SD Article 3

ARTICLE IN PRESS
Journal of Trace Elements in Medicine and Biology ] (]]]]) ]]]–]]]

www.elsevier.de/jtemb
REVIEW
Metals and apoptosis: Recent developments
Suresh Vir Singh Rana
Toxicology Laboratory, Department of Zoology, Ch. Charan Singh University, Meerut 250004, India
Received 20 February 2007; accepted 11 July 2008
Abstract
Apoptosis, also known as programmed cell death is a highly regulated and crucial process found in all multicellular
organisms. It is not only implicated in regulatory mechanisms of cells, but has been attributed to a number of diseases,
i.e. inflammation, malignancy, autoimmunity and neurodegeneration. A variety of toxins can induce apoptosis.
Carcinogenic transition metals, viz. cadmium, chromium and nickel promote apoptosis along with DNA base
modifications, strand breaks and rearrangements. Generation of reactive oxygen species, accumulation of Ca2+,
upregulation of caspase-3, down regulation of bcl-2, and deficiency of p-53 lead to arsenic-induced apoptosis. In the
case of cadmium, metallothionein expression determines the choice between apoptosis and necrosis. Reactive oxygen
species (ROS) and p53 contribute in apoptosis caused by chromium. Immuno suppressive mechanisms contribute in
lead-induced apoptosis whereas in the case of mercury, p38 mediated caspase activation regulate apoptosis. Nickel kills
the cells by apoptotic pathways. Copper induces apoptosis by p53 dependent and independent pathways. Beryllium
stimulates the formation of ROS that play a role in Be-induced macrophage apoptosis. Selenium induces apoptosis by
producing superoxide that activates p53. Thus, disorders of apoptosis may play a critical role in some of the most
debilitating metal-induced afflictions including hepatotoxicity, renal toxicity, neurotoxicity, autoimmunity and
carcinogenesis. An understanding of metal-induced apoptosis will be helpful in the development of preventive
molecular strategies.
r 2008 Elsevier GmbH. All rights reserved.
Keywords: Metals; Metalloids; Apoptosis; Cell proliferation; Carcinogenicity
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Arsenic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Arsenic toxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Apoptosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Molecular mechanisms of toxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Beryllium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Beryllium toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Apoptosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Tel./fax: +91 121 2774569.

E-mail addresses: sureshvs_rana@yahoo.com, sureshvs.rana@gmail.com (S.V.S. Rana).
0946-672X/$ - see front matter r 2008 Elsevier GmbH. All rights reserved.
doi:10.1016/j.jtemb.2008.08.002
Please cite this article as: Rana SVS. Metals and apoptosis: Recent developments. J Trace Elements Med Biol (2008), doi:10.1016/
j.jtemb.2008.08.002
ARTICLE IN PRESS
2 S.V.S. Rana / Journal of Trace Elements in Medicine and Biology ] (]]]]) ]]]–]]]
Cadmium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Cadmium toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Apoptosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Chromium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Chromium toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Apoptosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Copper . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Copper toxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Apoptosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Lead. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Apoptosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Mercury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Apoptosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Nickel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Nickel toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Apoptosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Selenium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Combined toxicity of heavy metals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Introduction Apoptosis is considered as an ongoing normal event

in the control of cell populations. However, apoptosis
Metals have been used by man since antiquity. can also be induced by a variety of xenobiotics including
Anthropogenic uses have led to global dispersion of many of the toxic metals resulting in the loss of affected
metals in the environment. Man, animals and plants are cell populations. Apoptosis essentially occurs when
exposed to a variety of metals through environment, cellular damage, including damage to genetic material,
food, water and soil. Metals being non-biodegradable has exceeded the capacity for repair (Fig. 1). Environ-
persist in the environment for a long period and cause mental metals can impair apoptosis and that suppres-
serious ecotoxicological problems. Additionally, many sion of the apoptotic response could facilitate aberrant
metallic compounds like zinc, copper, calcium, trivalent cell accumulation, which may be a critical step in the
chromium, and iron being essential to life have formed pathogenesis of malignancy or autoimmunity. One of
complex bio-geochemical cycles. Essential elements are the first genes shown to regulate apoptosis was Bcl-2.
involved in a variety of critical functions including Subsequently, a number of Bcl-2 related proteins were
control of gene transcription, nerve conductance, oxy- identified. Despite overwhelming evidence that Bcl-2
gen transport and as active centers in enzymes. There- proteins are evolutionarily conserved regulators of
fore, critical molecular events within the cell such as apoptosis, their precise biochemical function remains
gene expression, cell proliferation and cell death are controversial. There have been a multitude of reports
affected by trace elements. Some toxic metals may showing that enforced overexpression of Bcl-2 or of Bcl-
mimic the essential metals and thereby gain access to XL acts to delay the onset of apoptosis induced by
important molecular targets. It is clear that toxic metals toxicants. The vast majority of these reports concentrate
can both activate and inactivate cellular processes on apoptosis induced by DNA-damaging agents in
controlled by the essential metals. Even essential metals cancer cell lines and conclude that Bcl-2 or Bcl-XL
can be toxic. A few of the environmental metals, i.e. renders the cells drug resistant.
arsenic, chromium are carcinogenic [1]. Defining a Programmed cell death is a highly regulated but
mechanism of metal carcinogenesis is critical for human double-edged sword—it is crucial to developmental
health risk assessment. For many metals, aberrant cell processes in multicellular organisms but loss of regula-
proliferation, including alterations in apoptosis is an tory control is implicated in a growing number of
attractive aspect of a hypothetical mechanism of cancer diseases, including inflammation, malignancy, autoim-
induction. munity and neurodegeneration. Apoptosis-related genes
j.jtemb.2008.08.002
ARTICLE IN PRESS
S.V.S. Rana / Journal of Trace Elements in Medicine and Biology ] (]]]]) ]]]–]]] 3
well as impairment in carcinogenicity and development.

In addition, nicotine and alcohol perturb apoptosis and
are closely tied to the development of lung and liver
cancers. Although apoptosis is modulated by these
compounds, the molecular mechanisms that underpin
the changes remain unknown.
Metal-induced disorders of cell accumulation were
first discussed in a symposium held in 1999 at Louisville
(Kentucky) during the annual meeting of Society of
Toxicology. Metal-induced apoptotic mechanisms were
also reviewed by Pulido and Parrish [2]. Role of
oxidative stress and apoptosis in metal-induced carci-
nogenesis was also reviewed by Shi et al. [3]. Genetic and
epigenetic mechanisms in metal carcinogenesis and co-
carcinogenesis with special reference to arsenic, chro-
mium and nickel were discussed by Salnikow and
Zhitkovich [4]. The purpose of this review is to
summarize current understanding of the apoptotic
Fig. 1. An overview of the apoptotic pathway with arrows pathways initiated by toxic as well as essential metals.
(-) representing activation and circles (K) representing Characterization of apoptosis-related genes might be
inhibition. Interestingly, apoptosis mediated by death recep- helpful in pharmacological intervention in metal-in-
tors (FasL, TNF) and by the loss of survival factors use diverse duced pathologies.
signaling pathways, however a convergence between these two
pathways is seen at the mitochondria [2].
Arsenic
have been identified in most tissues and successful
Arsenic in the environment occurs in both organic
characterization of such genes presents potential targets
and inorganic forms, i.e. in its trivalent or pentavalent
for specific pharmacological intervention in a wide range
state. Absorbed arsenic, irrespective of from, is widely
of diseases. Many pathological conditions can be
distributed in the body. Arsenic poisoning among
attributed directly or indirectly to defects in the
industrial workers is characterized by perforation of
regulation of apoptosis that result in either a cell
the nasal septum, skin changes, and peripheral neuritis.
accumulation, in which cell eradication or cell turnover
There is substantial epidemiological evidence of an
is impaired, or cell loss, in which the cell-suicide
excessive risk of lung cancer among workers exposed to
program is inappropriately triggered. Identification of
arsenic. Arsine gas is a powerful hemolytic poison
the genes and gene products that are responsible for
encountered under some industrial conditions. The
apoptosis, together with emerging information about
literature on toxicology and environmental aspects of
the mechanisms of action and structures of apoptotic
arsenicals has recently been reviewed by the World
regulatory and effector proteins, has laid a foundation
Health Organization [5], and International Agency for
for the discovery of drugs, some of which are now
Research on Cancer (IARC) [6,7].
undergoing evaluation in human clinical trials. It is now
increasingly accepted that part of the efficacy of
conventional chemotherapeutic drugs is due to their Arsenic toxicity
ability to induce apoptosis with the aim of providing
death signals and abrogating survival signals. There is a Inhibition of mitochondrial respiration supported by
wide range of novel approaches to the induction of NAD-linked substrates that use the lipoic acid cofactor
apoptosis by down regulating survival signaling along for the pyruvate dehydrogenase complex is regarded as a
with many alternative strategies aimed at targeting primary mechanism by which arsenicals manifest cell
particular molecular abnormalities of neoplastic cells as injury/cell death and cancer [8]. Inorganic arsenicals
a means of inducing apoptosis (Fig. 1). produce oxidative stress by inhibiting mitochondrial
A number of toxicants can alter the rate of apoptosis. respiration, reactive oxygen species (ROS) generation
For example, the carcinogenic transition metals, chro- which may cause DNA mutations and development of
mium, cadmium and nickel are capable of causing an cancer [9]. Moreover, arsenicals are known to induce a
increase in apoptosis along with DNA base modifica- number of major stress protein families. ROS are known
tions, strand breaks and rearrangements. The polycyclic to induce SH-rich proteins metallothionein (MT) which
aromatic hydrocarbons (PAHs) also cause apoptosis as has antioxidative properties [10]. Alteration of nitric
j.jtemb.2008.08.002
ARTICLE IN PRESS
oxide synthetase (eNOS) has been correlated with inhibitor Ro-31-8220 partially blocked As2O3 mediated
‘‘black foot disease’’. apoptosis, meaning thereby that As2O3 might signal
apoptosis through PKC activation.
Considerable attention has been paid to arsenic-
Apoptosis induced apoptosis in carcinoma of different organs
[20]. Arsenic trioxide was found to inhibit the growth of
Apoptosis induced by arsenic (As) have been paid human ovarian carcinoma cell line SKOV3 [21]. The
considerable attention in the past however, present effects on cell proliferation and apoptotic parameters
review describes only the recent reports. During last 3 were examined. They could not attribute these changes
years, new and highly relevant information on arsenic- to apoptosis. Single cell electrophoresis (comet assay)
induced apoptosis has been gathered. Generation of was used to measure arsenic-induced genotoxic and
ROS, accumulation of Ca2+, upregulation of caspase-3, cytotoxic effects in human keratinocytes, melanocytes
down regulation of Bcl-2, deficiency of p53 are, in nut and dendritic cells. Chronically exposed dendritic cells
shell, the events that collectively lead to apoptosis showed the maximum genotoxic damage while melano-
during arsenic toxicity. There exists a general consensus cytes were more sensitive to arsenic cytotoxicity [22].
that As causes oxidative stress. Therefore, role of Apoptosis in gall bladder carcinoma was also studied
oxidative stress and associated biochemical events in [23]. As2O3-induced gall bladder carcinoma cell apop-
apoptosis deserve special mention. It was confirmed that tosis through downregulation of Bcl-2 was suggested,
As2O3-induced apoptosis through the oxidative pathway which may have important therapeutic implications in
depleting intracellular GSH [11]. It might have influ- gall bladder carcinoma patients. Another therapeutic
enced the downstream cascade following ROS genera- study suggested that As2O3 can induce apoptosis of
tion including mitochondrial depolarization and human gastric carcinoma cells MKN45, which is the
caspase-3 activation. Apoptosis induced by inorganic basis of its therapeutic effect [24]. Exposure to arsenic
arsenic and its methylated derivatives to intracellular increased the sensitivity of immune cells to in vitro
calcium disturbances [12]. It is well known that calcium sodium arsenite-mediated apoptosis [25]. Arsenite dis-
ion deregulation plays a critical role in apoptotic cell rupts mitosis and p53-deficient cells, in comparison to
death. A calcium increase in the nuclei might lead to p53 efficient cells, display greater sensitivity to arsenite-
toxic effects in the cell. Arsenic treatments were known induced mitotic arrest and apoptosis [26]. Arsenic
to elevate intracellular Ca2+ levels in a protozoan exposure can lead to various types of DNA damage. It
parasite Leishmania sp. [13]. As2O3 combined with high can cause DNA strand breaks and DNA oxidation
concentration of Ca2+ induced the opening of mito- [27,28]. Both NFkB and AP-1 are modulated in various
chondrial permeability transition pore (MPTP) that cells exposed to arsenic [29].
facilitated the release of cytochrome-c As2O3 induced Recently, activation of c-jun N-terminal kinase (NJK)
opening of MPTP and cytochrome-c release depend on pathway has been found critical to As-induced apopto-
mitochondrial calcium-induced calcium release sis in cultured rat liver cells [30]. Expression profiles of a
(mCICR) [14]. Mitochondrial function in a human number of signaling pathways were studied in the lung
proximal tubular cell line HK-2 at a subcytotoxic of mice offered arsenic in drinking water for 5 weeks
concentration of arsenite were assessed [15]. These [31]. Combined treatment of HL-60 cells with bortezo-
workers observed mitochondrial membrane depolariza- mib and arsenic trioxide resulted in higher cell apoptosis
tion that led to changes in MPTP and ended in rate than that induced by the respective agent alone [32].
apoptosis. As2O3-induced endoplasmic reticulum stress Investigations on synergistic effects of the other drugs/
mediated pathways of cell apoptosis in chronic myeloid protective agents on arsenic trioxide-induced apoptosis
leukemia K562 cell line were identified [16]. Promotion opens a new channel of research on arseniasis.
of lipid peroxidation and membrane permeability
changes played an important role in apoptotic process
in promyelocytic leukemia HL-60 cells [17]. Specific Molecular mechanisms of toxicity
pattern of apoptosis called post-mitotic apoptosis was
reported after chronic arsenic administration [18]. Ear- In recent years, scientific attention has been focused
lier observation that different arsenic compounds on understanding the relationships that must exist
manifest their toxicity by different mechanisms was between the in vivo methylation of inorganic arsenic
again addressed [19]. They demonstrated that arsenic and mechanisms of arsenical toxicity. This issue is of
trioxide was less effective than arsenite in the induction great practical importance, because the methylation of
of DNA protein cross links. In combination with inorganic arsenic was originally thought to be a
gamma radiation, arsenic trioxide induced more than detoxification pathway, but more recent studies have
an additive apoptotic effect than the sum of single suggested that highly toxic ROS generated by MMA
effects. Pretreatment with the protein kinase C (PKC) (III) and DMA (III) and mitochondrial toxicity may
j.jtemb.2008.08.002
ARTICLE IN PRESS
also play an important role in both cellular toxicity and

carcinogenicity of this element [8].
Recent studies have demonstrated that reduction of
AsV to AsIII in human erythrocyte lysates and rat liver
cytosol through an arsenic reductase, which required
glycolytic substrates, GSH and nicotinamide diamide
(NAD) for the activity of the enzyme. The enzyme
responsible for reduction of AsV to AsIII has not
been identified, but a glutathione (GSH) and NAD-
dependent AsV reductase activity that is linked
to glycolysis has been recently identified in rat liver
cytosol and human erythrocyte lysate by Nemeti and Fig. 2. Schematic representation of major cellular interactions
Gregus [33]. of tri- and pentavalent arsenic. Both forms, tri- or pentavalent
In another study, glycogen phosphorylase (GP) as the arsenic, can enter cells. Inside the cells, pentavalent arsenate
third phospholytic enzyme capable of reducing AsV can be reduced by glutathione to trivalent arsenite, and/or
in vitro was identified [34]. For reducing AsV by GP, GSH-As can be methylated to pentavalent or trivalent
GSH and glycogen are indispensable, suggesting that the monomethylated (MMA) or dimethylated (DMA) arsenic.
reduction is linked to glycogenolysis. While its in vivo DMAIII and MMAIII could react with sulfhydryl groups of
significance remains to be tested, further characteriza- some proteins. This will result in modification of protein
tion of the GP-catalyzed AsV reduction was needed. function and retention of arsenic inside the cell. Arsenic
Gregus and Nemeti [35] concluded that AsV is reduced methylation can deplete S-adenosylmethionine, which serves
as a universal donor of the methyl group. As a result, DNA or
by glycogen phosphorelase A in the course of or as a
histone methylation pattern may be changed. GSH-As
consequence of arsenolytic glycogen breakdown. The complexes can be excreted from cells by the MRP1 transpor-
bearing of this mechanism on apoptosis is yet to be ter. MMA or DMA along with other carcinogens or with UV
studied. radiation can induce DNA damage. The repair of this damage
The increase in cancer risk observed in epidemiologi- may also be inhibited by arsenic (after Salnikow and
cal studies is attributed mainly to the exposure to Zhitkovich [4]).
inorganic arsenite, which is more toxic than arsenate [4].
This may be due to a better cellular uptake of arsenite,
which, at equimolar concentration, is accumulated in dermatitis, acute pneumonitis, berylliosis and carcino-
many cell types much faster as compared with arsenate. genesis. In vitro studies have shown that beryllium-
Inside the cell, arsenate may be reduced to arsenite. induced morphologic transformation in mammalian
Neverthless, glutathione seems to play an important role cells [37].
in arsenate reduction and detoxification through con-
jugation (Fig. 2).
Arsenic-induced cellular responses with respect to Beryllium toxicity
apoptosis are summarized below:
Beryllium is an important industrial metal because of
Depletion of intracellular GSH [11].
its material properties, i.e. it is lighter than aluminum
Bax/Bak dependent release [36].
and six times stronger than steel. Acute exposure to
Intracellular Ca disturbances, PKC activation [12].
soluble beryllium compounds irritates the entire respira-
Activation of c-jun – N-terminal kinase (NJK)
tory tract. It may produce acute pneumonitis, and can
pathway [30].
result in total pulmonary edema. Beryllium compro-
DNA strand breaks in human fibroblast cells [27].
mises the immune system. Enzymes catalyzed by
Increased levels of 8-hydroxy-20 deoxyguanosine magnesium or calcium can be inhibited by beryllium,
(8-OHdG) [28].
however, succinic dehydrogenase is activated. Chronic
Activation of AP-1 and NF-kB [29].
exposure to insoluble beryllium compounds, particularly
the oxide, leads to berylliosis. Skin lesions such as
edematous, erythematous and papulovesicular dermati-
Beryllium tis are produced by occupational exposure to beryllium.
Although epidemiological studies are insufficient to
Beryllium has very few industrial applications. The confirm human carcinogenesis, the data strongly suggest
major sources of beryllium in the environment are that beryllium is associated with human cancer. Chronic
beryllium extraction plants, ceramic plants and beryl- beryllium disease (CBD, chronic pulmonary granulo-
lium alloy manufacturers. Twenty percent of world’s matosis, berylliosis) is the most common health problem
production is used in nuclear reactors. It causes contact caused by exposure to beryllium.
j.jtemb.2008.08.002
ARTICLE IN PRESS
Apoptosis Cadmium
There are reports showing that Be induces apoptosis Cadmium (Cd) may exert both acute and chronic
in macrophages [38]. They showed that beryllium- influences on human health. Acute poisoning has
induced apoptosis did not depend upon upregulation occasionally occurred in the past mainly because of
of TNF-a but is caspase dependent. Since it induces inhalation of fumes emanating at the time of dissolving
transcription, activation of c-fos, c-jun and c-myc by or breakage of substances containing Cd or when
activation of the PKC and MAPK pathways, a possible soldering with silver–cadmium solder. Chronic poison-
line to caspase activation has been speculated. More- ing occurs frequently under conditions when there is
over, Be stimulates the loss of surface CD14 in inadequate protection in industries handling Cd-con-
monocytes which has been linked to induction of taining material and in situations where environmental
apoptosis [39]. In contrast to macrophages, beryllium- contamination causes elevated levels of Cd in food. In
induced apoptosis does not occur in neutrophils [40]. the upper airway, chronic inflammation of the nose,
Sawyer and his group has been studying beryllosis for a pharynx, and larynx, as well as olfactory disturbances
number of years. A report from their laboratory showed are observed. In the lower airway, chronic obstructive
that beryllium-ferritin adduct-induced lung macro- lung disease of varying severity is found. That renal
phages CD95 (Fas) expression and the activation of injury induced by Cd exposure is an extremely
intracellular caspase 3, 8 and 9. Thus lung macrophages distinctive disorder. It was proven from a survey of
take up Be-ferritin, delivering physiologically relevant 12,559 inhabitants of a Cd-polluted region and 6435
levels of Be that promote Be antigen presentation and inhabitants of a non-Cd-polluted region is Japan. The
macrophage apoptosis. The latest report from the same most severe form of chronic Cd poisoning caused by
group demonstrated that Be stimulates the formation of prolonged oral Cd ingestion is Itai-Itai disease. The
reactive oxygen species which play a role in Be-induced clinical picture of Itai-Itai disease shows renal injury
macrophage apoptosis [41]. This information has been manifested by tubular and glomerular dysfunction and
claimed to be first one by the authors. However, bone injury consisting of a combination of osteomalacia
molecular markers of Be toxicity are yet to be and osteoporosis.
developed. Beryllium induces macrophage apoptosis
which reduces its clearance from the lung which in turn Cadmium toxicity
contributes to the host continual re-exposure and thus a
chronic granulomatous disorder, the CBD [42]. Cadmium is one of the most notorious heavy metals.
Cadmium inhibits plasma membrane calcium channels
and Ca2+ ATPase groups and hence can inhibit
Molecular mechanisms of toxicity enzymes; however, cells treated with cadmium showed
proliferation of peroxisomes that contain the enzyme
Chronic beryllium disease is a T-cell-mediated dis-
catalase. In addition, cadmium inhibits gluconeogenesis
order. Beryllium, acting as a hapten, interacts with
and oxidative phosphorylation. Cadmium is a direct
antigen-presenting cells in the lungs. Beryllium peptide enzyme poison. It exerts toxic effects on the lung,
associated with major histocompatibility (MHC) class II
kidney, liver and immune system.
molecule is recognized by the T-cell receptor with the
help of CD4+ molecules [43,44]. This interaction
triggers CD4+ T-lymphocyte activation and prolifera- Apoptosis
tion.
The T-cell-mediated process is orchestrated by cyto- Cadmium is known to induce apoptosis in human T
kines. Beryllium stimulated cells from BALF of CBD cells, mouse thymocytes, human mononuclear cells,
subjects produce high levels of IFNg protein and mRNA kidney cell lines, myocardial cells, smooth muscle cells,
with a transient increase in IL-2 protein and mRNA mouse liver cells and C6 glioma cells [46–50]. The
production [45]. The data show that Be-stimulated susceptibility to cadmium-induced apoptosis is depen-
CD4+ T-cell proliferation and production of proin- dent on basal or induced level of MT, which binds
flammatory cytokines are mediated primarily by cadmium to prevent toxic damage. In addition, it has
HLA-DP. been reported that cadmium modulates protein kinase,
Be-induced cellular responses with respect to apopto- phosphatase activities and transcription factors and
sis are summarized below: MAPK. Mitochondrial, caspases and ROS pathways all
seem to play a role in cadmium-induced apoptosis.
Activation of caspase-3 [38]. These aspects of apoptosis as reviewed by Orrenius [51]
Loss of surface CD14 in monocytes [39]. are exhibited by Fig. 3.
Stimulates the formation of ROS [41]. It was shown that cadmium could directly lead to the
Higher level of IFNg and IL-2 [45]. dysfunction of isolated mitochondria from mouse liver,
j.jtemb.2008.08.002
ARTICLE IN PRESS
Fig. 3. Receptor- and mitochondria-mediated apoptotic pathways. Bak, Bcl-2 homologous antagonist/killer; Bax, Bcl-2-associated
X protein; Bid, BH3 interacting domain death agonist; Cyt. c, cytochrome c; Apaf-1, apoptosis activating factor 1; CD95L, CD95
ligand; FADD, Fas-associated death domain; AIF, apoptosis inducing factor; EndoG, endonuclease G; HtrA2/Omi, high-
temperature requirement protein A2 [51].
including the inhibition of respiration, the opening of play a key role in the cascade of events leading to
permeability transition pore (PTP), the loss of trans- apoptosis in the hepatocytes of rainbow trout after
membrane potential and the release of cytochrome C exposure to cadmium. There did exist a relationship
[52]. However, these mitochondrial changes were between oxidative stress and cell death [56]. The effects
completely suppressed by Bcl-xL and ruthenium red. of cadmium on isolated oyster hemocytes, the main
Cadmium caused the PTP opening possibly through its immune system in mollusks were investigated by
binding to thiol groups of adenine nucleotide translo- Sokolova et al. [57]. They demonstrated that in this
cator (ANT). They concluded that mitochondrial organism also, Cd2+ induces apoptosis through a
pathway may involve cadmium-induced apoptosis. mitochondrial/caspase-independent pathway, suggest-
Cadmium-induced apoptosis was found to be accom- ing that a novel perhaps ancient apoptotic pathway is
panied by caspase-3 activation [53]. Both these events active in these cells. Studies using cDNA microarray and
could be reversed by N-acetyl-Asp-aldehyde (Ac-DEVD- quantitative real time PCR assay to determine the gene
CHO), a selective caspase-3 inhibitor, indicating that the expression profiles in the testes of CD-1 mice after a
caspase-3 pathway is involved in cadmium-induced single subcutaneous injection of 5 mmol/kg CdCl2
apoptosis in cortical neurons. Cadmium-induced devel- showed increased expression of the c-myc and Egry
opmental toxicity was mediated via ectopic occurrence genes suggesting acute stress responses [58]. Decreased
of apoptosis during development [54]. In cadmium- expression of proapoptotic genes, particularly caspase-3
treated embryos, significantly higher numbers of apop- and DNA repair genes possibly contributes to Cd-
totic cells were observed by confocal microscopy. induced carcinogenesis. Expression of Bcl-2 and p53 in
TUNEL assay and fluid cytometry were also employed relation to apoptosis was studied in the porcine renal
to study the dynamics of apoptosis. Cd-induced proximal tubule epithelial cells (LLC-PK1) [59]. They
apoptosis was found to be mediated by a mechanism suggested that the apoptosis of LLC-PK1 cells induced
involving intracellular GSH reactive oxidation [55]. In by cadmium might be associated with the inhibition of
another study, it was clearly shown that mitochondria the expression of Bcl-2 and p53. c-jun N-terminal kinase
j.jtemb.2008.08.002
ARTICLE IN PRESS
(JNK) and c-jun signaling cascade play a crucial role in acquisition of apoptotic resistance may play an im-
Cd-induced neuronal cell apoptosis and provides a portant role in cadmium carcinogenesis via tumor
molecular linkage between oxidative stress and neuronal initiation and malignant progression. The execution of
apoptosis [60]. Cd2+ toxicity in epithelial lung cells was apoptosis/necrosis in cadmium-treated human promo-
also studied [61]. They showed that MAPK p38 seemed nocytic cells under different forms of oxidative stress
to be involved in the Cd-induced apoptosis in Clara cells was also studied [70]. They suggested the existence of
and type 2 cells. The activity of PKC was suggested to two different oxidation-mediated necrotic pathways in
have a permissive role in the apoptotic process, located cadmium-treated cells, one of them resulting from ATP-
upstream of p38 phosphorylation. A comparison of dependent apoptosis and the other involving the
cadmium toxicity in plants and mammalian cells was concurrence of multiple regulatory factors.
made [62]. He suggested that features, viz. ability to Cd-induced apoptosis suppresses of NF-kB activity
remove the oxidized proteins, slightly different regula- which may be mediated by oxidative stress [71]. The
tion of cell cycle genes, specific pattern of apoptosis absence of apoptotic death was correlated with a specific
make plants more resistant to Cd2+-induced uncon- defect in activation of Bax. JNK dependent regulation
trolled cell proliferation. Recently it was demonstrated of Bax is essential to mediate the apoptotic release of
that toxic metalTM-induced apoptosis in cultured cytochrome c regardless of Bid and Bim activation [72].
murine podocytes through the extrinsic Fas-FADD Recent investigations on Cd-induced apoptosis intro-
caspase 8 pathway, rather than the mitochondrial duce us to a few new concepts, viz. apoptotic resistance,
apoptotic pathway [63]. They further concluded that MT-3 expression and suppression to NF-kB.
combined exposure to toxic metals induces less apopto- Relationship between metallothionein and apoptosis
sis than the individual exposure to arsenic, cadmium, in the liver and lung of rat has also been studied by Gurel
and mercury. Metallothionein (MT)-3 expression deter- et al. [73]. They reported that cadmium can suppress
mined the choice between apoptotic or necrotic cell apoptosis in vivo. The possible role of MT expression on
death in Cd-induced human proximal tubule cells. It was the suppression of apoptosis and the importance of free-
shown that cells which express MT-3 undergo necrosis Cd ion concentration on switching antiapoptotic effects
when exposed to Cd2+ whereas cells that have no basal to proapoptotic effects was discussed. Similarly a
expression of MT-3 undergo apoptotic cell death. They relationship between glutathione and apoptosis was also
confirmed that the unique N-terminal sequence of MT-3 recorded [74]. They demonstrated greater apoptosis in T
is required to elicit an effect on the mechanism of the cells in CD4(+) than CD8(+) cells related to higher
Cd2+-induced death of the proximal tubule cell [64]. depletion of intracellular glutathione. Cadmium at
A rapid and tranisient ROS generation by cadmium 5–20 mmol/kg could induce hepatocellular DNA damage,
triggered apoptosis via caspase-dependent pathway and expression of proto-oncogenes c-myc, c-fos, c-jun as well
subsequent mitochondrial pathway [65]. N-acetylcys- as apoptosis in rats. Cadmium caused apoptosis in
teine (NAC) inhibits Cd-induced apoptosis through LLC-PK1 cell, which was partially suppressed by
blocking ROS generation as well as the catalase pretreatment with selenium [75].
upregulation. Piperine (a plant alkaloid) modulated
Cd-induced alterations in murine thymocytes. The study
demonstrated the antioxidative, antiapoptotic and Molecular mechanisms of toxicity
restorative ability against cell proliferative mitogenic
response suggesting its therapeutic usefulness in im- Cadmium-induced changes in the expression of MT,
munocompromised conditions [66]. Another study p53 and proto-oncogenes such as c-jun may be
reported that antioxidants and caspase 3 inhibitors, important for the development of prostatic and testi-
viz: NAC and silymarin blocked cadmium-induced cular tumors in rats. One of the most extensively studied
apoptosis [67]. Cd-induced apoptosis in the testis of a properties of MTs relates to the hypothesis that they
dog fish was spedied (Squalus acanthias) using fluores- protect the cell against cadmium toxicity [76]. Studies in
cence technique [68]. He showed that Cd2+ targets only which the primary isoforms of MT (MT-1 and MT-II)
the spermatogenic stages where it specifically activates a are knocked out in mice have shown that these mice
cell death program in susceptible spermatogonial clones were more susceptible to cadmium toxicity than control
and negatively affects blood-testis barrier function. mice [77–79]. In addition, when MT-1 was over-
Question of apoptotic resistance was also addressed by expressed in transgenic mice, cadmium was less lethal
a few workers. Cadmium exposed rat liver epithelial and produced less nephrotoxicity at levels of exposure to
cells were found to be resistant to apoptosis induced by cadmium that injured control mice expressing normal
high concentration of cadmium [69]. It was expected to amounts of MT-1 [80]. Other studies have cautioned
be linked with specific suppression of the JNK pathway that MTs are not the sole factor in determining Cd
and associated with MT overexpression which in turn toxicity, because only a subset of the adverse effects of
may affect the signal transduction pathway. The Cd can be prevented by MT. Testicular necrosis in mice
j.jtemb.2008.08.002
ARTICLE IN PRESS
exposed to Cd could not be blocked by the over- adducts are most likely not essential for initiation of
expression of MT-1 but this may be because Cd was apoptosis. Additionally, ROS-mediated reactions of Cr
injected, and there was not enough time to induce MT as (VI) are capable of causing DNA damage, which
there would be if exposure occurred by ingestion [81]. In activates upstream kinases that phosphorylate p53 [88].
addition, progesterone-induced synthesis of MT actually Thus it is clear that p53 plays a role in chromium-induced
increased cadmium cytotoxicity in rat liver cell [82]. MT apoptosis, but the induction of ROS by Cr can also lead
can also increase the residence times of toxic metals in to apoptosis by other ways [89].
the body, which may lead to chronic effects when The p53 independent pathways involve the mitochon-
protective mechanisms are overwhelmed [83]. dria. Cr (VI) is a ROS promoting agent that results in
Cd-induced cellular response with respect to apopto- apoptosis, mitochondrial instability, and release of
sis are summarized below: cytochrome c, all of which are blocked by cyclosporine
A [90]. It was also shown that caspase-3, but not
Release of cytochrome C from mitochondria [52].
caspase-7, plays a role directly damaging the mitochon-
Caspase-3 activation [53].
dria, Cr (VI) may initiate the intrinsic pathways of
Intracellular GSH oxidation [55].
apoptosis, however, much remains to be elucidated on
Inhibition of the expression of Bcl2 and p53 [59].
the mechanism of Cr (VI)-induced apoptosis.
Involvement of Fas-FADD caspase 8 pathway in
Genomic and proteomic profiling of responses to
murine podocytes [63].
toxic metals in human lung cells was made to find out a
N-terminal sequence of MT-3 is required to induce
survival-based biological response at low doses to a
apoptosis in proximal renal tubular cells [64].
death response at high doses [91]. Chromium is an
industrial metal. It is basically used in chrome plating
and thus poses a serious occupational hazard. DNA
Chromium damage in chrome plating workers of Italy was studied
by Gambelunghe et al. [92]. They estimated DNA strand
Chromium toxicity breaks of single cell microgel electrophoresis and
apoptosis by flow cytometry after propidium iodide
Chromium is a transitional element with many staining of the cells. The increase in DNA strand breaks
industrial uses. Hexavalent chromium is a potent by comet assay was suggested to be a valid test for
teratogen, however, trivalent chromium has not been biological monitoring in workers exposed to genotoxic
found to be teratogenic. Hexavalent chromium is compounds such as Cr (VI). Apoptosis played an
significantly reduced to trivalent state by glutathione important role in the maintenance of cell cycle in the
in all tissues. During this reduction process, chromium lungs of Cr (VI)-treated rats [93]. Role of chromium in
may interact with cellular macromolecules and DNA. apoptosis, oxidative stress and carcinogenesis was also
Cr (VI) has been found to be a strong clastogen in reviewed [3]. Mode of cell death in murine J774
experimental animals producing chromosome aberra- macrophages incubated with Cr3+ ions was recognized
tions, sister chromosome exchanges, DNA strand [94]. In short incubation times (24 h), the non-inflam-
breaks, oxidized base damage, DNA–DNA and DNA– matory process of apoptosis was predominant whereas
protein cross links. at longer incubation times (48 h) necrosis was predomi-
nant at higher concentrations. Almost similar conclu-
Apoptosis sions were drawn by Catelas et al. [95]. Molecular
mechanisms of hexavalent chromium-induced apoptosis
Apoptosis induced by hexavalent chromium (Cr (VI)) in human bronchoalveolar cells are also known [96].
was first reported in Chinese hamster ovary (CHO) cells. They showed that p53 as the ‘‘necessary’’ player in Cr
Research on the mechanism of chromium-induced (VI)-induced apoptosis. Genes responsible for apopto-
apoptosis has suggested many possibilities. However, sis, cell cycle regulation and DNA repair in human
the exact mechanism remains so far unknown. Two fibroblasts that survived after lethal exposure to Cr (VI)
major pathways involved in Cr (VI)-induced apoptosis were identified [97]. They suggested that an alteration in
have been considered, i.e. p53-dependent and indepen- gene expression may favor cell survival and/or incom-
dent pathways. Cr (VI) induces the activation of p53 plete DNA repair after genotoxic exposure. All these
protein in CHO, human lung epithelium and human lung reports suggest that apoptosis must be considered as a
fibroblasts [84,85]. The reduction of Cr (VI) leads to the component of chromium-induced multistage carcino-
generation of CrV which also mediates in the generation genesis [98,99]. In addition, activation of p53 is one of
of free radicals [86]. These free radicals can then cause the critical steps in the induction of apoptosis [84,85].
DNA damage and disruption of cellular homeostasis. In Exposure to hexavalent chromium (Cr (VI)) is
CHO cells that were pretreated with vitamin C, Cr (VI)- associated with lung cancer. A study made in the liver
induced apoptosis was decreased [87]. Therefore, DNA of rats offered Cr (VI) contaminated water, revealed
j.jtemb.2008.08.002
ARTICLE IN PRESS
increased expression of Smad2/Smad4 and Dapk Copper

suggesting the involvement of transforming growth
factor (TGF) beta pathway in the apoptotic process Copper is an essential trace element. The primary
[100]. Increased expression of both caspase 8 and Daxx exposure pathway for copper is ingestion. Copper
genes suggests that a p160 (ROCK)-Rho-independent reduces glutathione. The amino acid transferases are
pathway operates, leading to cell contraction and inhibited in the presence of excess copper. Copper
membrane blebbing, the characteristic apoptotic fea- combines with thiol groups which reduce the oxidation
tures. Gene expression studies in human peripheral state II to I in copper and oxidizes the thiol groups to
blood mononuclear cells (PBMc) obtained from both disulfides, especially in the cell membrane. Copper is
men and women of each major ethnic group including associated with two genetic inborn errors of metabolism,
Caucasians, Hispanics, Asians and African-Americans i.e. Menke’s disease and Willson’s disease. Copper is
identified several functional families of genes including required for the function of over 30 proteins, including
those involved in immune response and cell cycle [101]. superoxide dismutase, ceruloplasmin, lysyl oxidase,
Protection against Cr(VI) toxicity involves a transcrip- cytochrome-c-oxidase, tyrosinase and dopamine-b-hy-
tional signaling loop that includes activation of Nrf2 by droxylase. The essentiality of copper resides in its
the toxic metal, transcription of ARE-driven genes and capacity to participate in one electron exchange reac-
reduction of ROS production [102]. tions. However, the same property that makes them
essential also generates free radicals that can be seriously
Molecular mechanisms of toxicity deleterious to cells.
Chromium (Cr (VI)) can generate ROS, activate Copper toxicity

MAPKs, NF-kB and HIF-1 in cells. Cr mediates free
radical generation by Fenton-type reaction, Haber- Acute gastrointestinal disturbances with vomiting,
Weiss reaction, or by reacting directly with cellular epigastric burns, and diarrhea may occur from acciden-
molecules [103]. It has been shown that Cr (VI) was able tal ingestion of food or beverages contaminated by
to enter A549 cells at low concentrations (o10 mM), copper, released from copper vessels and from hot water
resulting in an elevation of ROS in cells [104]. In the geysers [109], or from drinking water [110,111]. The
same cell line, Cr-induced ROS generation was shown to experience from suicidal copper sulfate poisoning shows
be responsible for the early stage of Cr-induced that gastrointestinal disturbances occur in all cases
apoptosis, whereas Cr-activated p53, mostly by ROS- admitted to the hospital, suggesting that these symp-
mediated free radical reactions, contributed to a late toms are the first to occur together with the feeling of
stage induction of apoptosis [89,105]. Cr (VI)-induced metallic taste [112].
ROS production, as well as oxidative damage to tissue Metal fume fever is an influenza-like syndrome with
and to DNA, was also observed in a number of cell fever, myalgias, profuse sweating, and other symptoms
lines, such as human peripheral blood mononuclear that usually occur 3–10 h after heavy exposure to a
cells, chronic myelogenous leukemic K562 cells, and variety of metal oxides. The symptoms usually disappear
J774A.1 murine macrophage cells. Moreover, p53 has after 24–48 h [113].
been shown to play a major role in Cr(VI)-induced
oxidative stress and toxicity [106]. ROS acted as a
second messenger mediating Cr(III)-induced apoptosis Apoptosis
in lymphocytes. It activated the Src-family tyrosine
kinases, which, in turn, led to the activation of caspase-3 Several reports confirm the role of reactive oxygen
in Cr-induced apoptotic cell death [107,108]. species (ROS) in cell death induced by heavy metals
Chromium-induced cellular responses with respect to [114]. The case of copper appears to be different. It is an
apoptosis are described below: essential element. Participation of Haber-Weiss reaction
in its toxicity, whereby it catalyzes the formation of
Activation of p53 in CHOP, human lung epithelium ROS by peroxidation of membranous lipids was also
and fibroblasts [84]. suggested. Studies on rat hepatocytes have indicated
ROS-mediated reactions are capable of causing DNA that the main sources of ROS generation in the presence
damage [88]. of copper were the lysosomes [115,116], whereas the
Oxidative stress is responsible for causing Cr-induced mitochondria, a significant source of ROS under basal
carcinogenesis [3]. conditions appeared not to be involved [117,118]. At the
Caspase-3 and not caspase-7 plays a role in Cr- same time, however, mitochondria are clearly important
induced apoptosis [90]. targets of metal toxicity and in many cases a close link
TGF (transforming growth factor) beta pathway is between metal-induced radical stress and mitochondrial
involved in apoptosis [100]. function has been established [119,120]. The induction
j.jtemb.2008.08.002
ARTICLE IN PRESS
of the mitochondrial permeability transition (MPT) various metals, including zinc, cadmium, and molybde-
remains to be a crucial phenomenon in many models of num, have been reported to interfere with its transport
necrotic and apoptotic cell death [121]. or availability in biological systems.
The impact of copper on mitochondrial function has Reactive oxygen species may be produced in the liver
received comparatively little attention. However, copper of experimental animals administered copper. There is
was reported to induce both necrotic and apoptotic cell some evidence that the liver toxicity may be associated
death in trout hepatocytes [122]. Role of X-linked with the induction of oxidative damage with resulting
inhibitor of apoptosis (XIAP) in copper metabolism was lipid peroxidation [130]. Lipid peroxidation of mito-
also observed [123]. They found that XIAP levels are chondrial membranes of liver cells [131], membranes of
greatly reduced by intracellular copper accumulation in hepatic lysosomes [132], rat hepatic mitochondria [133],
Wilson’s disease and other copper toxicosis disorders and malondialdehyde in the liver of copper-loaded rats
and in cells cultured under high copper conditions. [134] have been observed in different studies.
Dissolved copper triggered a dose dependent loss of Copper-induced cellular responses with respect to
neurons in identified lateral line neuromasts at concen- apoptosis are summarized below:
trations 4 or ¼ 20 mg/L [124]. Copper-induced neuro-
nal apoptosis is dependent on the induction and nuclear
Mitochondria are not the main source of ROS in
copper toxicity [118].
translocation of the tumor suppressor protein p53 [125].
They identified both p53 dependent and independent
XIAP has a role in copper-induced apoptosis [123].
mechanisms leading to apoptosis including insulin like
p53 dependent and p53 independent mechanism are
involved in copper-induced apoptosis [125].
growth factor binding protein-6, glutathione peroxidase,
bcl-2, RB-7, PUMA and several members of the
Conformational and transcriptional activity of p53 is
altered by copper [126].
redoxactive PIG family of proteins. They concluded
that following copper mediated neuronal DNA damage,
Activation of acid sphingomyelinase (Asm) triggers
copper-induced apoptosis in hepatocytes [128].
the regulation of a variety of pro and antiapoptotic
genes are responsible for determining neuronal fate.
Conformational and transcriptional activity of the
tumor suppressor protein p53 is altered by copper Lead
[126]. They not only identified genes that might play a
role in copper mediated apoptosis but also suggested Lead can disturb cellular and molecular processes in
that copper-induced oxidative processes result in the the body and affect many organs and physiological
biosynthesis of mutant p53 with altered transcriptional functions. It can interfere with certain cellular signaling
properties. Oxidative stress may play a central role in processes, the generation of action potentials in certain
the cell degeneration in Wilsons disease, at the main site nerve cells and the function of a number of enzymes.
of copper deposition, with discrete proapoptotic condi- Lead interferes with Na-K ATPase pump on cell
tions developing in distal areas [127]. membranes, the metabolism of vitamin D, heme
synthesis, enzymes involved in oxidative phosphoryla-
tion (cytochromes) and calcium uptake and metabolism.
Molecular mechanisms of toxicity In addition, lead can interfere with signal transmissions
in nerve cells including dopaminergic transmissions and
Recently a brand new mechanism of copper toxicity signaling processes at the pre- and post-synaptic
has been proposed [128]. His group showed that Cu(2+) junctions. Lead can depress the function of the adrenal
triggers hepatocyte apoptosis through activation of acid glands and the thyroid. Lead binds with sulfydryl
sphingomyelinase (Asm) and release of ceramide. groups and therefore may change the structure and
Genetic deficiency or pharmacological inhibition of function of certain proteins and enzymes. Lead inter-
Asm prevented Cu (2+)-induced hepatocyte apoptosis feres with heme biosynthesis. Lead binds with d-amino
and protected rats, genetically prone to develop levulinic acid dehydratase and inhibits its activity.
Wilson disease from acute hepatocyte death, liver failure
and early death. Another study suggested that copper Apoptosis
diethyl dithiocarbamate [Cu(DEDTC)] complex toxicity
is mediated through an increase in proapoptotic Exposure to inorganic lead induces apoptosis in rod
Bak/Bax via disruption of the peroxide and thiol photoreceptor cells [135], neuronal cells [136], hepato-
metabolism [129]. cytes [137] and macrophages [138] but not in human
Copper (Cu) is an essential metal for living systems mononuclear cells [139]. In lead-induced apoptosis, the
and is found in an assortment of enzymes, including mitochondria play a crucial role. Since lead mimics
superoxide dismutase (SOD), ferroxidases and cyto- calcium, calcium overload may trigger apoptosis.
chrome oxidase. Its transport is highly regulated and Calcium and lead both depolarize rod cell mitochondria
j.jtemb.2008.08.002
ARTICLE IN PRESS
due to the opening of the PTP, resulting in the Mercury

cytochrome C release, caspase activation and apoptosis.
PTP does not open due to oxidative stress [140]. Infact, Mercury has a great affinity for sulfydryl moieties and
apoptosis is mediated by Bax translocation to the hence binds and inactivates a variety of enzymes.
mitochondria and can be blocked by overexpression of Methylmercury also initiates lipid peroxidation which
Bcl-xl [141]. In rat cerebral cortex, hippocampus and can produce alterations in cell membrane. Elemental
cerebellum, lead-induced apoptosis results in an in- mercury damages the microtubules in the brain by
creased Bax/bcl-2 ratio [142]. Even though lead in- reacting with the protein tubulin. Inorganic forms of
creases TNFa expression in glial cells, this alone does mercury induce metallothionein. It concentrates mainly
not result in apoptosis. Pb2+-induced neurotoxicity may in the kidney. Elimination is primarily in the urine and
partially be mediated through p53 independent apopto- the feces with small amounts in breath, sweat and saliva.
sis and enhanced by glutamate [143]. Thus, the effects of Mercury has been used in human history for at least
lead on the mechanisms of cell death are not completely 3000 years. Mad hatter’s disease was attributed to
understood. Immunosuppression due to DNA damage mercury. Minamata disease is the classical example of
and death of peritoneal macrophages seems to be mercurial poisoning. Mercury exists in three forms.
important [144]. Elemental mercury is a liquid metal with a high boiling
Apoptotic effects of lead have not been studied very point and low vapor pressure. Mercurous salts are
recently. Lead exposure induced pycnosis and enuclea- found in calomel, mercuric chloride. Organic mercury
tion of peripheral erythrocytes in the domestic fowl compounds, the third form, such as methyl mercury are
[145]. They showed that presence of pycnotic nuclei was formed by natural processes. Elemental mercury is
not associated with DNA fragmentation, typical of readily absorbed through the pulmonary alveoli and
apoptosis. transported by the blood to the brain and other organs.
This form of mercury is excreted from the bowel,
Molecular mechanisms of toxicity kidney, liver and skin. Organic mercury is well absorbed
orally or through the skin and distributes throughout
As to mechanism of the mutagenic effect, evidence the body. Some of organic mercury is converted into
shows that lead accumulates in the cell nucleus [146]. mercuric ions in the body. The major route of
However, there is only limited evidence of direct genotoxic elimination of organic mercury is by the faces.
or DNA-damaging effects except for lead chromate, Mercury is a well known enzyme poison. It may bind
where hexavalent chromium is probably the cause. Hence, to a variety of enzyme systems including those of
lead has mostly been negative in in vitro genotoxic assays. microsomes and mitochondria, producing non-specific
Rather, lead-induced nongenotoxic/epigenetic mechan- cell injury or cell death. It has a particular affinity for
isms seem to affect DNA. Thus, lead exposure may sulfydryl groups. In liver cells, methyl mercury forms
increase the susceptibility to genotoxic agents. Hence, lead soluble complexes of glutathione, which are secreted in
may bind to and deplete, glutathione [147], interfere with bile as a glutathione complex. The cysteine complex of
DNA repair [148] and bind to histones, thus decreasing methyl mercury enters the endothelial cells of blood
their DNA protection [149]. In accordance with this, there brain barrier on the large neural amino acid transporter.
was a multiplicative effect for coexposure in work Mercuric mercury, but not methyl mercury, induces the
environments to lead, cobalt and cadmium, as regards synthesis of metallothionein in kidney cells.
induction of DNA single-strand breaks [150].
Lead-induced ALA accumulation can also generate Apoptosis
reactive oxygen species, which may damage DNA [146].
Furthermore, experimental evidence shows that lead can In this very decade, several laboratories have tried to
substitute for zinc in several proteins that function as delineate the process of mercury-induced apoptosis.
transcriptional regulators, including protamines. Lead Induction of germ cell apoptosis and reproductive
also reduces the binding of these proteins to recognition toxicity of methyl mercury in Wistar male rats was
elements in genomic DNA, which suggests an epigenetic recorded [151]. A 20-fold increase in DNA fragmenta-
involvement of lead in altered gene expression. tion was recorded after 14 days of exposure. It was
Lead-induced cellular responses with respect to suggested that methylmercury impairs spermatogenesis
apoptosis are suggested below: by germ cell detection via cell- and stage-specific
apoptosis. Molecular effects of methyl mercury occur-
Apoptosis is mediated by Bax translocation to the ring at low concentrations were also studied [152].
mitochondria and blocked by overexpression of Bcl-2 Growing evidence appeared showing that mercurial
[140]. compounds are toxic to human immune system. Methyl
Expression of TNFa alone is not responsible for mercuric chloride was found to be a potent human cell
apoptosis [142]. apoptogen. Moreover, mitochondria appeared to be a
j.jtemb.2008.08.002
ARTICLE IN PRESS
target organelle for the induction of cell death. Induction been linked to neurodegeneration was reviewed [161].
of oxidative stress was found to be the critical step in the Hg toxicity has been studied in plantlets of alfalfa
activation of death signaling pathways. Additionally, (Medicago sativa) [162]. They correlated GSH/GSSG
mercury acts as a genotoxin significantly altering the pool with apoptosis. Recently, a few interesting reports
expression of gene that affect cell survival and apoptosis have emerged linking apoptosis with inhibition of Ca(V)
[153]. Hg2+ enhanced the sensitivity of kidney cells to 3.1 (T type) calcium channel. Interaction of inorganic
apoptotic stimuli as a consequence of inhibition of NF- mercury with this channel may significantly contribute
kB activity [154]. Thus a new direction to understand to neuronal symptoms of mercury poisoning during
mercurial toxicity was given by these workers. Different both acute poisoning and long-term environmental
pathways of mercury-induced cytotoxicity in T and B exposure [163]. Induction of apoptosis in the tubular
lymphocytes and involvement of ROS, Ca2+ home- epithelial Madin-Darby canine kidney (MDCK) cell line
ostasis and inflammatory cytokine gene expression was was also investigated [164]. They attributed apoptosis to
suggested [155]. Modulation of several lymphocyte release of cytochrome C from the mitochondria into the
signaling pathways by inorganic mercury was implicated cytosol. They also suggested that activation of caspase-3
as an environmental factor linked to autoimmune is involved in HgCl2-induced apoptosis.
disease. Low and nontoxic concentration of Hg2+ Mercury-induced cellular responses with respect to
impaired CD95 agonist induced apoptosis in representa- apoptosis are described below:
tive Type I and Type II T-cell lines [156]. Hg2+ treatment
blocks the CD95 agonist induced activation of initiator
Mercury alters gene expression [154].
and effector caspases as well as the association between
It inhibits NFkB activity [154].
CD95 and the signaling adaptor, FADD. They indicated
It impairs CD95 agonist induced apoptosis in
respercutative type I and type II T cell lines [156].
that the Hg2+ sensitive step within the CD95 death
pathway is localized to the level of the death inducing
p38 mediated caspase activation regulated mercury-
induced apoptosis [67].
signaling complex (DISC). Disruption of proper DISC
formation may be a biochemical mechanism whereby
Hg2+ contributes to autoimmune disease. Mercury-
induced death in murine macrophages was studied by Nickel
Kim and Sharma [67]. They reported that macrophage
death is a mix of necrosis and apoptosis. Mercury- Nickel (Ni) and its compounds are widely used in
induced ROS were involved in p38 activation. p38 industry. Ni is an essential trace nutrient in plants and
mediated caspase activation regulates mercury-induced certain animal species (e.g. rat and chick), however, it
apoptosis and p38-mediated TNFa regulates necrosis in has not been shown to be essential in humans. The
these cells. Calcium regulates ROS production and toxico-kinetics of nickel compounds depends on their
mercury-induced ROS modulate downstream p38 that solubility in water and biological fluids. Skin sensitiza-
regulates both apoptosis and necrosis. MeHg, in tion is believed to occur as a result of nickel binding to
neutrophils, play a possible role in chromatin digestion proteins (particularly on the cell surface) and hapten
leading to apoptosis [157]. They indicated that MeHg formation. Essentially the body perceives the nickel-
induces necrosis at higher concentrations by a rapid protein complex as foreign and mounts an immune
increase of Ca2+ and apoptosis at lower concentrations reaction to it. Nickel may substitute for certain other
acid. Role of NFkB in mercury-induced renal failure was metals (especially zinc) in metal dependent enzymes,
emphasized [158]. Inhibition of NFkB activity may leading to altered protein function. It readily crosses the
define a molecular mechanism underlying the pathogen- cell membrane via calcium channels and competes with
esis of Hg2+ toxicity in kidney cells. Further, the effects calcium for specific receptors. Nickel can crosslink
of relatively low and non-cytotoxic concentrations of aminoacids to DNA and lead to formation of reactive
Hg2+ that impair CD95 mediated apoptosis by targeting oxygen species. Nickel carbonyl can also suppress
a plasma membrane proximal signaling event [159]. natural killer cell activity and production of interferons.
Ultra structural studies supported mercury-induced The mechanism of nickel-induced carcinogenesis is
apoptosis [160]. They observed that low concentrations controversial. The nickel ion (Ni2+) alone does not
of HgCl2 induce apoptosis by inhibiting mitochondrial form premutagenic DNA lesions, suggesting that nickel
function, and the OK cell line of kidney may be causes indirect DNA damage, perhaps due to oxidative
considered a useful tool for the study of programmed stress or blocking DNA repair mechanisms.
cell death involving mercurial species and other heavy
metals. Nickel toxicity
Mercury-induced toxic processes that were activated,
as well as its effects on the cellular cytoskeleton, its Nickel is treated as a respiratory carcinogen in
genotoxicity or the production of compounds that have workplace. Inhalation is the most serious toxicologic
j.jtemb.2008.08.002
ARTICLE IN PRESS
concern followed by dermal exposure. The intracellular The cytotoxic effects of nickel involved significant
distribution and binding of nickel is not well under- morphological changes and chromosomal condensation
stood. Cysteine, histidine and aspartic acid form nickel [178]. Indication of apoptotic cell death by nickel was
complexes either single or as nickel-ligand species [165]. mediated by reduction of Bcl-2 expression. The mechan-
In vivo binding with metallothionein has also been isms implicated in nickel-induced antiapoptotic effect in
demonstrated in liver and kidney. Nickel binding human bronchial epithelial cells were also studied [179].
metalloprotein known as nickeloplasmin has also been
identified. Molecular mechanisms of toxicity
Nickel can activate several cellular stress response

Apoptosis signaling pathways involving MAPKs, PI3K, HIF-1,
NFAT and NF-kB [180,181]. Although a thorough
Although inhalation or ingestion of nickel (II) is review of nickel and other metal induction of these
known to induce multiple genotoxic effects, little signaling pathways can also be found [182], a few
research has been done to understand nickel-induced particularly salient mechanisms related to nickel will be
apoptosis. Ni-induced apoptosis was first reported in briefly summarized here. Nickel is now well known for
CHO cells. Since nickel induces oxidative damage its capacity to stabilize and activate the HIF-1a protein
resulting in an increase of ROS production [166], it is and to up-regulate a battery of hypoxia-inducible genes.
possible that nickel-induced ROS are involved in Although some signaling pathways may involve nickel-
apoptosis. In endothelial cells nickel activates NF-kB, induced ROS, the formation of ROS is not thought to
a transcription factor with both pro and antiapoptotic be involved in nickel’s activation of HIF-1-dependent
properties [167]. Nickel exposed cells have a reduced genes [183]. When Affymetrix gene chips were used to
GSH, which is a marker of oxidative stress [168]. study nickel treated (1 mmol/L NICl2, 24 h) HIF-1a
Depletion of glutathione significantly enhances nickel- competent versus knockout cells, numerous genes were
induced apoptosis [169]. Recently a few laboratories found to be up- or down-regulated in a HIF-dependent
have contributed to Ni-induced apoptosis. Ni can manner [184–186]. This dose of nickel chloride is
modulate cellular responses through some common nontoxic, yielding approximately 90% survival of
effectors involving in both apoptotic and cell cycle human A549 lung cells. Some examples of these
regulator pathways [170]. Molecular mechanisms viz. nickel-induced genes include 1,4-a-glucan branching
gene silencing, DNA hypermethylation and inhibition of enzyme 1 (GBE1) and Bcl-2 binding protein Nip3
histone acetylation have also been studied during nickel (BNIP3). Serpina3g, a member of the mouse serpin
carcinogenesis [171]. Possibility of Fas ligand expression family, was downregulated by nickel by means of HIF-
in nicked-induced apoptosis of murine T cell hybridoma 1a dependent pathways, as was asparaginyl hydroxylase
cells was also investigated [172]. A comparison of the FIH-1 and acetyltransferase ARD-1 in A549 cellsare
toxic effects of Cu, Fe, Ni, V and Zn on rat lung [185]. Although the exact mechanism for HIF-1 activa-
epithelial cells was made [173]. They studied the tion by Ni is not yet confirmed, several hypotheses have
mechanisms of cell death and cytokine secretion. Ni been proposed. These include the ability of nickel to
toxicity in testis of mice was studied by Doreswamy et stabilize HIF-1a protein by inhibiting the post-transla-
al. [174]. They suggested that its toxicity is related to tional modifications of HIF-1a; the impairment of prolyl
enhanced production of reactive oxygen species, prob- hydroxylase activities by cellular iron depletion caused
ably mediated through oxidative damage to macromo- by nickel competition for the DMT-1 transporter, as
lecules including damage to DNA. Ni toxicity in an well as by substitution of nickel for iron in the Hif-prolyl
in vitro model of human oral epithelium was studied hydroxylase.
[175]. They showed that very low concentration of nickel Nickel-induced cellular responses with respect to
can cause oxidative imbalance leading to apoptosis. apoptosis are suggested below:
Similarly, role of oxidative stress, mitochondrial mem-
brane potential and calcium homeostasis in human Oxidative stress leads to apoptosis [175].
lymphocyte death was studied by M’Bemba-Meka Inhibition of Bcl-2 expression has been correlated
et al. [176]. with Ni-induced apoptosis [183].
Recently, it has been shown that Ni and V ions induce
apoptosis in T-lymphocytes [177]. They indicated that
these metal ions can kill the cells via apoptotic and Selenium
nonapoptotic pathways.
Although effects of nickel (II) on the immune system Selenium is used in a wide variety of industries
have long been recognized, little is known about including electronics, glass, ceramics, glass coloring,
the effects of nickel on induction of apoptosis. steel, pigment manufacturing and rubber production.
j.jtemb.2008.08.002
ARTICLE IN PRESS
Selenium is irritating to the eyes, skin, nose and throat. cies from all domains of life have been recently
Selenium is an essential trace element and an integral characterized. At least nine selenoprotein families exist
component of glutathione peroxidase. Selenium com- for which definite function has not yet been attributed.
pounds are found in the selenium analogs of the sulfur Functional characterization of these newly discovered
containing amino acids such as cysteine and methionine. members might reveal novel functions.
Se-cysteine is found in the active sites of the enzyme
glutathione peroxidase which uses glutathione to reduce Molecular mechanisms of toxicity
organic hydroperoxides.
Excess of selenium results in liver atrophy, necrosis A moderate genotoxic activity of selenium com-
and hemorrhage. The mechanism of toxicity is unknown pounds (i.e., selenite, selenate, selenide, selenocysteine,
but may involve redox cycling. Sulfydryl enzymes are and selenosulfide) has been found in several in vitro
attacked by soluble selenium compounds. systems [182,193]. There is one in vivo study showing
The requirement of selenium for life and its beneficial chromosomal aberrations and increased SCE in hamster
role in human health has been known for several bone marrow cells after selenite treatment [194]. This
decades. This is attributed to low molecular weight occurred only at doses of 3, 4 and 6 mg Se/kg bw
selenium compounds as well as to its presence within at intraperitoneally that were associated with severe
least 25 proteins named as selenoproteins. Recent systemic toxicity including lethality some hours after
evidence points to a role of selenium compounds as dosing. The numbers of aberrations in these groups were
well as selenoproteins in the prevention of some forms of 13–55% compared with 0.9–1% in the controls. Doses
cancer. Selenium and its effects on apoptosis have been of 0.3, 0.6, 1, and 2 mg Se/kg bw did not cause any
recently investigated. Genotoxic and nongenotoxic clastogenic effects. Mice fed high doses (7–28 mg/kg bw)
classes of selenium may exert differential apoptosis of selenite or selenate showed dose-dependent chromo-
efficacy depending upon the p53 status of the cancer some aberrations and affection of spindle structure.
cells [168]. Selenium at 5–20 mmol/kg can induce DNA A nonpregnant macaque dosed with 600 mg seleno-
damage, apoptosis and over expression of c-myc, c-fos methionine for 15 days (lethal dose) showed, in
and c-jun in rat hepatocytes [176]. Selenite induces comparison with the control animal, a seven-fold
apoptosis by producing superoxide to activate p53 and increase in bone marrow micronuclei [195]. In pregnant
to induce p53 mitochondrial translocation [187]. Activa- macaques receiving 0, 150 or 300 mg selenomethionine/
tion of p53 in turn synergistically enhances superoxide kg bw and showing signs of selenosis, fetal bone marrow
production and apoptosis induced by selenite. Selenium smears did not show any increase in the number of
inhibits cell apoptosis induced by oxisterols in vascular micronuclei [196].
smooth muscle cells (VSMC) [188]. It was related with Studies in vitro indicate that the mutagenic effects of
anti oxidation of selenoproteins. Effectiveness of sele- selenium salts are associated with production of reactive
nium compounds as chemopreventive agents in vivo is oxygen radicals and that glutathione promotes these
correlated with their abilities to effect the regulation of reactions. It is well known that auto oxidizing selenium
the cell cycle, to stimulate apoptosis and to inhibit metabolites, such as hydrogen selenide, can undergo
tumor cell migration and invasion in vitro [189]. Prior to redox cycling, producing oxygen radicals and cause
occurrence of apoptosis, Se compounds alter the DNA strand breaks [197–199]. In vivo only toxic
expression and/or activities of signaling molecules, amounts were shown to be active, keeping in mind the
mitochondria associated factors, transcriptional factors, central role of hydrogen selenide in the metabolism of
tumor suppressor genes and cellular reduced glu- most selenium compound it is likely that overproduction
tathione. It was demonstrated that methylselenol of this and other autoxidizing selenium metabolites
metabolite pool has many desirable attributes of could promote the formation of DNA reactive oxygen
chemoprevention whereas the hydrogen selenide pool radicals. It follows, given such a mechanism, that
with excess of selenoprotein synthesis can lead to DNA expression of selenium-dependent genotoxic activity is
single-strand breaks. Cancer prevention by selenium likely to be concentration and threshold dependent, but
with apoptotic approach was also studied [190]. Further this remains to be shown.
cytoprotective effects of selenium on cadmium-induced Selenium-induced cellular responses with respect to
LLC-PKT cells apoptosis by activating c-jun N-terminal apoptosis are described below:
kinase (JNK) pathway was reported [191]. Selenium and
zinc antagonize oxidative stress, apoptosis and cell cycle Genotoxic and nogenotoxic classes of selenium exert
changes induced by excess fluoride [192]. differential apoptosis efficacy depending upon the
Despite that past 10 years have been exciting in p53 status of cancer cells [168].
selenium research a better understanding of mechanistic Overexpression of c-myc, c-fos and c-jun causes
issues is needed for the molecular aspects of selenium- apoptosis in rat hepatocytes [184].
dependent chemoprevention. Selenoproteiomes in spe- Selenium and zinc antagonize apoptosis [192].
j.jtemb.2008.08.002
ARTICLE IN PRESS
Combined toxicity of heavy metals A cell must contain a controlling mechanism governing
the decisive fork between the proliferative and antipro-
Toxicity studies of interactions are relatively limited. liferative states including growth arrest, differentiation,
Recent in vitro studies [200] compared cadmium and cellular aging and apoptosis. Understanding proliferation
arsenic interactions in both rat and human cell lines. controls is therefore fundamental for understanding
These studies explained a number of the mechanistic controls in other cellular processes. Experimental evi-
molecular factors that contribute to cellular resistance to dence proved that caspases and mitochondria both play
arsenic toxicity. important roles in the initiation and execution of
Apoptosis in Chinese hamster ovary cells was apoptosis. In the intrinsic pathway death signals act
observed 48 h after treatment with 300 mmol/L chro- directly or indirectly on the mitochondria, resulting in the
mium (Na2CrO4) for 2 h. Cadmium alone at concentra- release of cytochrome c and formation of the apoptosome
tions of 1.5 or 10 mmol/L (as CdCl2) did not induce complex. Importance of mitochondrial antioxidant de-
apoptosis in these cells at times up to 72 h after fense system in the regulation of apoptosis has long been
treatment. When these cells, however, were concurrently recognized. Over recent years, many new cell cycle and
exposed to cadmium and chromium, chromium-induced apoptosis-related molecules have been discovered, often
apoptosis was markedly suppressed in a cadmium with blurred roles. Survivin is a bifunctional molecule
concentration-related fashion. The experimental find- that has a role both as an inhibitor in apoptosis and an
ings indicate that cadmium can block chromium- orchestrator of cell division; the resulting cross-talk
induced apoptosis [201]. The activation of the JNK, between the processes promotes a balance between
p38 and ERK mitogen-activated protein kinases by proliferation and death with limits on the growth and
Cr(VI) is mediated through oxidative stress, but survival of cells suffering oncogenic mutations. It has
their activation does not affect cytotoxicity. In the become increasingly clear that intracellular proteolysis
experiments, the p38 activation by Cr(VI) showed a via the ubiquitin/proteasome pathway has a fundamental
positive relationship to oxidative stress, whereas the role in cell cycle regulation, protein degradation in
JNK activity was enhanced by either a quencher mitosis and apoptosis, as well as in other fundamental
(e.g., mannitol) or activator (H2O2) of redox reactions physiological processes including antigen processing,
in Cr (VI)-exposed human non-small cell lung carcino- signal transduction, transcription and the flux of
ma CL3 cells [202]. substrates through metabolic pathways. The calcium-
The p53 protein is a zinc-binding protein containing dependent thiol proteases, calpains, are widely expressed
several reactive cysteines. The protein seems to control with ubiquitous and tissue-specific isoforms. Calpains
the timely production of reactive oxygen intermediates, have been implicated in basic cellular processes including
which may initiate apoptosis. The activity, however, is cell proliferation, apoptosis, differentiation, cytoskeletal
under the control of changes in metal levels and in rearrangements and cell migration.
cellular redox status. This redox sensitivity may be one In addition to the massive array of molecules now
of the biochemical mechanisms by which p53 acts as a known to be involved in cell division and cell death,
sensor of multiple stress [203]. It has been shown that another ever-increasing list of molecules involved in
a-difluoromethylornithine (DFMO), a highly effective related processes has been developed. Hyaluronan, a
chemopreventive agent in esophageal carcinogenesis, high molecular weight glycosaminoglycan, is an extra
reverses and counteracts espophageal cell proliferation/ cellular matrix component of tissues that facilitates cell
cancer initiation in zinc-deficient rats by way of locomotion which plays a major role in wound healing,
stimulating apoptosis [204]. cell proliferation, mitotic cell rounding, de-adhesion and
migration. Furthermore, recent studies have shown that
hyaluronan is involved in the intracellular regulation of
Conclusions the cell cycle and gene transcription.
Disorders of apoptosis and cell accumulation may
There appears to be no unifying mechanism by which play critical roles in some of the most severe and
metals act to alter the apoptotic process. However, debilitating metal-induced afflictions including neuro-
understanding these mechanisms of apoptosis caused by toxicity, hepatotoxicity, renal toxicity, autoimmunity
carcinogenic and non-carcinogenic metals may open and carcinogenesis. Doping the mechanisms of aberrant
avenues to manipulate cells during metal toxicity. In an apoptosis resulting from metal exposure may allow the
analogous fashion, enhanced apoptosis may destroy development of preventive strategies in metal poisoning.
specific critical cell populations or may allow damaged
cells to escape appropriate destruction. Suppression of
apoptosis may facilitate aberrant cell accumulation
References
which may be critical step in the pathogenesis of [1] IARC. IARC monographs on the evaluation of carcino-
malignancy or autoimmunity. genic risk of chemicals to man. Lyon, France: World
j.jtemb.2008.08.002
ARTICLE IN PRESS
Health Organization, International Agency for Research reticulum mediated apoptosis by imatinib mesylate
on Cancer; 1990. p. 49. combined with arsenic trioxide in chronic myeloid
[2] Pulido MD, Parish AR. Metal-induced apoptosis: leukemia. Blood 2006;107:1582–90.
mechanisms. Mutat Res 2003;533:227–41. [17] Ye HQ, Gan L, Yang XL, Xu HB. Membrane toxicity
[3] Shi H, Hudson LG, Liu KG. Oxidative stress and accounts for apoptosis induced by realgar nanoparticles,
apoptosis in metal ion induced carcinogenesis. Free in promyellocytic leukemia HL-60 cells. Biol Trace Elem
Radical Biol Med 2004;37:582–93. Res 2005;103:117–32.
[4] Salnikow K, Zhitkovich A. Genetic and epigenetic [18] Bashir S, Sharma Y, Irshad M, Nag TC, Tiwari M,
mechanisms in metal carcinogenesis and cocarcinogen- Kabra M, et al. Arsenic induced apoptosis in rat liver
esis: nickel, arsenic and chromium. Chem Res Toxicol following repeated 60 days exposure. Toxicology 2006;
2007;21(1):28–44. 217:63–70.
[5] WHO. Environmental health criteria, 224, arsenic and [19] Hornhardt S, Gomolka M, Walsh L, Jung T. Compara-
arsenic compounds. 2nd ed. Geneva: World Health tive investigations of sodium arsenite, arsenic trioxide
Organization; 2001. p. 385–92. and cadmium sulphate in combination with gamma
[6] IARC Monographs. Evaluation of carcinogenic risks to radiation on apoptosis, anicronulei induction and DNA
humans: some drinking-water disinfectants and con- damage in a human lymphoblastoid cell line. Mutat Res
taminants, including arsenic, vol. 84. Lyon: Interna- 2006;600:165–76.
tional Agency for Research on Cancer; 2004. 512p. [20] Cheung WM, Chu PW, Kwong YL. Effects of arsenic
[7] IARC Monographs. Evaluation of the carcinogenic risks trioxide on the cellular proliferation, apoptosis and
to humans: cobalt in hard metals and cobalt sulfate, differentiation of human neuroblastoma cells. Cancer
calcium arsenide, indium phosphide and vanadium Lett 2006;246(1–2):122–8.
pentoxide, vol. 86. Lyon: International Agency for [21] Bornstein J, Sagi S, Haj A, Harroch J, Fares F. Arsenic
Research on Cancer; 2006. 330p. trioxide inhibits the growth of human ovarian carcinoma
[8] NRC. Arsenic in drinking water. Washington, DC: cell line. Gynecol Oncol 2005;99:726–9.
National Academy Press; 1999. p. 310. [22] Graham-Evans B, Cohly HH, Yu H, Tchounwon PB.
[9] Liu SX, Davidson MM, Tang X, Walker WF, Athar M, Arsenic induced genotoxic and cytotoxic effects in
Ivanov V, et al. Mitochondrial damage mediates human keratinocytes, melanocytes and endritic cells.
genotoxicity of arsenic in mammalian cells. Cancer Res Int J Environ Res Public Health 2004;1:83–9.
2005;65:3236–42. [23] Ai Z, Lu W, Qin X. Arsenic trioxide induces gall bladder
[10] Gottschag E, Moore NE, Ryan AK, Travis LC, Waller carcinoma cell apoptosis via downregulation of Bcl-2.
RC, Pratt S, et al. Phenotypic anchoring of arsenic and Biochem Biophys Res Commun 2006;348:1075–81.
cadmium toxicity in three hepatic-related cell systems [24] Shao QS, Ye ZY, Ling ZQ, Ke JJ. Cell cycle arrest and
reveals compound- and cell-specific selective up-regula- apoptotic cell death in cultured human gastric carcinoma
tion of stress protein expression: implications for cells mediated by arsenic trioxide. World J Gastroenterol
fingerprint profiling of cytotoxicity. Chem Biol Interact 2005;11:3451–6.
2006;161:251–61. [25] Gonzalez-Rangel Y, Portales-Perez DP, Galicia-Cruz O,
[11] Li JJ, Tang Q, Li Y, Hu BR, Ming ZY, Fu Q, et al. Role Escudero-Lourdes C. Chronic exposure to arsenic
of oxidative stress in the apoptosis of hepatocellular sensitizes CD3+ and CD56+ human cells to sodium
carcinoma induced by combination of arsenic trioxide arsenite mediated apoptosis. Proc West Pharmacol Soc
and ascorbic acid. Acta Pharmacol Sin 2006;27:1078–84. 2005;48:89–91.
[12] Florea AM, Yamoah EN, Dopp E. Intracellular calcium [26] McNeely SC, Xu X, Taylor BF, Zacharias W, McCabe
disturbances induced by arsenic and its methylated Jr MJ, States JC. Exit from arsenite-induced mitotic
derivatives in relation to genomic damage and apoptosis arrest is p53 dependent. Environ Health Perspect
induction. Environ Health Perspect 2005;113:659–64. 2006;114(9):1401–6.
[13] Mehta A, Shaha C. Mechanism of metalloid induced [27] Yih LH, Lee TC. Arsenite induces p53 accumulation
death in Leishmamia spp.: role of iron, reactive oxygen through an ATM-dependent pathway in human fibro-
sprcies, Ca2+, and glutathione. Free Radical Biol Med blasts. Cancer Res 2000;60:6346–52.
2006;40:1857–68. [28] Matsui M, NIshigori C, Toyokuni S, Takada J,
[14] Ma XD, Qiao DF, Tian XM, Yan F, Ma AD. Akaboshi M, Ishikawa M, et al. The role of oxidative
Mechanism of opening of mitochondrial permeability DNA damage in human arsenic carcinogenesis: detec-
transition pore induced by arsenic trioxide. Ai Zhang tion of 8-hydroxy-20 -deoxyguanosine in arsenic related
2006;25:17–21 [in Chinese]. Bowen’s disease. J Invest Dermatol 1999;113:26–31.
[15] Peraza MA, Cromey DW, Carolus B, Carter DE, [29] Chen F, Lu Y, Zhang Z, Vallyathan V, Ding M,
Gandolfi AJ. Morphological and functional alterations Castranova V, et al. Opposite effect of NF-kappa B and
in human proximal tubular cell line induced by low level c-jun N-terminal kinase on p-53 independent GADD 45
inorganic arsenic: evidence for targetting of mitochon- induction by arsenite. J Biol Chem 2001;276:11414–9.
dria and initiated apoptosis. J Appl Toxicol 2006;26: [30] Qu W, Liu J, Fuquay R, Saavedra JE, Keefer LK,
356–67. Waalkes MP. The nitric oxide prodrug, V-PYRRO/NO,
[16] Du Y, Wang K, Fang H, Li J, Xiao D, Zheng P, et al. mitigates arsenic-induced liver cell toxicity and apopto-
Coordination of intrinsic, extrinsic and endoplasmic sis. Cancer Lett 2007;256(2):238–45.
j.jtemb.2008.08.002
ARTICLE IN PRESS
[31] Andrew AS, Bernardo V, Warnke LA, Davey JC, [46] Azzouqiel B, Tsangaris GT, Pellegrini O, Manuel Y,
Hampton T, Mason RA, et al. Exposure to arsenic at Benvieniste J, Thomas Y. Cadmium induces apoptosis in
levels found in US drinking water modifies expression in a human T cell line. Toxicology 1994;88:127–39.
the mouse lung. Toxicol Sci 2007;100(1):75–87. [47] Dong S, Shen HM, Ong CN. Cadmium induced
[32] Sun QX, Meng FY, Fu YB, Li L, Tian S. HL-60 cells apoptosis and phenotypic changes in mouse thymocytes.
apoptosis induced by bortezomib alone or in combina- Mol Cell Biochem 2001;222:11–20.
tion with arsenic trioxide in vitro. Nan Fang Yi Ke Da [48] Gennari A, Cortese E, Boreri M, Casado J, Prieto P.
Xue Xue Bao 2007;27(7):1022–5. Sensitive end points for evaluating cadmium induced
[33] Nemeti, Gregus. Reduction of arsenate to arsenite by acute toxicity in LLC_PK1 cells. Toxicology 2003;183:
human erythrocyte lysate and rat liver cytosol-charac- 21–220.
terization of a glutathione- and NAD-dependent ar- [49] Choi MK, Kim BH, Chang YY, Han MS. Cadmium
senate reduction linked to glycolysis. Toxicol Sci 2005; induced apoptosis in h9c2, a7r5 and c6-glial cell. Bull
85(2):847–58. Envion Contam Toxicol 2002;69:335–41.
[34] Nemeti, Gregus. Glutathione-dependent reduction of [50] Habeebu SS, Liu J, Klaassen CD. Cadmium induced
arsenate by glycogen phosphorylase a reaction coupled apoptosis in mouse liver. Toxicol Appl Pharmacol 1998;
to glycogenolysis. Toxicol Sci 2007;100(1):36–43. 149:203–9.
[35] Nemeti, Gregus. Glutathione-dependent reduction of [51] Orrenius S. Reactive Oxygen species in mitochondria-
arsenate by glycogen phosphorylase responsiveness to mediated cell death. Drug Metab Rev 2007;39:443–55.
endogenous and xenobiotic inhibitors. Toxicol Sci 2007; [52] Li M, Xia T, Jiang CS, Li LJ, Fu JL, Zhou ZC.
100(1):44–53. Cadmium directly induced the opening of membrane
[36] Bustamante J, Nutt L, Onvemius S, Gogvadze V. Arsenic permeability pore of mitochondria. Which possibly
stimulates release of cytochrome c from isolated mito- involved in cadmium triggered apoptosis. Toxicology
chondria via induction of mitochondrial permeability 2003;194:19–33.
transition. Toxicol Appl Pharmacol 2005;207:110–6. [53] Lopez E, Figueroa S, Oset-Gasque J, Gonzalez MP.
[37] Dipaolo JA, Casto BC. Quantitative studies of in vitro Apoptosis and necrosis: two distinct events induced by
morphologic transformation of Syrian hamster cells by cadmium in cortical neurons in culture. Br J Pharmacol
inorganic metal salts. Cancer Res 1979;39:1008–19. 2003;138:901–11.
[38] Sawyer RT, Fadok VA, Kittle LA, Majer LA, Newman [54] Chan PK, Cheng SH. Cadmium-induced ectopic apop-
LS. Beryllium-stimulated apoptosis in macrophage cell tosis in zebrafish embryos. Arch Toxicol 2003;77(2):
lines. Toxicology 2000;149:129–42. 69–79.
[39] Kittle LA, Sawyer RT, Fadok VA, Maier LA, Newman [55] Jimi S, Uchiyama M, Takaki A, Suzamiya J, Hara S.
LS. Beryllium induces apoptosis in human lung macro- Mechanisms of cell death induced by cadmium and
phages. Sarcoidosis Vasc Diffuse Lung Dis 2002;19: arsenic. Am NY Acad Sci 2004;1011:325–31.
101–13. [56] Risso-de Faverney C, Orsini N, de Sousa G, Rahmani R.
[40] Lavastre V, Roberge CJ, Pelletier M, Ganthier M, Girad Cadmium induced apoptosis through the mitochondrial
D. Toxaphene but not beryllium induces human pathway in rainbow trout hepatocytes: involvement of
neutrophil chemotaxis and apoptosis via reactive oxygen oxidative stress. Aquat Toxicol 2004;69:247–58.
species (ROS): involvement of caspases and ROS in the [57] Sokolova IM, Evans S, Hughes FM. Cadmium induced
degradation of cytoskeletal proteins. Clin Immunol apoptosis in oyster hemocytes involves disturbance of
2002;104:40–8. cellular energy balance but no mitochondrial perme-
[41] Sawyer RT, Dobis DR, Goldstein M, Velsor L, Maier ability transition. J Exp Biol 2004;207:3369–80.
LA, Fontenpot AP, et al. Beryllium stimulated reactive [58] Zhou T, Jia X, Chapin RE, Maronpot RR, Harris MW,
oxygen species and macrophage apoptosis. Free Radical Liu J, et al. Cadmium at a nontoxic doses alters gene
Biol Med 2005;38:928–37. expression mouse testes. Toxicol Lett 2004;154:191–200.
[42] Marchand-Adam S, Guilon F, Brauner M, Valevre D. [59] Cai Y, Ren X, Xu D, Wang M, Wu X. Apoptosis
Chronic beryllium disease: a model of interaction induced by cadmium and the expression of Bcl-2 and p53
between environmental exposure and genetic predisposi- genes in LLC-P1 cells. Wai Sheng Yan Jiu 2004;33:663–5
tion. Pathogenesis and clinical features (Part 2). Rev Mel [in Chinese].
Respir 2005;22(2 Part 1):271–87. [60] Kim SD, Moon CK, Eun SY, Ryu PD, Jo SA.
[43] Newman LS. Significance of the blood beryllium Identification of ASK1, MKK4, JNK, c-jun and
lymphocyte proliferation test. Environ Health Perspect caspase-3 as a signalling cascade involved in cadmium
1996;5:953–6. induced neuronal cell apoptosis. Biochem Biophys Res
[44] Saltini C, Winestock K, Kirby M, Pinkston P, Crystal Commun 2005;328:326–34.
RG. Maintenance of alveolitis in patients with chronic [61] Lag M, Refsnes M, Lilleaas EM, Holme JA, Becher R,
beryllium disease by beryllium-specific helper T cells. N Schwarze PE. Role of mitogen activated protein kinates
Engl J Med 1989;320(17):1103–9. and protein kinase C in cadmium induced apoptosis of
[45] Tinkle SS, Newman LS. Beryllium-stimulated release of primary epithelial lung cells. Toxicology 2005;211:253–64.
tumor necrosis factor-alpha, interleukin-6, and their [62] Deckert J. Cadmium toxicity in plants: is these any
soluble receptors in chronic beryllium disease. Am J analogy to its carcinogenic effects in mammalian cells?
Respir Crit Care Med 1997;156(6):1884–91. Biometals 2005;18:475–81.
j.jtemb.2008.08.002
ARTICLE IN PRESS
[63] Eichler T, Ma Q, Kelly C, Mishra J, Parikh S, Ransom [76] Nordberg GF, Jin T, Nordberg M. Sub-cellular targets
RF, et al. Single and combination toxic metal exposures of cadmium nephrotoxicity: cadmium binding to renal
induce apoptosis in cultured murine podocytes exclu- membrane proteins in animals with or without protective
sively via the extrinsic caspase 8 pathway. Toxicol Sci metallothionein synthesis. Environ Health Perspect
2006;90:392–9. 1994;102(Suppl. 3):191–4.
[64] Somji S, Garrett SH, Sens MA, Sens DA. The unique N- [77] Masters BA, Kelly EJ, Quaife CJ, Brinster RL, Palmiter
terminal sequences of metallothionein-3 is required to RD. Targeted disruption of metallothionein I and II
regulate the choice between apoptotic or necrotic cell genes increases sensitivity to cadmium. Proc Natl Acad
death of human proximal tubule cells exposed to Cd2+. Sci USA 1994;91(2):584–8.
Toxicol Sci 2006;90:369–76. [78] Michalska AE, Choo KH. Targeting and germ-line
[65] Oh SH, Lim SC. A rapid and transient ROS generation transmission of a null mutation at the metallothionein I
by cadmium triggers apoptosis via caspase dependent and II loci in mouse. Proc Natl Acad Sci USA 1993;
pathway in HspG-2 cells and this is inhibited through 90(17):8088–92.
N-acetylcysteine mediated catalase upregulation. Toxicol [79] Zheng H, Liu J, Choo KH, Michalska AE, Klaassen CD.
Appl Pharmacol 2006;212:212–23. Metallothionein-I and -II knock-out mice are sensitive to
[66] Pathak N, Khandelwal S. Modulation of cadmium cadmium-induced liver mRNA expression of c-jun and
induced alterations in murine thymocytes by piperine: p53. Toxicol Appl Pharmacol 1996;136(2):229–35.
oxidative stress, apoptosis, phenolyting and blastogen- [80] Liu Y, Liu J, Iszard MB, Andrews GK, Palmiter RD,
esis. Biochem Pharmacol 2006;72:486–97. Klaassen CD. Transgenic mice that overexpress metal-
[67] Kim SH, Sharma RP. Mercury induced apoptosis and lothionein-I are protected from cadmium lethality and
necrosis in murine macrophages: role of calcium induced hepatotoxicity. Toxicol Appl Pharmacol 1995;135(2):
reactive oxygen species and p38 mitogen-activated 222–8.
protein kinase signaling. Toxicol Appl Pharmacol [81] Dalton T, Fu K, Enders GC, Palmiter RD, Andrews
2004;196:47–57. GK. Analysis of the effects of overexpression of
[68] McClusky LM. Stage dependency of apoptosis and the metallothionein-I in transgenic mice on the reproductive
blood testis barrier in the dogfish shark (squalus toxicology of cadmium. Environ Health Perspect 1996;
acanthias) cadmium induced changes as assessed by 104(1):68–76.
vital fluorescence techniques. Cell Tissue Res 2006;325: [82] Shimada H, Hochadel JF, Waalkes MP. Progesterone
541–53. pretreatment enhances cellular sensitivity to cadmium
[69] Qu W, Fuquay R, Sakurai T, Waalkes MP. Acquisition despite a marked activation of the metallothionein gene.
of apoptotic resistance in cadmium induced malignant Toxicol Appl Pharmacol 1997;142(1):178–85.
transformation: specific perturbation of JNK signal [83] Satoh M, Nishimura N, Kanayama Y, Naganuma A,
transduction pathway and associated metallothionein Suzuki T, Tohyama C. Enhanced renal toxicity by
over expression. Mol Carcinog 2006;45:561–71. inorganic mercury in metallothionein-null mice. J
[70] Sancho P, Fernandez C, Yuste VJ, Amran D, Ramos Pharmacol Exp Ther 1997;283(3):1529–33.
AM, deBlas E, et al. Regulation of apoptosis/necrosis [84] Wang S, Leonard SS, Ye J, Ding M, Shi X. The role of
execution in cadmium treated human promonocytic cells hydroxyl radical as a messenger in Cr(VI) induced p-53
under different forms of oxidative stress. Apoptosis activation. Am J Physiol 2000;279:868–75.
2006;11:673–86. [85] Carlisle DL, Pritchard DE, Singh J, Patierno SR.
[71] Xie J, Shaikh ZA. Cadmium induced apoptosis in Chromium (VI) induces p53 dependent apoptosis in
rat kidney epithelial cells involved decrease in diploid human lung and mouse dermal fibroblasts. Mol
nuclear factor-kappa B activity. Toxicol Sci 2006;91: Carcinogen 2000;28:111–8.
299–308. [86] Shi X, Chiu A, Chen CT, Halliwell B, Castranova V,
[72] Papadakis ES, Finegan KG, Wang S, Robinson AC, Valliathan V. Reduction of chromium (VI) and its
Guo C, Kayahara M, et al. The regulation of Bax by relationship to carcinogenesis. J Toxicol Environ Health
c-jun N-terminal protein kinase (JNK) is a prerequisite B Crit Res 1999;2:87–104.
to the mitochondrial induced apoptotic pathway. FEBS [87] Blakenship LJ, Carlisle DL, Wise JP, Ornstein JM, Dye
Lett 2006;580:1320–6. LE, Patierno SR. Induction of apoptotic cell death by
[73] Gurel Z, Ozcelik D, Dursun S. Apoptotic rate and particulate lead chromate: differential effects of vitamins
metallothionein levels in the tissues of cadmium and C and E on genotoxicity and seurvival. Toxicol Appl
copper-exposed rats. Biol Trace Elem Res 2007;116(2): Pharmacol 1997;146:270–80.
203–18. [88] Ashcroft M, Kubbutat MH, Vousden KH. Regulation
[74] Pathak N, Khandelwal S. Impact of cadmium in T of p53 function and stability by phosphorylation. Mol
lymphocyte subsets and cytokine expression: differential Cell Biol 1999;19:1751–8.
regulation by oxidative stress and apoptosis. Biometals [89] Ye J, Wang S, Leonard SS, Sun Y, Butterworth L,
2007;21:179–87. Antonini J, et al. Role of reactive oxygen species and p53
[75] Liu Y, Zhang SP, Cai YQ. Cytoprotective effects of in chromium (VI) induced apoptosis. J Biol Chem
selenium on cadmium-induced LLC-PK1 cells apoptosis 1999;274:34974–80.
by activating JNK pathway. Toxicol In Vitro 2007;21(4): [90] Pritchard DE, Singh J, Carlisle DL, Patierno SR. Cyclo-
677–84. sporin A inhibits chromium (VI) induced apoptosis and
j.jtemb.2008.08.002
ARTICLE IN PRESS
mitochondrial cytochrome C release and restores clono- [106] Bagchi D, Bagchi M, Stohs SJ. Chromium (VI)-induced
genic survival in CHO cells. Carcinogenesis 2000;21: oxidative stress, apoptotic cell death and modulation of
2027–33. p53 tumor suppressor gene. Mol Cell Biochem 2001;
[91] Andrew AS, Warren AJ, Barchowsky A, Temple KA, 222(1–2):149–58.
Klei L, Soucy NV, et al. Genomic and proteonomic [107] Balamurugan K, Rajaram R, Ramasami T, Narayanan
profiling of responses to toxic metals in human lung S. Chromium(III)-induced apoptosis of lymphocytes:
cells. Environ Health Perspect 2003;111:825–35. death decision by ROS and Src-family tyrosine kinases.
[92] Gambelunghe A, Piccinini R, Ambrogi M, Villarini M, Free Radical Biol Med 2002;33(12):1622–40.
Moretti M, Marchetti C, et al. Primary DNA damage in [108] Balamurugan K, Rajaram R, Ramasami T. Caspase-3:
chrome plating workers. Toxicology 2003;188:187–95. its potential involvement in Cr(III)-induced apoptosis of
[93] Izzotti A, Bagnasco M, Cartiglia C, Longobrali M, De lymphocytes. Mol Cell Biochem 2004;259(1–2):43–51.
Flora S. Proteomic analysis as related to transcriptions [109] Semple AB, Parry WH, Phillips DE. Acute copper
data in the lung of chromium (VI) treated rats. Int J poisoning: an outbreak traced to contaminated water
Oncol 2004;24:1513–22. from a corroded geyser. Lancet 1960;2(7152):700–1.
[94] Huk OL, Catelas I, Mwale F, Antoniou J, Zukor DJ, [110] Spitalny KC, Brondum J, Vogt RL, Sargent HE, Kappel
Petit A. Induction of apoptosis and necrosis by metal S. Drinking-water-induced copper intoxication in a
ions in vitro. J Arthroplasty 2004;19:84–7. Vermont family. Pediatrics 1984;74(6):1103–6.
[95] Catelas I, Petit A, Vali H, Fragisktos C, Meillenr R, [111] Knobeloch L, Ziarnik M, Howard J, Theis B, Farmer D,
Zukor DJ, et al. Quantitative analysis of macrophase Anderson H, et al. Gastrointestinal upsets associated
apoptosis vs necrosis induced by cobalt and chromium with ingestion of copper-contaminated water. Environ
ions in vitro. Biomaterials 2005;26:2441–53. Health Perspect 1994;102(11):958–61.
[96] Russo P, Catassi A, Cesario A, Imperatori A, Rotolo N, [112] Chuttani HK, Gupta PS, Gulati S, Gupta DN. Acute
Fini M, et al. Molecular mechanisms of hexavalent copper sulfate poisoning. Am J Med 1965;39(5):849–54.
chromium-induced apoptosis in human bronchoalveolar [113] Mueller EJ, Seger DL. Metal fume fever – a review.
cells. Am J Respir Cell Mol Biol 2005;33:589–600. J Emerg Med 1985;2(4):271–4.
[97] Pritchard DE, Ceryak S, Ramsey KE, O’Brien TJ, Ha L, [114] Stohs SJ, Bagchi D. Oxidative mechanisms the toxicity
Fornsaglio JL, et al. Resistance to apoptosis, increased of metal ions. Free Radical Biol Med 1995;18:321–36.
growth potential and altered gene expression in cells that [115] Pourahmad J, Ross S, O’Brien PJ. Lysosomal involve-
survived genotoxic hexavalent Cr (VI) exposure. Mol ment in hepatocyte cytotoxicity induced by Cu(2+) but
Cell Biochem 2005;279:169–81. not Cd(2+). Free Radical Biol Med 2001;30:89–97.
[98] Manning FC, Xu J, Patierno SR. Transcriptional [116] Pourahmad J, O’Brien PJ, Jokar F, Daraei B. Carcino-
inhibition by carcinogenic chromate. Relationship to genic metal induced sites of reactive oxygen species
DNA damage. Mol Carcinog 1994;6:270–9. formatin in hepatocytes. Toxicol In Vitro 2003;17:803–10.
[99] Singh J, Carlisle DL, Pritchard DE, Patierno SR. [117] Kannan K, Jain SK. Oxidative stress and apoptosis.
Chromium induced genotoxicity and apoptosis: relation- Pathophysiology 2000;7:153–63.
ship to chromium carcinogenesis. Oncol Rep 1998;5: [118] Siraki AG, Pourahmad J, Chan TS, Khan S, O’Brien PJ.
1307–18. Endogenous and endobiotic induced reactive oxygen
[100] Rafael AI, Almeida A, Santos P, Parreira I, Madeira VM, species formation by isolated hepatocytes. Free Radical
Alves R, et al. A role for transforming growth factor-beta Biol Med 2002;32:2–10.
apoptotic signaling pathway in liver injury induced by [119] Xiang L X, Shao JZ. Role of intracellular Ca(2+) ,
ingestion of water contaminated with high levels of reactive oxygen species, mitochondria transmembrane
Cr(VI). Toxicol Appl Pharmacol 2007;224(2):163–73. potential and antioxidant enzymes in heavy metal
[101] Gavin IM, Gillis B, Arbieva Z, Prabhakar BS. Identi- induced apoptosis in fish cells. Bull Environ Contam
fication of human cell responses to hexavalent chro- Toxicol 2003;71:114–22.
mium. Environ Mol Mutagen 2007;48:650–7. [120] Rauen U, Petrat F, Sustmann R, de Groot H. Iron
[102] He X, Lin GX, Chen MG, Zhang JX, Ma Q. Protection induced mitochondrial permeability transition in cul-
against chromium(VI)-induced oxidative stress and tured hepatocytes. J Hepatol 2004;40:607–15.
apoptosis by Nrf2. Recruiting Nrf2 into the nucleus [121] Lemasters JJ. Necraprosis and the mitochondrial perme-
and disrupting the nuclear Nrf2/Keap1 association. ability transition: shared pathways to necrosis and
Toxicol Sci 2007;98(1):298–309. apoptosis. Am J Physiol 1999;276:G1–6.
[103] Leonard SS, Roberts JR, Antonini JM, Castranova V, [122] Krumschnabel G, Manzl C, Berger C, Hofer B.
Shi X. PbCrO4 mediates cellular responses via reactive Oxidative stress, mitochondrial permeability transition
oxygen species. Mol Cell Biochem 2004;255(1–2):171–9. and cell death in Cu exposed trout hepatocytes. Toxicol
[104] Liu K, Husler J, Ye J, Leonard SS, Cutler D, Chen F, Appl Pharmacol 2005;209:62–73.
et al. On the mechanism of Cr (VI)-induced carcinogen- [123] Mufti AR, Burstein E, Csomos RA, Graf PC, Wilkinson
esis: dose dependence of uptake and cellular responses. JC, Dick RD, et al. XIAP is a copper binding protein
Mol Cell Biochem 2001;222(1–2):221–9. deregulated in Wilson’s disease and other copper
[105] Wang S, Shi X. Mechanisms of Cr(VI)-induced p53 toxicosis disorders. Mol Cell 2006;21:775–85.
activation: the role of phosphorylation, mdm2 and [124] Linbo TL, Stehr CM, Incardona JP, Scholz NL.
ERK. Carcinogenesis 2001;22(5):757–62. Dissolved copper triggers cell death in the peripheral
j.jtemb.2008.08.002
ARTICLE IN PRESS
mechanosensory system of larval fish. Environ Toxicol opening the mitochondrial permeability transition pore.
Chem 2006;25:597–603. J Biol Chem 2000;275:12175–84.
[125] Vanlandingham JW, Tassabehji NM, Somers RC, [141] He L, Perkins GA, Poblenz AT, Harris JB, Hung M,
Levenson CW. Expression profiling of p53 target genes Ellishman MH, et al. Bcl-xL overexpression locks bax
in copper mediated neuronal apoptosis. Neuromol Med mediated mitochondrial contact site formation and
2005;7:311–24. apoptosis in rod photoreceptors of lead exposed mice.
[126] Tassabehji NM, Vanlandingham JW, Levenson CW. Proc Natl Acad Sci USA 2000;100:1022–7.
Copper alters the conformation and transcriptional [142] Sharifi AM, Baniasadi S, Jorjani M, Rahimi F,
activity of the tumor suppressor protein p53 in human Bakhshayesh M. Investigation of acute lead poisoning
HepG2 cells. Exp Biol Med 2005;230:699–708. on apoptosis in rat hippocampus in vivo. Neurosci Lett
[127] Samuele A, Mangiagalli A, Armentero MT, Fancellu R, 2002;329:45–8.
Bazzini E, Vairetti M, et al. Oxidative stress and [143] Loikkanen J, Chralova K, Naarala J, Vahakangas KH,
pro-apoptotic conditions in a rodent model of Savolaiene KM. Pb2+-induced toxicity is associated with
Wilson’s disease. Biochem Biophys Acta 2005;174: p53-independent apoptosis and enhanced by glutamate
325–30. in GT1-7 neurons. Toxicol Lett 2003;144:235–46.
[128] Brewer GJ. A brand new mechanism for copper toxicity. [144] Gargioni R, Filipak NF, Buchi DF, Randi MA, Franco
J Hepatol 2007;47(4):621–2. CR, Paludo KS, et al. Cell death and DNA damage in
[129] Viola-Rhenals M, Rieber MS, Rieber M. Role of peritoneal macrophages of mice (Mus musculus) ex-
peroxidases, thiols and Bak/Bax in tumor cell suscept- posed to inorganic lead. Cell Biol Int 2006;30:615–25.
ibility to Cu[DEDTC](2). Biochem Pharmacol 2007; [145] Hirango T, Ohyama K, Hashigaya A, Ishikawa T,
74(6):841–50. Muramoto W, Kitagawa H, et al. Lead exposure induces
[130] Gaetke LM, Chow CK. Copper toxicity, oxidative pycnosis and enucleation of peripheral erythrocytes in
stress, and antioxidant nutrients. Toxicology 2003; the domestic fowl. Vet J 2007.
189(1–2):147–63. [146] Silbergeld EK, Waalkes M, Rice JM. Lead as a
[131] Britton RS. Metal-induced hepatotoxicity. Semin Liver carcinogen: experimental evidence and mechanisms of
Dis 1996;16(1):3–12. action. Am J Ind Med 2000;38(3):316–23.
[132] Bremner I. Manifestations of copper excess. Am J Clin [147] Hunaiti AA, Soud M. Effect of lead concentration on
Nutr 1998;67(5 Suppl.):1069S–73S. the level of glutathione, glutathione S-transferase,
[133] Sokol RJ, Devereaux M, Mierau GW, Hambidge KM, reductase and peroxidase in human blood. Sci Total
Shikes RH. Oxidant injury to hepatic mitochondrial Environ 2000;248(1):45–50.
lipids in rats with dietary copper overload. Modification [148] Hartwig A. Role of DNA repair inhibition in lead- and
by vitamin E deficiency. Gastroenterology 1990;99(4): cadmium-induced genotoxicity: a review. Environ
1061–71. Health Perspect 1994;102(Suppl. 3):45–50.
[134] Zhang SSZ, Noordin MM, Rahman SOA, Haron J. [149] Quintanilla-Vega B, Hoover D, Bal W, Silbergeld EK,
Effects of copper overload on hepatic lipid peroxidation Waalkes MP, Anderson LD. Lead effects on protami-
and antioxidant defense in rats. Vet Hum Toxicol ne–DNA binding. Am J Ind Med 2000;38(3):324–9.
2000;42(5):261–4. [150] Hengstler JG, Bolm-Audorff U, Faldum A, Janssen K,
[135] Fox DA, He L, Poblenz AT, Medrano CJ, Blocker YS, Reifenrath M, Götte W, et al. Occupational exposure to
Srivastava D. Lead induced alterations in retinal cGMP heavy metals: DNA damage induction and DNA repair
phosphodiesterase trigger calcium over load, mitochon- inhibition prove co-exposures to cadmium, cobalt and
drial dysfunction and rod photoreceptor apoptosis. lead as more dangerous than hitherto expected. Carci-
Toxicol Lett 1998;102–103:359–61. nogenesis 2003;24(1):63–73.
[136] Shabani A, Rabbani A. Lead nitrate induced apoptosis [151] Homma-Takeda S, Kugenuma Y, Iwamuro T, Kumagai
in alveolar macrophages from rat lung. Toxicology Y, Shimojo N. Impairment of spermatogenesis in rats by
2000;149:109–14. methyl mercury: involvement of stage and cell specific
[137] Columbano A, Ledda-Columbano GM, Coni PP, Faa germ cell apoptosis. Toxicology 2001;169:25–35.
G, Lignori C, Santa Cruz G, et al. Occurrence of cell [152] Castoldi AF, Coccini T, Ceccatelli S, Manzo L.
death (apoptosis) during the involution of liver hyper- Neurotoxicity and molecular effects of methyl mercury.
plasia. Lab Invest 1985;52:670–5. Brain Res Bull 2001;55:197–203.
[138] Cheng YJ, Yang BC, Hsich WC, Huang BM, Liu MY. [153] Shenker BJ, Pankoski L, Zekavat A, Shapiro IM.
Enhancement of TNFa expression does not trigger Mercury induced apoptosis in human lymphocytes:
apoptosis upon exposure of glial cells to lead and caspase activation is linked to redox status. Antioxid
lipopolysaccharide. Toxicology 2002;178:183–91. Redox Signal 2002;4:379–89.
[139] de la Fuente H, Portales-Perez D, Baranda L, Diaz- [154] Woods JS, Dieguez-Acuna FJ, Ellis ME, Kushleika J,
Barriga F, Saaredra-Alanis V, Layseca E, et al. Effect of Simmunds PL. Attentuation of nuclear factor KappaB
arsenic, cadmium and lead on the induction of apoptosis (NF-kappaB) promotes apoptosis of kidney epithelial
of normal human mononuclear cells. Clin Exp Immunol cells: a potential mechanism of mercury induced nephro-
2002;129:69–77. toxicity. Environ Health Perspect 2002;110:819–22.
[140] He L, Poblenz AT, Medrano CJ, Fox DA. Lead and [155] Kim SH, Sharma RP. Cytotoxicity of inorganic mercury
calcium produce rod photoreceptor cell apoptosis by in murine T and B lymphoma cell lines: involvement of
j.jtemb.2008.08.002
ARTICLE IN PRESS
reactive oxygen species, Ca(2+) homeostasis and cyto- [170] Lee SH, Kim DK, Seo YR, Woo KM, Kim CS, Cho
kine gene expression. Toxicol In Vitro 2003;17: MH. Nickel (II) induced apoptosis and G2/M envich-
385–95. ment. Exp Mol Med 1998;30:171–6.
[156] McCabe Jr MJ, Whitekus MJ, Hyun J, Eckles KG, [171] Cangul H, Broday L, Salnikow K, Sutherland J, Peng
McCollum G, Rosenspire AJ. Inorganic mercury W, Zhang Q, et al. Molecular mechanisms of nickel
attenuates CD95 mediated apoptosis by interfering with carcinogenesis. Toxicol Lett 2002;127:65–75.
formation of the death inducing signaling complex. [172] Kim K, Lee SH, Seo YR, Perkins SN, Kasprzak KS.
Toxicol Appl Pharmacol 2003;190:146–56. Nickel(II) induced apoptosis in murine T cell hybridoma
[157] Kuo TC, Lin-Shiau SY. Early acute necrosis and cells is associated with increased far ligand expression.
delayed apoptosis induced by methyl mercury in murine Toxicol Appl Pharmacol 2002;185:41–7.
peritoneal neutrophils. Basic Clin Pharmacol Toxicol [173] Riley MR, Boesewetter DE, Kim AM, SIrvent FP.
2004;94:274–81. Effects of metals Cu, Fe, Ni, U and Zn on rat lung
[158] Dieguez-Acuna FJ, Polk WW, Ellis ME, Simmonds PL, epithelial cells. Toxicology 2003;190:171–84.
Kushleika JV, Woods JS. Nuclear factor kappa B [174] Doreswamy K, Shrilatha B, Rajesh Kumar T, Mur-
activity determines the sensitivity of kidney epithelial alidhara. Nickel induced oxidative stress in testis of
cells to apoptosis: implications for mercury induced mice: evidence of DNA damage and genotoxic effects.
renal failure. Toxicol Sci 2004;82:114–23. J Androl 2004;25:996–1003.
[159] McCabe Jr MJ, Eckles KG, Langdon M, Clarkson TW, [175] Trombetta D, Mondello MR, Cimino F, Cristani M,
Whitekus MJ, Rosenspire AJ. Attenuation of CD95- Pergolizzi S, Saija A. Toxic effects of nickel in an in vitro
induced apoptosis by inorganic mercury: caspase 3 is not model of human oral epithelium. Toxicol Lett 2005;159:
a direct target of low levels of Hg2+. Toxicol Lett 219–25.
2005;155:161–70. [176] M’Bemba-Meka P, Lemieux N, Chakrabarti SK. Role
[160] Carranza-Rosales P, Said-Fernandez S, Sepulveda-Saar- of oxidative stress, mitochondrial membrane potential
edra J, Cruz-Vega DE, Gandolfi AJ. Morphologic and and calcium homeostasis in human lymphocyte death
functional alterations induced by low doses of mercuric induced by nickel carbonate hydroxide in vitro. Arch
chloride in the kidney OK cell line: ultrastructural Toxicol 2006;80:405–20.
evidence for an apoptotic mechanism of damage. [177] Au A, Ha J, Hernandez M, Polotsky A, Hungerford DS,
Toxicology 2005;210:111–21. Frondoza CG. Nickel and vanadium metal ions induce
[161] Crespo-Lopez ME, Herculano AM, Corvelo TC, Do apoptosis of T-lymphocyte Jurkat cells. J Biomed Mater
Naseimento JL. Mercury and neurotoxicity. Rev Neurol Res A 2006;79(3):512–21.
2005;40:441–7. [178] Guan F, Zhang D, Wang X, Chen J. Nitric oxide and
[162] Ortega-Villasante C, Rellan-Alvarez R, Del Campo FF, bcl-2 mediated the apoptosis induced by nickel(II) in
Carpena-Ruiz RO, Hernandez LE. Cellular damage human T hybridoma cells. Toxicol Appl Pharmacol
induced by cadmium and mercury in Medicago-sativa. 2007;221(1):86–94.
Exp Bot 2005;56:2239–51. [179] Ding J, Zhang X, Li J, Song L, Ouyang W, Zhang D, et
[163] Tarabova B, Kurejova M, Sulova Z, Drabova M, al. Nickel compounds render anti-apoptotic effect to
Lacinova L. Inorganic mercury and methyl mercury human bronchial epithelial Beas-2B cells by induction of
inhibit the Cav 3.1 channel expressed in human cyclooxygenase-2 through an IKKbeta/p65-dependent
embryonic kidney 293 cells by different mechanisms. and IKKalpha- and p50-independent pathway. J Biol
Pharmacol Exp Therap 2006;317:418–27. Chem 2006;281(51):39022–32.
[164] Lee JH, Youm JH, Kwon KS. Mercuric chloride induces [180] Harris GK, Shi X. Signaling by carcinogenic metals and
apoptosis in MDCK cells. Prov Med Pub Health metal-induced reactive oxygen species. Mutat Res
2006;39:199–204. 2003;533(1–2):183–200.
[165] Sunderman FW. Mechanisms of nickel carcinogenesis. [181] Lu H, Shi X, Costa M, Huang C. Carcinogenic effect of
Scand J Work Environ Health 1989;15:1–12. nickel compounds. Mol Cell Biochem 2005;279(1–2):45–67.
[166] Dally H, Hartwig A. Induction and repair inhibition of [182] Davidson T, Ke Q, Costa M. In: Nordberg G, Nordberg
oxidative DNA damage by nickel (II) and cadmium (II) M, Fowler B, editors. Handbook on the toxicology of
in mammalian cells. Carcinogenesis 1997;18:1021–6. metals. San Diego: Elsevier, Inc.; 2006 [Chapter 5]. p. 79–99.
[167] Goebeler M, Roth J, Brocker EB, Sorg C, Schulze- [183] Salnikow K, Davidson T, Costa M. The role of hypoxia-
Osthoff K. Activation of nuclear factor-kappa B gene inducible signaling pathway in nickel carcinogenesis.
expression in human endothelial cells by the common Environ Health Perspect 2002;110(Suppl. 5):831–4.
haptens nickel and cobalt. J Immunol 1995;155: [184] Davidson T, Salnikow K, Costa M. Hypoxia inducible
2459–67. factor-1 alpha-independent suppression of aryl hydro-
[168] Li GX, Hu H, Jiang C, Schuster T, Lü J. Differential carbon receptor-regulated genes by nickel. Mol Pharma-
involvement of reactive oxygen species in apoptosis col 2003;64(6):1485–93.
induced by two classes of selenium compounds in human [185] Salnikow K, Davidson T, Kluz T, Chen H, Zhou D,
prostate cancer cells. Int J Cancer 2007;120(9):2034–43. Costa M. GeneChip analysis of signaling pathways
[169] Lynn S, Yew FH, Chen KS, Jan KY. Reactive oxygen effected by nickel. J Environ Monit 2003;5(2):206–9.
species are involve din nickel inhibition of DNA repair. [186] Salnikow K, Davidson T, Zhang Q, Chen LC,
Environ Mol Mutagen 1997;29:208–16. Su W, Costa M. The involvement of hypoxia-inducible
j.jtemb.2008.08.002
ARTICLE IN PRESS
transcription factor-1-dependent pathway in nickel [196] Choy WN, Henika PR, Willhite CC, Tarantal AF.
carcinogenesis. Cancer Res 2003;63(13):3524–30. Incorporation of a micronucleus study into a develop-
[187] Zhao R, Xiang N, Domann FE, Zhong W. Expression mental toxicology and pharmacokinetic study of L-
of p53 enhances selenite-induced superoxide production selenomethionine in nonhuman primates. Environ Mol
and apoptosis in human prostate cancer cells. Cancer Mutagen 1993;21(1):73–80.
Res 2006;66(4):2296–304. [197] Anundi I, St(ahl A, Högberg J. Effects of selenite on O2
[188] Tang R, Liu H, Wang T, Huang K. Mechanisms of consumption, glutathione oxidation and NADPH levels
selenium inhibition of cell apoptosis induced by oxyster- in isolated hepatocytes and the role of redox changes in
ols in rat vascular smooth muscle cells. Arch Biochem selenite toxicity. Chem Biol Interact 1984;50(3):277–88.
Biophys 2005;441(1):16–24. [198] Garberg P, Sta( hl A, Warholm M, Högberg J. Studies of
[189] Zeng H, Combs Jr GF. Selenium as an anticancer the role of DNA fragmentation in selenium toxicity.
nutrient: roles in cell proliferation and tumor cell Biochem Pharmacol 1988;37(18):3401–6.
invasion. J Nutr Biochem 2008;19(1):1–7. [199] Nuttall KL. A model for metal selenide formation under
[190] Rikiishi H. Apoptotic cellular events for selenium biological conditions. Med Hypotheses 1987;24(2):
compounds involved in cancer prevention. J Bioenerg 217–21.
Biomembr 2007;39(1):91–8. [200] Madden EF, Fowler BA. Mechanisms of nephrotoxicity
[191] Liu Y, Zhang SP, Cai YQ. Cytoprotective effects of from metal combinations: a review. Drug Chem Toxicol
selenium on cadmium-induced LLC-PK1 cells apoptosis 2000;23(1):1–12.
by activating JNK pathway. Toxicol In Vitro 2007; [201] Shimada H, Shiao YH, Shibata M, Waalkes MP.
21(4):677–84. Cadmium suppresses apoptosis induced by chromium.
[192] Yu RA, Yang CF, Chen XM. DNA damage, apoptosis J Toxicol Environ Health A 1998;54:159–68.
and C-myc, C-fos, and C-jun overexpression induced by [202] Chuang SM, Liou GY, Yang JL. Activation of JNK,
selenium in rat hepatocytes. Biomed Environ Sci p38 and ERK mitogen-activated protein kinases by
2006;19(3):197–204. chromium(VI) is mediated through oxidative stress but
[193] Kramer GF, Ames BN. Mechanisms of mutagenicity does not affect cytotoxicity. Carcinogenesis 2000;21:
and toxicity of sodium selenite (Na2SeO3) in Salmonella 1491–500.
typhimurium. Mutat Res 1988;201(1):169–80. [203] Hainaut P, Mann K. Zinc binding and redox control of
[194] Norppa H, Westermarck T, Oksanen A, Rimaila- p53 structure and function. Antioxid Redox Signal
Pärnänen E, Knuutila S. Chromosomal effects of sodium 2001;3:611–23.
selenite in vivo. II. Aberrations in mouse bone marrow [204] Fong LY, Nguyen VT, Pegg AE, Magee PN. Alpha-
and primary spermatocytes. Hereditas 1980;93(1):97–9. difluoromethylornithine induction of apoptosis: a me-
[195] Choy WN, Willhite CC, Cukierski MJ, Book SA. chanism which reverses pre-established cell proliferation
Primate micronucleus study of L-selenomethionine. and cancer initiation in esophageal carcinogenesis in
Environ Mol Mutagen 1989;14(2):123–5. zinc-deficient rats. Toxicol Lett 2001;13:51–6.
j.jtemb.2008.08.002

SD Article 3

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

SD Article 3

Uploaded by

Copyright:

Available Formats

ARTICLE IN PRESS

Journal of Trace Elements in Medicine and Biology ] (]]]]) ]]]–]]]

Received 20 February 2007; accepted 11 July 2008

Keywords: Metals; Metalloids; Apoptosis; Cell proliferation; Carcinogenicity

Tel./fax: +91 121 2774569.

Introduction Apoptosis is considered as an ongoing normal event

well as impairment in carcinogenicity and development.

also play an important role in both cellular toxicity and

increased expression of Smad2/Smad4 and Dapk Copper

Chromium (Cr (VI)) can generate ROS, activate Copper toxicity

due to the opening of the PTP, resulting in the Mercury

Nickel can activate several cellular stress response

You might also like