2003). Another study reported OTA-
induced dysregulation of numerous pathways such as nu-
cleosome regulation in rat renal cortex model (Jennings
et al. 2012).
Global or localized epigenetic interaction of OTA
There is not much data available on differences between glob-
al and localized epigenetic patterns related to OTA. However,
the results of numerous recent studies have revealed that the
carcinogenic effects induced by OTA do not follow a classical
carcinogenesis model but involve a complex network of cel-
lular alterations including epigenetic modifications. It might
be speculated that OTA exhibits effects on global epigenetic
patterns via the RAS gene (Ozden et al. 2015; Wu and
Brenner 2014; Gazin et al. 2007; Wajapeyee et al. 2013;
Serra et al. 2014).
Gene silencing
Gene silencing refers to epigenetic regulation of the genes to
prevent its expression, either at the transcriptional or at the
translational level. It is achieved through the aforementioned
mechanisms of DNA methylation, histone modification, and
RNAi (Nephew and Huang 2003). A study by Marin-Kuan
et al. (2007) evaluated the influences of OTA on histone
deacetylases (HDACs), a group of enzymes involved in gene
silencing. With regard to OTA nephron-carcinogenicity, an
increased HDAC enzymatic activity and elevated HDAC3
protein expression have been observed (Fig. 2). These find-
ings were particularly relevant since HDAC-induced gene
Environ Sci Pollut Res
silencing has been demonstrated to contribute to the process
of tumor development.
OTA may lead to Alzheimer’s disease
It has been recognized that OTA toxicity can lead to AD
progression. Moreover, the neurotoxicity of OTA has been
confirmed by brain examinations (Belmadani et al. 1998a;
Sava et al. 2006a). Different levels of OTA in rodents’ brains
propose that it can actively cross the blood-brain barrier
(BBB) and accumulates inside the brain following a dose of
OTA in mice. Higher level of OTA was observed in the cer-
ebellum, pons, and cerebral cortex regions of the brain
(Belmadani et al. 1998b; Sava et al. 2006a, 2006b) as well
as in the ventral mesencephalon, striatum, and hippocampus.
Nevertheless, moderately high levels of OTA were present in
the hippocampus, an essential site of neurodegeneration in
AD (Belmadani et al. 1998b). AD is a neurodegenerative dis-
ease that has features indicating its progression such as hered-
itary predisposition, gender, hypertension, head injury, and
chemical exposures which are manifested by changes in the
brain regions like entorhinal zone and neocortex and by ex-
plicit arrangements of subcortical cores and amygdale hippo-
campus. Various research works showed the p38 mitogen-
initiated protein kinase (MAPK) is responsible for the pro-
gression of AD and inhibition of p38 MAPK has an amelio-
rative effect on dementia due to neurodegeneration (Kim and
Choi 2010; Zlokovic 2011). Different investigations discover
the crucial mechanisms of AD which is correlated with p38
MAPK actions, for example, synaptic plasticity,
excitotoxicity, and tau phosphorylation (Munoz and Ammit
2010; Wang et al. 2014).
Brain-derived neurotrophic factor (BDNF) abnormal ex-
pression in the brain leads to various disorders such as neuro-
psychiatric and neurodegenerative disorders (Berton et al.
2006). A number of researches have revealed shreds of evi-
dence on neurological disorders such as AD, Huntington’s
disease, Parkinson’s disease (PD), and schizophrenia brought
about by diminishing in the expression of BDNF which leads
to oxidative stress and apoptotic assault (Murer et al. 2001;
Caccamo et al. 2010). Thus, the effect of OTA on BDNF
expression revealed that treatment with OTA diminished ex-
pression of BDNF in a dose-dependent way. Likewise, OTAs’
impact on TH expression was additionally examined and it
was also considerably reduced in a dose-dependent way.
The mentioned outcomes reinforce prior research results,
which have also reported treating with OTA ameliorates TH
immunoreactivity in the fibers of the striatum, corpus striatum,
and substantia nigra by upregulating the oxidative stress and
lipid peroxidation with temporary limitation of oxidative
DNA repair activity. As a result, a decrease in the level of
striatal dopamine and its metabolites occurs (Torack and
Environ Sci Pollut Res
Morris 1992; Kastner et al. 1993). Studies have examined at
all stages in AD the expression of p38-MAPK, JNKs, and
ERKs and found that their expression causes the progression
of neurodegenerative disorders (Liu et al. 2007; Wang et al.
2014).
After OTA administration, caspase-3 and 9 were activated.
Moreover, neurotoxicity due to OTA was compelled by cas-
pase inhibitors. Programmed cell death caused by OTA oc-
curred due to lost mitochondria membrane potential. In gen-
eral, present information showed neurotoxicity of OTA is
demonstrated even in moderately low doses. OTA initiated
neurotoxicity which is mediated by apoptosis. OTA might
also be utilized for the pathogenesis of neurodegenerative dis-
orders (for example AD and PD) where apoptotic progres-
sions are mainly included. In general, current information
shows that OTA prompts apoptosis in both the SH-SY5Y
cells and the essential neurons. Numerous neurodegenerative
disorders like AD and PD are identified with neuronal cell
death and low regenerative capability of the CNS tissue
(Bhat et al. 2016; Friedlander 2003). It has been well-
established that OTA leads to ERK-1/2 phosphorylation in a
MAPK-dependent way while JNK-1/2 was unchanged which
caused nephropathy in human proximal tubule-derived cells
(Schulz et al. 2018). It is of significance to limit the potential
harm brought about by OTA and other mycotoxins, due to a
decrease in their event in the food chain.
Strategies to lessen OTA toxicity
European food safety authority has listed more prominent
compounds that are harmful to humans as well as for agro-
economic sectors including aflatoxins, fumonisins, trichothe-
cene, zearalenone, and OTA (EFSA 2004; Streit et al. 2012;
Wielogórska et al. 2016). It has been revealed that OTA is
involved in human kidney disease propagation such as
Balkan endemic nephropathy (BEN) which was diagnosed
with an elevated level of OTA with focal segmental
glomerulosclerosis (FSGS). This study illustrated that patients
with a history of water-damaged buildings had high levels of
mold and dietary history, since mycotoxins were observed in
the urine and other tissue samples that contribute towards the
main illness (Hooper et al. 2009; Hope and Hope 2012). It is
evident that the presence of indoor water damage and a higher
level of OTA would be avoided for further exposure to people
living in that place. Various epigenetic mechanisms of OTA
have a vital role in the progression of oxidative stress,
genotoxicity, carcinogenicity, and nephrotoxicity.
Sometimes higher level of OTA leads to kidney chronic dis-
ease which should be kept in mind as during kidney transplan-
tation as it persists at the time of transplantation (Chen and Wu
2017; Pfohl-Leszkowicz and Manderville 2007; Tao et al.
2018). For the therapeutic approach to reverse OTA
alterations, different adsorbents (yeast-based products, OTA,
T-2 binders, modified zeolite, esterified glucomannans, mixed
organic and inorganic compounds with enzymes, and Bacillus
amyloliquefaciens ASAG1) are used to protect the gastroin-
testinal tract from the absorbing the OTA. However, long-
term use of these agents leads to specific and non-specific
problems (Chang et al. 2015; Garcia et al. 2003; Pfohl-
Leszkowicz et al. 2015; Trailović et al. 2013). It is being
well-established that certain physical conditions and chemical
and biological agents’ applications lead to reduce and/or pre-
vent OTA-induced toxicity in human and animal products as
shown in Tables 2 and 3. The use of household meat process
methods such as cooking, frying, roasting, and baking reduces
OTA level in meat sausage which depends on the processing
modality used (Pleadin et al. 2014). In another study, it has
been explored that cholestyramine has the potential to bind
with OTA in addition to resin and bile acid which prevent
its absorption, leading to eliminate via feces and reduce the
chances of enterohepatic circulation of OTA (Kerkadi et al.
1999; Madhyastha et al. 1992). Utilization of sodium bicar-
bonate (NaHCO3) helps in OTA ionization, inhibiting its gas-
trointestinal absorption and enhancing elimination via urine
(Yong et al. 1987). However, long-term use of both cholestyr-
amine and NaHCO3 is not recommended. As the side effects
are mainly related to gastrointestinal tract disorders, it is dif-
ficult to use cholestyramine as therapy and increase fat-
soluble vitamins timing. Most of the patients have the capacity
to tolerate pure resin instead of market available resin mixed
with sugar, artificial color, and other additives (Kőszegi and
Poór 2016). Kidney disease patients also suffer from hyper-
lipidemia, so the use of cholestyramine has a role in lowering
the lipid. It has been reported that the long-term usage of
cyanidin 3-O-β-D-glucoside (C3G) has demonstrated to
counter the noxious effect of OTA through possible
dimethylarginine dimethylaminohydrolase/nitric oxide syn-
thase pathway (Sorrenti et al. 2012). Studies on sweat have
revealed that the presence of sauna leads to an increase in the
excretion of OTA (Hope and Hope 2012). The use of L-me-
thionine, phenylalanine, and phenobarbital is suggested to
protect against the developmental toxicity and reduce the me-
tabolism of OTA which cause a reduction in OTA toxicity
(Kayoko et al. 1985; Abdel-Wahhab et al. 1999). A number
of studies revealed that aspartame works for the delivery of
phenylalanine by cleavage with the peptide and has an effect
on the binding property and transport of toxin (Baudrimont
et al. 1997; Creppy et al. 1996, 1998; Creppy et al. 1980;
Kayoko et al. 1985). A number of researches indicated that
clay and zeolite both have the efficacy to bind with mycotoxin
in animals and they are also useful in human disorders caused
by OTA (Piva and Galvano 1999; Whitlow 2006). The use of
licorice and melatonin is also safe to apply in cases of ochra-
toxin toxicity (Abdel-Wahhab et al. 2005; Malekinejad et al.
2011; Hope and Hope 2012). The use of superoxide dismutase
 Environ Sci Pollut Res

Table 2 OTA reduction via physical conditions and chemical agents

Origin of OTA Conditions Decline in OTA content (%) References

Physical parameters
Inoculation 180 °C, 10 min 31.1 (Nehad et al. 2005)
Inoculation 175–204 °C, 7–9 min > 90 (Romani et al. 2003)
Inoculation 200–220 °C, 10–15 min 22.5–93.9 (Barcelo and Barcelo 2018)
Inoculation 180–240 °C, 5–12 min 8–98 (Ferraz et al. 2010)
Natural Dark to light 69–96 (Van der Stegen et al. 2001)
Natural 200 °C, 3 min 65–100 (La Pera et al. 2008)
Natural Industrial roasting 66.5 (Perez de Obanos et al. 2005)
Chemical agents
Natural Alkaline hydrogen peroxide and calcium hydroxide – (Karlovsky et al. 2016)
Natural Sodium hydroxide and calcium hydroxide – (Milani and Maleki 2014)
Natural Monomethylamine and calcium hydroxide – (Scott 1996)
Natural Ammonium and calcium hydroxide – (Karlovsky et al. 2016)
Natural Ethyl acetate and 2% formic acid 80 (Boone 2017)
Natural Dichloromethane and 2% formic acid 80 (Bortoli and Fabian 2001)
Natural Methylene chloride and 2% formic acid 80 (Bortoli and Fabian 2001)
Natural Alkaline treatment 98 (Amezqueta et al. 2008)
Natural Ozonization (O3), 10 wt.% and 15 s – (Scott 1996)
Inoculation Formic acid, 0.25–1% – (Varga et al. 2010)
Inoculation Propionic acid, 0.25–1% – (Varga et al. 2010)
Inoculation Sorbic acid, 0.25–1% – (Varga et al. 2010)
Inoculation Sodium hypochlorite, 0.25–1% – (Scott 1996)
Inoculation Alkaline hydrogen peroxide, 0.05–0.1% – (Aiko and Mehta 2015)

and catalase enzymes and/or the support of glutathione system
by NAC are likely to be potential agents which possess anti-
oxidants and detoxification effects (Cui et al. 2013; Liu et al.
2012; Pfohl-Leszkowicz et al. 2002; Yang et al. 2014b).
Some of the in vitro and in vivo models illustrated that
vitamins A, C, and E are also successful candidates for reduc-
ing OTA-induced cytotoxicity and genotoxicity (Baldi et al.
2004; Fusi et al. 2010; Fusi et al. 2008; Grosse et al. 1997;
Hoehler and Marquardt 1996; Hundhausen et al. 2005;
Kumari and Sinha 1994). The use of flavonoids and polyphe-
nols has a positive effect on OTA-exposed cells. These com-
pounds reverse the toxic effects through the presence of anti-
oxidant activities that work as superoxide anion scavengers
(Bakr Abdu 2011; Hundhausen et al. 2005; Poór et al. 2012;
Sorrenti et al. 2013). Utilizing drugs such as piroxicam which
is a nonsteroidal anti-inflammatory drug (NSAID) specially
used for arthritis has also a role in binding with plasma pro-
teins that prevent OTA binding and transport to target organs;
however, large doses might lead to nephrotoxicity
(Baudrimont et al. 1995). Two important catechins—
epigallocatechin gallate (EGCG) and epicatechin gallate
(ECG)—have the potential role in inhibiting ROS and DNA
fragmentation along with the enhancement of proliferation
rate (Costa et al. 2007). Rosmarinic acid and gallic acid have
the ability to decrease ROS production, protein, DNA synthe-
sis, and cell death caused by OTA and aflatoxin B1 (Renzulli
et al. 2004). Cyanidin-3-0-β-glucopyranoside, which is a nat-
ural free-radical scavenger, lead to a reduction in DNA frag-
mentation and inhibition of caspase-3 activation and DNA and
protein synthesis caused by OTA in a human hepatoma cell
line and human colonic adenocarcinoma cell line (Di
Giacomo et al. 2007; Guerra et al. 2005; Russo et al. 2005).
Ellagic acid and silybin have shown anti-apoptotic, anti-oxi-
dant, anti-diabetic, and antimicrobial activities in the isolated
pancreatic islets. The results showed that dietary polyphenols
significantly inhibit LPO and DNA protective effect in islet
cells exposed to free radical due to oxidative stress. The anti-
apoptotic effect of ellagic acid and silybin is related to Bcl2
independent mechanisms. They both have also a hepatopro-
tective and anti-apoptotic role in the OTA toxicity. Also, lactic
acid–producing bacteria degrade OTA and reduce its cytotox-
ic effects (Essid and Petzinger 2011; Luz et al. 2018;
Sepúlveda et al. 2011). Flavonoid such as diosmetin increase
ATP levels in kidney cells and relieve ATP depletion–induced
OTA toxicity. Polyphenols such as luteolin, chlorogenic acid,
and caffeine have shown a protective role through the
Environ Sci Pollut Res

Table 3 OTA reduction via biological agents

Biological agents used to reduce OTA References

Carboxypeptidase A (Hu et al. 2018; Luz et al. 2018)

Commercial proteases (pancreatin from porcine pancreas, protease A, and Prolyve PAC from (Abrunhosa et al. 2006)
Aspergillus niger)
Commercial hydrolases (Amano A, crude lipase preparation from Aspergillus niger) (Zhang et al. 2017)
Aspergillus niger hydrolytic metalloenzyme (Zhang et al. 2017)
Rumen microbes (Cho et al. 2016)
Bacillus subtilis, Bacillus licheniformis (Böhm et al. 2000; Petchkongkaew et al. 2008)
Nocardia corynebacterioides, Rhodococcus erythropolis, Mycobacterium sp. (Holzapfel et al. 2002)
Lactobacillus sp. (Fuchs et al. 2008; Piotrowska and Żakowska
2000)
Eubacterium callenderi, E. ramulus, Streptococcus pleomorphus, Lactobacillus vitullinus, (Schatzmayr et al. 2002; Schatzmayr et al. 2006)
Sphingomonas paucimobilis, S. saccharolytica, Stenotrophomonas nitritreducens, Ralstonia
eutropha, R. basilensis, Ochrobactrum sp., Agrobacterium sp.
Pseudomonas cepacia, Pseudomonas putida, Rhodococcus erythropolis, Agrobacterium (Schatzmayr et al. 2012)
tumefaciens, Comamonas acidovorans
Protozoa (Gallo et al. 2015; Özpinar et al. 2002)
Aspergillus niger, Aspergillus fumigatus (Cho et al. 2016)
Aspergillus niger, Aspergillus versicolor, Aspergillus wentii, Aspergillus ochraceus (De Bellis et al. 2015; Zhang et al. 2016)
Aspergillus niger, Aspergillus japonicus (Bejaoui et al. 2006)
Pleurotus ostreatus (Chen et al. 2018; Engelhardt 2002)
Saccharomyces cerevisiae (Piotrowska and Żakowska 2000)
Saccharomyces cerevisiae, Saccharomyces bayanus (Bizaj et al. 2016)
Rhizopus stolonifer, R. microsporus, R. homothallicus, R. oryzae (Varga et al. 2005)
Trichosporon mycotoxinivorans (Molnar et al. 2004)
Phaffia rhodozyma, Xanthophyllomyces dendrorhous (Péteri et al. 2007)
Saccharomyces cerevisiae, Kloeckera apiculata (Angioni et al. 2007)
Aureobasidium pullulans (De Felice et al. 2008)
Cryptococcus flavus, Cryptococcus laurentii, Cryptococcus curvatus, Cryptococcus humicolus, (Peromingo et al. 2018; Schatzmayr et al. 2012;
Trichosporon ovoides, Trichosporon dulcitum, Trichosporon guehoae, Trichosporon mucoides, Schatzmayr et al. 2003)
Trichosporon coremiiforme, Trichosporon cutaneum, Trichosporon laibachii, Trichosporon
moniliforme, Rhodotorula mucilaginosa, Rhodotorula fujisanensis

amelioration of OTA-induced DNA toxicity of the brain and
blood cells of BALB/c mice. However, chlorogenic acid had
shown the best protective effect (Cariddi et al. 2015; Poór et al.
2014). The most vital role of quercetin is the modulation of
Nrf2 signaling cascade which inhibits OTA-mediated apopto-
sis, DNA fragmentation, inhibition of caspase signals activa-
tion, and micronucleus formation (Abdel-Wahhab et al. 2017;
Abdel-Wahhab et al. 2016; De Oliveira et al. 2016; Nabavi
et al. 2016; Ramyaa and Padma 2013; Ramyaa and Padma
2014). Quercetin also downregulates NF-κB and COX-2.
The use of carotenoid lycopene decreases OTA-mediated ap-
optosis, DNA damage, and oxidative stress. Several studies
showed that certain plants have beneficial effects on OTA
cytotoxicity and genotoxicity (Abdel-Wahhab et al. 2008;
Aydin et al. 2013; Chakraborty and Verma 2010; Palabiyik
et al. 2013). The use of zinc and selenium supplementation
has a vital role in most of the cofactors and enzymes for normal
physiological activities. Both minerals alleviate OTA-
mediated DNA toxicity by improving the expression of sele-
nium involved in enzymatic activity (Gan et al. 2015; Zheng
et al. 2013). The presence of all data regarding the therapeutic
remedies for OTA genotoxicity, carcinogenicity, oxidative
stress, apoptosis, and nephrotoxicity in human cell lines and
animal models illustrated that the above-mentioned agents
would be useful. So, all possible short- and long-term OTA
toxicity can be prevented by the use of such agents in the near
future, to reduce and eliminate OTA from target cells or
bodies.
Conclusion
It is concluded that OTA has several genotoxic and epigenetic
mechanisms leading to cellular and molecular aberrations. It

causes oxidative stress, DNA damage, carcinogenicity, and
nephrotoxicity involving different mechanisms. These mech-
anisms (p38 MAPK, JNKs, and ERKs dysfunctions, BDNF
disruption, TH overexpression, caspase-3 and -9 activation,
and ERK-1/2 phosphorylation) of OTA also lead to AD pro-
gression. On the other hand, the promising objective of this
review is to treat and disrupt the normal toxicokinetics of OTA
such as the prevention of cellular uptake and increasing its
elimination from the body. So, the above-mentioned natural,
synthetic, and semisynthetic agents shown in Table 2 are ca-
pable to reverse and prevent OTA-induced toxicity via differ-
ent mechanisms. The use of mentioned phytochemicals,
drugs, and trace elements are recommended to attenuate
OTA-mediated effects; however, still, it is the need of this
new era to run in vivo and in vitro studies to understand the
exact mechanisms in order to know how these physical con-
ditions, chemical and biologically active enzymes, microbes,
and/or proteins decline OTA-induced toxicity.
Acknowledgments The authors wish to thank and acknowledge their
respective universities and institutes.
Authors’ contributions KN gave the idea and prepared the outlines and
draft of the manuscript. SA, SZAS, FK, and MB designed the figures
along with comprehensive tables along with critical editing and reviewing
of the whole manuscript. All the authors have read and approved the final
version.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
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