International Journal of Scientific Research in Environmental Sciences (IJSRES), 1(8), pp. 202-216, 2013 Available online at http://www.ijsrpub.com/ijsres

ISSN: 2322-4983; ©2013 IJSRPUB

http://dx.doi.org/10.12983/ijsres-2013-p202-216

202

Review Paper

A Review of Genetic and Epigenetic Mechanisms in Heavy Metal Carcinogenesis:

Nickel and Cadmium

Zienab Saedi, Shahin Gavanji*, Sahar Davodi

1Department of Biotechnology, Faculty of Advanced Sciences and Technologies, University of Isfahan, Isfahan, Iran

*Corresponding Author: shahin.gavanji@yahoo.com

Received 11 June 2013; Accepted 25 July 2013

Abstract. Heavy metals constitute an important class of environmental contaminants that classified as human carcinogens

according to the US Environmental Protection Agency and the International Agency for Research on Cancer. They affect

human health through occupational and environmental exposure. Multiple experimental epidemiological studies indicate that

heavy metals such as Nickel and Cadmium can induce several types of cancer significantly pulmonary cancers, but the

mechanisms underlying the carcinogenesis are not well understood yet. This metals are genotoxic elements for human, while

they are typically weak mutagens, indicating that indirect mechanisms may be primary responsible for their genotoxicity.

Several studies suggest that epigenetic mechanisms may play an important role in metal-induced carcinogenesis. Here, we

review studies that investigate the common mechanisms of nickel and cadmium-induced carcinogenesis, include DNA

methylation, histone modification, induction of oxidative stress, interference with DNA repair system, and interruption of cell

growth and proliferation through signaling pathway and dysregulation of tumor suppressor genes.

Key words: Nickel, Cadmium, Genotoxicity, Molecular mechanism

1. INTRODUCTION

Pollution of the biosphere with heavy metals due to

man-made activities poses an important

environmental and human health problem (Kabir et

al., 2012; Han et al., 2002; Gavanji et al., 2012).

Increasing data show a link between heavy

metal exposure and aberrant changes in both genetic

and epigenetic factors in humans. Nickel and

cadmium are heavy metals which exposure to their

compounds can induce several kinds of cancers

specially pulmonary cancer (Grimsrud et al., 2003;

Waalkes, 2000; Gavanji et al., 2013). Exposure of

Syrian hamster embryo (SHE) cells to nickel

subsulfide resulted in morphological transformation

and the transformed cells were able to induce

sarcomas in nude mice. Also the exposure of mouse

embryo fibroblast C3H/10T 1/2 cells to nickel sulfide

also led to cell transformation (Salnikow and Costa,

2000). It has been shown that cadmium can induce

malignant transformation of the human prostate

epithelial cell line (RWPE-1) (Achanzar et al., 2001).

Molecular mechanisms underlying Ni and Ca cell-

transforming ability are not well understood. Both of

them are weak mutagens and do not exhibit positive

effects in a wide range of mutation tests (IARC,

2012). Thus Several types of indirect mechanisms

have been identified that may contribute to their

genotoxic potentials, such as induction of oxidative

DNA damage and gene silencing by changes in DNA

methylation patterns (Aritaa and Costa, 2009).

2. METHODOLOGY

Firstly, based on our research about heavy Metal,

articles regarding to effects of heavy Metal on

eukaryotic cells were searched in several data bases

available through UI (University of Isfahan) library

website and Google scholar too. Referral articles (150

articles) include which were published between 1981

to 2013. Then they were reviewed during 8 months

and important points related to the effect of heavy

Metal on eukaryotic cells were studied particularly.

We, in this review, studied the molecular mechanism

of heavy Metal on eukaryotic cells.

2.1. Nickel

Nickel is a hard, silvery-white transition metal with

the atomic number 28. It is the 24th most abundant

element. The most important oxidation state of nickel

is +2. Other valences include -1, 0, +1, +3 and +4

(Tundermann et al., 2005). Nickel and its compounds

are widely used in modern industry. It is used in

conjunction with other metals to form alloys to

produce coins, jewelry, and stainless steel as well as

for nickel plating and manufacturing Ni-Cd batteries

and for catalyze the production of carbon

nanoparticles (Grandjean, 1984). The production,

Saedi et al.

A Review of Genetic and Epigenetic Mechanisms in Heavy Metal Carcinogenesis: Nickel and Cadmium

203

processing, and recycling of nickel products has

resulted in a high level of pollution such that nickel

contamination now occurs in water, soil and the

ambient air (Lippmann et al., 2006). Combustion of

fossil fuels produces the greatest contribution of

nickel compounds in the ambient air (Merian, 1984).

Nickel compounds can enter the body through

inhalation, ingestion, and dermal absorption

(Grandjean, 1984) and they have been found to be

carcinogenic based upon numerous epidemiological

studies (Doll et al., 1970). The International Agency

for Research on Cancer (IARC) evaluated the

carcinogenicity of nickel in 1990. All Ni (II)

compounds were recognized as human carcinogens

(Group 1) and metallic nickel is classified as possibly

carcinogenic to humans (Group 2B) (kasprzak et al.,

2003). It has been found that exposures to nickel

compounds are associated with increased nasal and

lung cancer incidence (Andersen., 1996; Grimsrud et

al., 2003). A summary of toxicity of various nickel

species and compounds are shown in table 1. The

carcinogenicity of nickel has been explained by

several mechanisms such as inhibition of DNA repair

(Woźniak and Błasiak, 2004), oxidative stress (Chen

et al., 2003) and deregulation normal growth control

(Salnikow and Zhitkovich, 2008) which are discussed

below.

2.2. Cellular uptake

Carcinogenesis of metal compounds depends on their

ability to enter the cell and it’s probably related to

their solubility in water. Water-soluble nickel

compounds possess lower toxic and carcinogenic

potential as compared to insoluble nickel compounds

because Water-soluble compounds such as Nickel

acetate, bromide, chloride, iodide, nitrate and sulfate

are quickly flushed from tissue and therefore has a

limited ability to enter the cell via the divalent metal

transporter 1 (DMT1) (Funakoshi et al., 1997;

Denkhaus and Salnikow, 2002). Some of soluble

nickel compounds enters cell via calcium channels

(Refsvik and Andreassen, 1995; Funakoshi et al.,

1997). NiCI2 and NiSO4 enter cells with relative ease,

possibly following conjugation with serum proteins or

amino acids such as histidine (Costa et al., 1981).

Insoluble nickel compounds possibly enter the cell

through phagocytosis. many results clearly indicate

that water-insoluble nickel compounds such as

crystalline nickel sulfide(Nis) and crystalline nickel

sub sulfide (Ni3S2) phagocytized by a large variety of

different cells in culture (Costa et al., 1981). Ni

carbonyl, a highly toxic form of Ni, is lipid soluble

allowing it to pass through the cellular membrane and

in turn significant absorption occurs through

inhalation and skin contact )Muñoz and Costa, 2012).

Numerous studies point to the cell nucleus as the site

of nickel attack (Salnikow et al., 1994; Lee et al.,

1995). Nickel chloride has been shown in different

cell lines in culture to be transported to the nucleus

(Edwards et al., 1998; Schwerdtle and Hartwig, 2006).

2.3. Induction of oxidative stress

Nickel compounds are able to cause the cell

transformation and chromatin damage )Cai and

Zhuang, 1999; M’Bemba-Meka et al., 2005) but they

are not mutagenic in a wide range of bacterial

mutagenesis assays and are only weakly mutagenic in

cultured mammalian cells (Biggart and Costa, 1986;

klein et al., 1991; Kerckaert et al., 1996). One possible

explanation for this is nickel cause the DNA damage

and cell transformation via generation of reactive

oxygen species (ROS) (Salnikow and Costa, 2000).

Like many other carcinogenic metals, nickel

compounds are able to induce the formation of ROS.

Nickel is a redox-active metal that can catalyse

Fenton-type reactions (Huang et al., 1993; Chen et al.,

2003). In cells treated with nickel compounds,

increase in DNA stand breaks, DNA–protein

crosslinks and sister chromatid exchange was

observed and these are shown to result from the

increase in reactive oxygen species (Chakrabarti et al.,

2001; M’Bemba-Meka et al., 2005, 2007). Nickel (II)

ions can catalyze the generation of OH radicals from

H2O2. These radicals attack the DNA bases and cause

to formation of typical OH-induced products of DNA

bases in isolated human chromatin (Nackerdien et al.,

1991; Lloyd and Phillips, 1999).

2.4. Inhibition of DNA repair

There is accumulating evidence that carcinogenic

nickel compounds disturb DNA repair systems by

diverse mechanisms. Ni (II) disturbed the first step of

nucleotide excision repair (NER), that involves

recognition of damaged DNA (Hartmann and

Hartwig, 1998). It had found that repair inhibition by

Ni (II) may be caused by the displacement of zinc in

zinc finger structures of DNA repair proteins such as

XPA protein (Asmuss et al., 2000a). There is some

evidence that Ni (II) inhibits the repair of O6-

methylguanine via silencing of the DNA repair gene

O6-methylguanine DNA methyltransferase (MGMT)

expression (Iwitzki et al., 1998; Ji et al., 2008).

Soluble nickel chloride also inhibits base excision

repair (BER), via inhibition the base-excision repair

enzyme, 3-methyladenine-DNA glycosylase II (Dally

and Hartwig, 1997; Wang et al., 2006). Nickel

Inhibition of DNA Repair may be mediated by

Reactive Oxygen Species. Ni enhances the

intracellular H2O2 level, which may increase

International Journal of Scientific Research in Environmental Sciences (IJSRES), 1(8), pp. 202-216, 2013

204

oxidative damage in DNA repair enzymes and thereby

reduce this enzymes activity (Lynn et al., 1997;

Gavanji et al., 2013). Nickel Ions Inhibit DNA Repair

Enzyme ABH2 and Histone Demethylase JMJD1A.

These enzymes are iron- and 2-oxoglutarate-

dependent dioxygenases that uses the 2-His-1-

carboxylate motif to bind the cofactor ferrous iron ion

at their active sites. Ni (II) competes with Fe(II) and

replaces it at the iron-binding site thus inhibit enzyme

activity (Chen et al., 2010).

2.5. Epigenetic mechanisms, gene silencing and

Deregulation of cell proliferation

The epigenetic dysregulation of gene expression is

one of primary causes in cancer (Egger et al., 2004;

Ke et al., 2006). Silencing of tumor suppressor genes

by epigenetic mechanisms represents one of the main

mechanisms of nickel carcinogenesis. Both water-

soluble and water-insoluble nickel compounds are

able to cause gene silencing via diverse epigenetic

mechanisms (Costa et al., 2005). Nickel inactivates

transcription of genes by inducing DNA methylation

and chromatin compaction (Lee et al., 1995). So it

seems that Heterochromatinization is a potential

mechanism of nickel-induced carcinogenesis (Ellen et

al., 2009). Nickel compounds cause posttranslational

epigenetic modifications of histone proteins, thus

derailing the normal programming of gene expression

(Sutherland and Costa, 2003; Zhou et al., 2009). It has

been shown that the transcriptional suppression of

MGMT (O6-methylguanine DNA methyltransferase)

expression in NiS-transformed cells mediate by

epigenetic Histone modifications at the promoter

region of MGMT gene (Ji et al., 2008). Recently,

Arita et al, demonstrated that exposure to nickel

compounds, can induce changes in global levels of

posttranslational histone modifications in peripheral

blood mononuclear cells (Arita et al., 2012). Recent

studies show that cells treated with nickel have

decreased histone acetylation, and altered histone

methylation patterns (Broday et al., 2000; Sutherland

and Costa, 2003; Chen et al., 2006). Nickel exposure

increased the level of H3K4 trimethylation in both the

promoters and coding regions of several genes

including CA9 and NDRG1 that were increased in

expression in A549 cells (Tchou-Wong et al., 2011).

It also increased lysine 9 in histone H3 (H3K9)

dimethylation by inhibiting the demethylating enzyme

JHDM2A (Chen et al., 2010). Nickel is a potent

inhibitor of histone H4 acetylation in yeast and in

mammalian cells (Broday et al., 2000). The loss of

histone acetylation and DNA methylation worked

together in gptgene silencing in G12 transgenic cell

line by nickel (Zoroddu et al., 2002; Yan et al., 2003).

Nickel also causes ubiquination and phosphorylation

of histones (Karaczyn et al., 2006; Ke et al., 2008).

Nickel ions may deregulate cell proliferation by

inactivating apoptotic processes. P53 is an important

tumor suppressor gene and transcription factor which

involved in the regulation of cell proliferation and

apoptosis (Bates and Vousden, 1999). Nickel ions

inhibit binding of p53 to scDNA and to

its consensus sequence in linear DNA fragments

(Palecek et al., 1999). In another study it was

observed that nickel-immortalized cells revealed

abnormal p53 expression and a T--C transition

mutation in codon 238 (Maehle et al., 1992). The

Fragile Histidine Triad (FHIT) gene is a tumor

suppressor gene that locates in a fragile chromosomal

site sensitive to deletions. in tumors the expression of

FHIT gene was frequently found to be reduced even

lost (Kasprzaker et al., 2003). It was found in vitro

that Ni (ІІ) had strong inhibitory effect on the

enzymatic activity of Fhit protein. Also in nickel-

induced tumors, aberrant transcripts or loss of

expression of the FHIT gene and Fhit protein was

observed (Kowara et al., 2002; Ji et al., 2006). It

appears that amplification of certain oncogenes is a

common correlate of the progression of some nickel

induced tumors and cancers (Sunderman et al., 1990).

Elevated expression of oncogenic c-myc mRNA was

reported in nickel transformed mouse 10T1/2 cells

(Landolph, 1994). In the past few years, many studies

have been conducted on the molecular mechanisms of

nickel carcinogenesis which focused on the activation

of proto-oncogenes and inactivation of anti-oncogenes

caused by gene amplification, DNA methylation,

chromosome condensation, and so on that were

induced by nickel. However, the researches on

tumorigenic molecular mechanisms regulated by

microRNAs (miRNAs) are rare. By establishing a

cDNA library of miRNA from rat muscle tumor tissue

induced by Ni3S2, Zhang et al (2013) found that the

expression of miR-222 was significantly up regulated

in tumor tissue compared with the normal tissue. They

concluded that miR-222 may promote cell

proliferation infinitely during nickel-induced tumor

genesis in part by regulating the expression of its

target genes CDKN1B and CDKN1C.

2.6. Cadmium

Cadmium (atomic number, 48; relative atomic mass,

112.41) is a heavy metal that belongs to group IIB of

the periodic table. The oxidation state of about all

cadmium compounds is +2, although a few

compounds have been reported in that it is +1. (IARC,

1993).Cadmium (cd) is a toxic transition metal that

has been designated a human carcinogen by the

National Toxicology program. Cadmium found

naturally in ores together with zinc, lead and copper.

Saedi et al.

A Review of Genetic and Epigenetic Mechanisms in Heavy Metal Carcinogenesis: Nickel and Cadmium

205

Sources of human exposure to cadmium include

certain batteries manufacturing, some electroplating

processes and consumption of tobacco products.

Multiple epidemiological studies have linked

occupational exposure to cadmium with pulmonary

cancer, while fewer studies have linked it to prostate,

renal, liver, hematopoietic system, urinary bladder,

pancreatic, and stomach cancers (Waalkes and Misra,

1996; Waalkes, 2000; Hu et al., 2002). A summary of

toxicity of various cadmium species and compounds

are shown in table 2. Cadmium is a weak mutagenic

and has a poorly DNA binding affinity, suggesting

that it promote carcinogenesis through epigenetic

mechanisms (Arita and Costa, 2009). suggested

mechanisms for Cd-carcinogenesis include such as

formation of reactive oxygen species (ROS) and/or

interference with anti-oxidative enzymes, inhibition of

DNA repair enzymes, deregulation of cell

proliferation, suppressed apoptosis (Waalkes, 2003).

2.7. Cellular uptake

Investigation of the cellular cadmium uptake

mechanism in the rat jejunum showed that, this

process is done through nonspecific binding to anionic

sites on the membrane, then followed by a

temperature –dependent and limiting internalization

step (Foulkes., 1989). Hinkle indicated that a major

mechanism for cellular uptake of cadmium is

dependent to voltage-sensitive calcium channels

(Patricia et al., 1987). Studies showed that Mn

transport system is used for cellular dc uptake.

Divalent metal transporter 1 (DMT1) is the only

known mammalian transporter involved in the uptake

of both Cd and Mn (Himeno et al., 2002). Exgenous

glutathione (GSH) prevent cellular uptake through

form a complex with cadmium outside of the cells

(Kang, 1992).

2.8. Induction of oxidative stress

Cadmium is a bivalent cation and unable to produce

reactive oxygen speacies (ROS) directly, nevertheless

cd-induced oxidative estress reported in multitude

studies (Wang et al. 2004, Valko et al. 2005; Zhou et

al., 2009). Cadmium sulfide enhanced hydrogen

peroxide production in human leukocytes, and

cadmium chloride induced the formation of

superoxide in rat and human phagocytes (Sugiyama,

1994). Experiments in both in vivo and in vitro,

indicated that cadmium has inhibitory effect on

antioxidant enzymes through the interaction with their

thiol groups (Stohs et al., 2001; Valko et al., 2006;

Gavanji et al., 2013). Cadmium also can replace of

copper and iron in various proteins, and hence

increase the cellular amount of free redox-active

metals (Price and Joshi, 1983; Dorta et al., 2003).cd-

exposured for long-term enhanced lipid peroxidation

and inhibited activity of superoxide dismutase (SOD)

in rat liver , kidney and testesis (Patra et al., 1999).

Investigation of cd-effects on basic motility

characteristics in bovine seminal plasma and

spermatozoa, shown that cd can increase the

development of oxidant stress so decrease of male

fertility (Tvrdá, 2013).

2.9. Inhibition of DNA repair

Cadmium also exert comutagenic effects by

disturbances several types of DNA-repair

mechanisms, i.e. base excision, nucleotide excision,

mismatch repair, and the exclusion of the pre-

mutagenic DNA precursor 7,8-dihydro- 8-oxoguanine

(Hartwig and Schwerdtle, 2002). In base-excision

repair, sub-lethal concentrations of cadmium do not

generate oxidative damage as such, but suppress the

repair of oxidative DNA damage in mammalian cells

(Dally and Hartwig, 1997; Fatur et al.,

2003).Exposure of human cells to cd low

concentration decrease removal of x-ray-induced 8-

oxoguanin ( 8-oxoG) adducts, that in turn increase the

mutation frequency, this occurs through decrease in

hOGG1 ( human8-oxoguanine-DNA glycosylase-1)

activity (Youn et al., 2005; Bravard et al., 2009).

Recently studies shown that hOGG1 significantly

reduced in the presence of in human spermatozoa

(Smith et al., 2013). On analysis dedicated microarray

in vitro shown inhibitory effects of cadmium in both

base and nucleotide exision/repair pathways

(Candéias, 2010). In nucleotide-excision repair,

cadmium suppress the removal of thymine dimers

after UV irradiation by inhibiting the incision at the

DNA lesion (Hartwig and Schwerdtle, 2002; Fatur et

al., 2003). Schwerdtle et al. indicated that cadmium

compounds such as CdO and soluble CdCl2 inhibit the

nucleotide excision repair in a dose-dependent manner

at low concentration (2010). Cadmium suppress the 8-

oxo-dGTPases activity, therefore disturbs the

exclusion of 8-oxo-dGTP, a product of oxidative

modification of dGTP, from the nucleotide pool

(Bialkowski and Kasprzak, 1998). Additionally cd

can displace the zinc in DNA-repair proteins such as

xerodermapigmentosum group A (XPA) that is

involved in nucleotide-excision repair and inhibit their

function (Asmuss et al., 2000b). Recent evidence

suggests that existence of Microsatellite instability,

one of the phenotypes of defective DNA mismatch

repair, in nuclear indicating genotoxic effects induced

by cadmium (Oliveira et al., 2012).

International Journal of Scientific Research in Environmental Sciences (IJSRES), 1(8), pp. 202-216, 2013

206

Table 1: toxicity and carcinogenicity of various nickel species and compounds

2.8. Epigenetic mechanisms, gene silencing and

Deregulation of cell proliferation

Most studies indicate cadmium is poorly mutagenic,

and has a weak DNA binding affinity, so probably

promote carcinogenesis through indirect or epigenetic

mechanism including aberrant activation of oncogenes

and suppression of apoptosis (Waalkes, 2003; Arita

and Costa, 2009). Multiple studies are shown that

cadmium can induce epigenetic effects in experiment

Name Formula Solubility Reference Methods Results

Nickel metal

powder

Ni Insoluble Oller et al, 2008 Wistar rat inhalation study increased incidence of neoplasm of

the respiratory tract was not observed

Nickel subsulfide

Ni3S2 Low National Toxicology

Program, 1996

In f344/n rats and b6c3fl

mice inhalation study

there was clear evidence of

carcinogenic activity of nickel

subsulfide in male F344/N rats based

on increased incidences of

alveolar/bronchiolar adenoma,

carcinoma

Nickel sulfide

NiS

Crystalline

(low)

Amorphous

(low)

Costa, 1991

Literature Review

Amorphous nickel sulfide is a weak

carcinogen compared to crystalline

nickel sulfide, likely due to

differences in extent of endocytosis

Nickel arsenide

(orcelite)

Ni5As2

Low Sunderman and

Kilmer, 1983

Intramuscular Injection to

male Fischer rats

Within 2 years, the incidences of

sarcomas at the injection site were

17/20 (85%) in Ni5As2-treated rats

Nickel carbonate NiCO3 Low Ciccarelli and

Wetterhahn, 1982

Intraperitoneal Injection to

rats

A dose response to both single-strand

breaks and cross-links was observed

in kidney nuclei

Nickel(II) oxide NiO Low Clemens and

Landolph, 2003

Nickel refinery dust

phagocytized by

cultured mouse embryo

cells

Equally cytotoxic to orcelite-

containing particles but no dose-

dependent morphological

transformation observed

Nickel(III)

oxide

Ni2O3

Variable

depending on

calcination

temperature

Schwerdtle et al,

2002

Human lung cell culture

As a co-carcinogen, nickel oxide

inhibited DNA repair

Nickel chromate NiCrO4 Insoluble Sunderman, 1984 single intramuscular

injection to male Fischer

rats

Within 2 years, the incidences of

sarcomas at the injection site were

(6%) in NiCrO4-treated rats

Nickel(II) sulfate

NiSO4 High Ohshima, 2003

V79 Chinese hamster cells Induced genetic and chromosomal

instability

Kasprzak et al, 1983 Intramuscular Injection to

rats

No tumors were found in animals

which had been injected i.m. with 15

doses of 4.4 mumol of NiSO4

Saedi et al.

A Review of Genetic and Epigenetic Mechanisms in Heavy Metal Carcinogenesis: Nickel and Cadmium

207

animals and mammalian cells in vitro (Martinez-

Zamudio and Ha, 2011; Wang et al., 2012; Waalkes,

2003; DFG, 2006). Sevral studies have reported that

cadmium can induce changes in global and gene

specific DNA methylation levels (Takiguchi, 2003;

Benbrahim-Tallaa, 2007; Huang, 2008). Cd can alter

the epigenetic programming in chick embryos through

down regulation of DNA methyltransferases and

following diminishment of DNA methylation (Doi et

al., 2011). In vitro and ex vivo experiments shown

that cd inhibit DNA methyltransferase (MeTase) in a

noncompetitive manner with DNA , possibly through

an interaction with the methyltransferase DNA

binding domain (Takiguchi et al., 2003). Gene-

specific DNA hypermethylation and gene silencing

have been reported in cadmium-exposed cells,

including the p16INK4a, RASSF1A and MT-1 genes (

Takiguchi et al., 2003; Benbrahim-Tallaa et al., 2007).

It has been proposed that the teratogenic effect of Cd

could also be mediated by epigenetic mechanisms,

because altered DNA methylation has been linked to

ventral body wall defect (VBWD) in chick embryos

after Cd treatment (Doi et al., 2011; Menoud and

Schowing., 1987; Thompson and Bannigan, 2001).

These data suggest that Cd may act as a teratogen to

induce VBWD by perturbing DNA methylation.

Benbrahim reported that cadmium exposure During

the 10-weeks induced malignant transformation,

increased activity DNA methylteransferase (DNMT)

that were associated with over-expression of

DNMT3b. This pattern DNA hypermethylation

together with up-regulation of DNMT3b may provide

biomarkers to specifically identify cadmium-induced

human prostate cancers (Benbrahim-Tallaa et al.,

2007). Cd – exposed human embryo lung fibroblasts

(HLF) increase both global DNA methylation and

DNMT activity. Also significantly elevated growth

rates of the HLF cells, decreased cell population of

G0/G1-phase and increased cell population of S-phase

(Jiang et al., 2008). Another study Using K562 cells

(chronic myelogenous leukemia cell line), showed

that Cd stimulated cell proliferation did not suppress

in the attenuation of ROS generation with N-

acetylcysteine (Huang et al., 2008). However,

methionine could suppress Cd-induced global DNA

hypomethylation and cell proliferation. It was

concluded by the authors that global DNA

hypomethylation, rather than ROS, is the potential

facilitator of Cd-stimulated K562 cell proliferation.

Recently studies indicate that cd-exposed DNA

methylation in early life is sex-specific and related to

lower birth (Kippler, 2013). Exposure to Cd induce

the hypermethylation of RASAL1 and KLOTHO,

associated-genes with renal fibro genesis, suggest that

this pattern may be an epigenetic marker of the

progress for chronic kidney disease (Zhang et al.,

2013). Epigenetic changes in expression of MT-3

were studied in human breast epithelial cancer cells

(Somji et al., 2011). These studied showed that the

MT-3 gene is silenced by histon modification of the

MT-3 promotor. Cadmium affects multitude cellular

processes, including signal transduction pathways,

cell proliferation, differentiation, and apoptosis. At

Submicromolar concentrations, cadmium stimulated

cell growth and DNA synthesis, and the proliferation

of rat myoblast, epithelial and chondrocyte cells

(Zglinicki et al., 1992) and of rat macrophages (Misra

et al., 2002). Cadmium decreased level of estrogen

receptor and other estrogen-regulated genes in human

breast caner cell line MCF-7, and induced the growth

of these cells 5-6 fold (Garcia-Morales et al., 1994).

Cadmium exposure also increased uterine weight and

density of the mammary gland and induced

tumorigenesis in the lining of the uterus (Johnson,

2003). Cadmium-induced apoptosis occurs by

Caspase-9 activation triggered by cytochrome-c in

human promyelocytic Leukemia HL-60 cells (Kondoh

et al., 2002) or through reactive oxygen species (ROS)

pathway and translocation of apoptosis-inducing

factor (AIF) from mitochondria into the nucleus

(Shih., 2004). Recently studies showed that cadmium

induce P53-dependent apoptosis in human prostate

epithelial cells (Aimola et al., 2012). Cadmium

elevates intracellular free calcium ion ([Ca2+]i) level,

leading to neuronal apoptosis partly by activating

mitogen-activated protein kinases (MAPK) and

mammalian target of rapamycin (mTOR) pathways

(Xu et al., 2011). Several studies have shown that

cadmium in addition to stimulating mitogenicdirectly,

indicate the negative controls of cell proliferation.

Subtoxic levels of cadmium can suppress the P53-

dependent cell cycle arrest in G(1) and G(2)/M phases

induced by gamma-irradiation through conformational

changes of wild-type P53(Méplan et al., 1999). It was

reported that Cd reduce and inactive expression of the

tumor suppressor genes, RASSF1A and P16, through

over expression of de novo DNA methytransferase

(Benbrahim et al., 2007). Recently, Cd has been

shown to enhance estrogen receptor alpha activity and

stimulate uterine and mammary gland growth in mic

and plays an important role in the promotion of breast

cancer (Siewit et al., 2010).

3. RESULTS AND DISCUSSION

During the past centuries, commercial and industrial

use of heavy metal compounds increased, and the

progress of industrialization has led to increased

emission of pollutants into ecosystems (Järup, 2003).

The potential anthropogenic heavy metal inputs in the

pedosphere increased tremendously after the 1950s. In

2000, the cumulative industrial age anthropogenic

International Journal of Scientific Research in Environmental Sciences (IJSRES), 1(8), pp. 202-216, 2013

208

global production of Cd and Ni was 1.1 and 36,

million tons (Fengxiang et al., 2002). The evidence

described above demonstrates that exposure to nickel

and cadmium compounds can disturb multitude

cellular processes, including signal transduction

pathways, cell proliferation, and apoptosis. The

mechanisms underlying this effects are not well

understood yet, but three predominant mechanisms

have been identified to explain Ni and Cd toxicity and

carcinogenicity: (1) interference with cellular redox

reactions and induction of oxidative stress, which may

cause oxidative DNA damage (Chen et al., 2003;

Stohs et al., 2001); (2) inhibition of DNA repair

systems resulting in genomic instability and

accumulation of critical mutations(Hartmann and

Hartwig., 1998; Fatur et al., 2003); (3) deregulation of

cell proliferation by induction of signaling pathways

or inactivation of growth controls such as tumor

suppressor genes (Palecek et al., 1999; Méplan et al.,

1999). Zhang et al (2013) identified a novel molecular

mechanism of nickel-induced tumorigenesis which

regulated by microRNAs (miRNAs). They stated that

miR-222 may promote cell proliferation infinitely

during nickel-induced tumorigenesis in part by

regulating the expression of its target genes CDKN1B

and CDKN1C. Some recent studies have suggested

that Cadmium and nickel play a role in breast cancer

development by acting as metalloestrogens--metals

that bind to estrogen receptors and mimic the actions

of estrogen (Martin et al., 2003). Aquino et al, have

discussed the various epidemiological, in vivo, and in

vitro studies that show a link between the heavy

metals, cadmium and nickel, and breast cancer

development, in a review article in 2012. One of the

potential mechanisms for nickel induced

carcinogenesis is mediated by reactive oxygen

speacies resulting oxidative estress. Nickel is a redox-

active metal that can catalyse Fenton-type reactions

(Chen et al., 2003). Unlike the nickel, cadmium is a

non-redox metal therefore unable to produce reactive

oxygen speacies directly (Wang et al., 2004). But it

can induce generation of ROS through inhibitory

effect on antioxidant enzymes by interaction with

their thiol groups (Valko et al., 2006). Cadmium

exhibit remarkable potential to inhibit DNA damage

repair, and it has been identified as a major

mechanism for its carcinogenicity (Giagenis et al.,

2006). In summary, the direct effect of toxic metals on

the genes and chromosomes such as DNA damage,

mutation and chromosomal aberrations is weak and

rare and usually observed at higher concentrations

(Hartwig, 1995). Therefore the main mechanism in

their carcinogenecity is epigenetic mechanism.

4. CONCLUSION

The aim of this review was to evaluate the potential

carcinogenicity and the general mechanism of nickel

and cadmium. Genomic mutation studies showed that

both nickel and cadmium compounds are very weak

mutant. The effects of these heavy metals on human

body which were investigated in epidemiological

studies and analytical experiments showed the

damages in the cells. These damages were caused by

the increase of free radicals and stimulation of

oxidative stress, Inhibition of DNA repair, and

deregulation of cell proliferation by Epigenetic

mechanisms.

REFERENCES

Achanzar WE, Diwan BA, Liu J, Quader ST, Webber

MM, Waalkes MP (2001). Cadmium-induced

malignant transformation of human prostate

epithelial cells. Cancer Research 61: 455-458.

Aimola P, Carmignani M, Volpe AR, Di Benedetto A,

Claudio L, Waalkes M.P, Bokhoven A, Tokar

E.J, Claudio P (2012). Cadmium Induces p53-

Dependent Apoptosis in Human Prostate

Epithelial Cells. PLoS ONE 7(3): e33647.

Andersen A, Berge SR, Engeland A, Norseth T

(1996). Exposure to nickel compounds and

smoking in relation to incidence of lung and

nasal cancer among nickel refinery workers. Occupational and Environmental Medicine

53(10): 708-713.

Aquino NB, Sevigny MB, Sabangan J, Louie MC

(2012). The role of cadmium and nickel in

estrogen receptor signaling and breast cancer:

metalloestrogens or not?. Journal of

environmental science and health. Part C,

Environmental carcinogenesis and

ecotoxicology reviews 30(3):189-224.

Aritaa A, Costa M (2009). Epigenetics in metal

carcinogenesis: nickel, arsenic, chromium and

cadmium. Metallomics 1: 222-228.

Arita A, Niu J, Qu Q, Zhao N, Ruan Y, Nadas A,

Chervona Y, Wu F, Sun H, Hayes RB, Costa M

(2012). Global levels of histone modifications

in peripheral blood mononuclear cells of

subjects with exposure to nickel. Environmental

Health Perspectives, 120(2): 198-203.

Asmuss M, Mullenders LH, Hartwig A (2000a).

Interference by toxic metal compounds with

isolated zinc finger DNA repair proteins.

Toxicology Letters, 112–113:227-231.

Asmuss M, Mullenders LHF, EkerA ,Hartwig A.

(2000b). Differential effects of toxic metal

compounds on the activities of Fpg and XPA,

Saedi et al.

A Review of Genetic and Epigenetic Mechanisms in Heavy Metal Carcinogenesis: Nickel and Cadmium

209

two zinc finger proteins involved in DNA

repair. Carcinogenesis, 21: 2097-2104.

Bassendowska-Karska E, Zawadzka-Kos M (1987).

Cadmium sulfate does not induce sister

chromatid exchanges in human lymphocytes in

vitro. Toxicology Letters, 37(2): 173-175.

Bates S, Vousden KH. 1999. Mechanisms of p53-

mediated apoptosis. Cellular and Molecular

Life Sciences, 55(1):28-37.

Benbrahim-Tallaa L, Waterland R, Dill A, Webber M,

Waalkes M (2007). Tumor suppressor gene

inactivation during cadmium-induced malignant

transformation of human prostate cells

correlates with overexpression of de novo DNA

methyltransferase. Environmental Health

Perspectives, 115: 1454–1459.

Bialkowski K, Kasprzak KS (1998). A novel assay of

8-oxo-2′-deoxyguanosine 5′-triphosphate

pyrophosphohydrolase (8-oxo-dGTPase)

activity in cultured cells and its use for

evaluation of cadmium(II) inhibition of this

activity. Nucleic Acids Research, 26: 3194-

3201.

Biggart NW, Costa M (1986).Assessment of the

uptake and mutagenicity of nickel chloride in

salmonella tester strains. Mutation Research,

175: 209-15.

Bravard A, Campalans A, Vacher M, Gouget B,

Levalois C, Chevillard S, Radicella JP (2009).

Inactivation by oxidation and recruitment into

stress granules of hOGG1but not APE1 in

human cells exposed to sub-lethal

concentrations of cadmium. Mutation Research,

685: 61-69.

Broday L, Peng W, Kuo MH, Salnikow K, Zoroddu

MA, Costa M (2000). Nickel compounds are

novel inhibitors of histone H4 acetylation.

Cancer Res., 60: 238-241.

Cai Y, Zhuang Z (1999). DNA damage in human

peripheral blood lymphocyte caused by nickel

and cadmium. Zhonghua Yu Fang Yi XueZaZhi

33(2): 75-77.

Candéias S, Pons B, Viau M, Caillat S , Sauvaigo S

(2010). Direct inhibition of excision/synthesis

DNA repair activities by cadmium: analysis on

dedicated biochips. Mutation Research, 694:

53-59.

Chakrabarti SK, Bai C, Subramanian KS (2001).

DNA-protein crosslinks induced by nickel

compounds in isolated rat lymphocytes: role of reactive oxygen species and specific amino

acids. Toxicology and Applied Pharmacology,

170: 153-165.

Chen CY, Wang YF, Huang WR, Huang YT (2003).

Nickel induces oxidative stress and

genotoxicity in human lymphocytes.

Toxicology and Applied Pharmacology, 189:

153-159.

Chen H, Giri N.C, Zhang R, Yamane K, Zhang Y,

Maroney M, Costa M (2010). Nickel ions

inhibit histone demethylase JMJD1A and DNA

repair enzyme ABH2 by replacing the Ferrous

Iron in the catalytic centers. Journal of

Biological Chemistry, 285(10): 7374-7383.

Chen H, Ke Q, Kluz T, Yan Y, Costa M (2006).

Nickel ions increase histone H3 lysine 9

dimethylation and induce transgene silencing.

Molecular and Cellular Biology, 26(10): 3728-

3737.

Ciccarelli RB, Wetterhahn KE (1982). Nickel

distribution and DNA lesions induced in rat

tissues by the carcinogen nickel carbonate.

Cancer Research, 42(9): 3544-3549.

Clemens F, Landolph JR (2003). Genotoxicity of

Samples of Nickel Refinery Dust.

Toxicological Sciences 73:114–123.

Costa M (1991). Molecular mechanisms of nickel

carcinogenesis. Annual review of

pharmacology and toxicology, 31: 321–337.

Costa M, Davidson TL, Chen H, Ke Q, Zhang P, Yan

Y, Huang C, Kluz T (2005). Nickel

carcinogenesis: epigenetics and hypoxia

signalling. Mutation Research , 592(1-2): 79-

88.

Costa M, Simmons-Hansen J, Bedrossian CW,

Bonura J, Caprioli RM (1981). Phagocytosis,

cellular Distribution, and Carcinogenic Activity

of Particulate Nickel Compounds in Tissue

Culture. Cancer Research, 41: 2868-2876.

Dally H, Hartwig A (1997). Induction and repair

inhibition of oxidative DNA damage by

nickel(II) and cadmium(II) in mammalian cells.

Carcinogenesis, 18: 1021-1026.

Denkhaus E, Salnikow K. Nickel essentiality, toxicity,

and carcinogenicity (2002). Critical Reviews in

Oncology Hematology, 42: 35-56.

DFG ( 2006). Deutsche forschungsgemeinschaft list

of MAK and BAT values: Cadmium and

cadmium compounds. Weinheim: Wiley-VCH-

Verlag, 22: 1-41.

Doi T, Puri P, McCann ,Bannigan J , Thompson J

(2011). Epigenetic effect of cadmium on global

de novo DNA hypomethylation in the

cadmium-Induced Ventral Body Wall Defect

(VBWD) in the Chick Model. Toxicological

Sciences 120:475-480.

Doll R, Morgan L, Speizer F (1970). Cancers of the

lung and nasal sinuses in nickel workers, Br.

Cancer 24:623-632.

Dorta DJ, Leite S, DeMarco KC (2003). A proposed

sequence of events for cadmium-induced

International Journal of Scientific Research in Environmental Sciences (IJSRES), 1(8), pp. 202-216, 2013

210

mitochondrial impairment. Journal of Inorganic

Biochemistry 97:251-257.

Dote E, Dote T, Shimizu H, Shimbo Y, Fujihara M,

Kono K (2007). Acute lethal toxicity,

hyperkalemia associated with renal injury and

hepatic damage after intravenous administration

of cadmium nitrate in rats. Journal of

Occupational Health 49(1):17-24.

Edwards DL, Wataha JC, Hanks CT (1998). Uptake

and reversibility of uptake of nickel by human

macrophages. Journal of Oral Rehabilitation

25:2-7.

Egger G, Liang G, Aparicio A, Jones PA (2004).

Epigenetics in human disease and prospects for

epigenetic therapy. Nature 429:457-463.

Ellen T.P, KluzT,Harder M.E, Xiong J, Costa M

(2009). Heterochromatinization as a Potential

Mechanism of Nickel- Induced Carcinogenesis.

Biochemistry 48(21):4626-4632.

Fatur T, Lah TT, Filipic M (2003). Cadmium inhibits

repair of UV-, methyl methanesulfonate- and

N-methyl-Nnitrosourea- induced DNA damage

in Chinese hamster ovary cells. Mutation

Research 529:109-116.

Fengxiang X. Han, Amos Banin, Yi Su, David L.

Monts, John M. Plodinec, William L. Kingery,

Glover E. Triplett (2002). Industrial age

anthropogenic inputs of heavy metals into the

pedosphere. Naturwissenschaften 89(11): 497-

504.

Foulkes EC (1989). On the mechanism of cellular

cadmium uptake. Biological Trace Element

Research 21:195-200.

Funakoshi T, Inoue T, Shimada H, Kojima S (1997).

The mechanisms of nickel uptake by rat

primary hepatocyte cultures: role of calcium

channels. Toxicology 124:21-26.

Garcia-Morales P, Saceda M, Kenney N, Kim N,

Salomon DS, Gottardis MM, Solomon HB,

Sholler PF, Jordan VC, Martin MB (1994).

Effect of cadmium on estrogen receptor levels

and estrogen-induced responses in human

breast cancer cells. The Journal of Biological

Chemistry 17;269(24):16896-16901.

Gavanji, S, Larki, B, Mehrasa M (2013). A review of

Effects of Molecular mechanism of Silver

Nanoparticles on Some microorganism and

Eukaryotic Cells. Technical Journal of

Engineering and Applied Sciences 3(1): 48-58.

Gavanji S, Shams M, Shafagh N, jalali Zand A, Larki

B, Doost Mohammadi M, Taraghian AH,

niknezhad SV (2012). Destructive Effect of

SilverNanoparticles on Biocontrol Agent Fungi

Trichoderma viride and T. harzianum. Caspian

Journal of Applied Sciences Research 1(12):83-

90.

Gavanji S, Abdul Aziz H, Larki B, Mojiri A ( 2013).

Bioinformatics Prediction of Interaction of

Silver Nitrate and Nano Silver on Catalase and

Nitrat Reductase. International Journal of

Scientific Research in Environmental Sciences,

1(2):26-35.

Gavanji S, Abdul Aziz H, Larki B, Mojiri A ( 2013).

Computational Prediction and Analysis of

Interaction of Silver Nitrate with Chitinase

Enzyme. International Journal of Scientific

Research in Environmental Sciences 1(4):50-

62.

Giagenis C, Gatzidou E, Theocharis S (2006). DNA

repair system as targets of cadmium toxicity.

Toxicology and Applied Pharmacology

213:282-290.

Glaser U, Hochrainer D, Otto FJ, Oldiges H (1990).

Carcinogenicity and toxicity of four cadmium

compounds inhaled by rats. Toxicological and

Environmental Chemistry 27:153–152.

Grandjean P (1984). Human exposure to nickel.

IARC Scientific Publications Series 1984:469-

485.

Grimsrud TK, Berge SR, Martinsen JI, Andersen A

(2003). Lung cancer incidence among

Norwegian nickel-refinery workers. Journal of

Environmental Monitoring 5:190-197.

Han F, Banin A, Su Y, Monts D, Plodinec J, Kingery

W, Glover E (2002). Industrial age

anthropogenic inputs of heavy metals into the

pedosphere. Naturwissenschaften 89:497-504.

Hartmann M, Hartwig A (1998). Disturbance of DNA

damage recognition after UV-irradiation by

nickel(II) and cadmium(II) in mammalian cells.

Carcinogenesis 19:617-621.

Hartwig A, Schwerdtle T (2002). Interactions by

carcinogenic metal compounds with DNA

repair processes: toxicological implications.

Toxicology Letters 127:47-54.

Hartwig A (1995). Current aspects in metal

genotoxicity. Biometals 8:3-11.

Himeno S, Yanagiya T, Enomoto S, Kondo

YandImura N (2002). Cellular cadmium uptake

mediated by the transport system for

manganese. Tohoku Journal Of Experimental

Medicine 196:43-50.

Hu J, Mao Y, White K (2002). Renal cell carcinoma

and occupational exposure in Canada.

Occupational Medicine 52:157-164.

Huang D, Zhang Y, Qi Y, Chen C, Ji W (2008).

Global DNA hypomethylation, rather than

reactive oxygen species (ROS), a potential

facilitator of cadmium-stimulated K562 cell

proliferation. Toxicology Letters 179:43-47.

Huang X, Frenkel K, Klein CB, Costa M (1993).

Nickel induces increased oxidants in intact

Saedi et al.

A Review of Genetic and Epigenetic Mechanisms in Heavy Metal Carcinogenesis: Nickel and Cadmium

211

cultured mammalian cells as detected by

dichlorofluorescein fluorescence. Toxicology

and Applied Pharmacology 120:29-36.

IARC (1993). Beryllium, cadmium, mercury, and

exposures in the glass manufacturing

industry.Working Group views and expert

opinions, Lyon, 9–16 February 1993. IARC

monographs on the evaluation of carcinogenic

risks to humans 58:1-415.

IARC (2012). Monographs on the Evaluation of the

Carcinogenic Risks to Humans, arsenic, metals,

fibres, and dusts A review of human

carcinogens. IARC Scientific Publications,

IARC, Lyon; vol 100.

Iwitzki F, Schlepegrell R, Eichhorn U, Kaina B,

Beyersmann D, Hartwig A (1998). Nickel(II)

inhibits the repair of O6-methylguanine in

mammalian cells. Archives of Toxicology

72:681-689.

Järup L (2003). Hazards of heavy metal

contamination. British Medical Bulletin 68:167-

82.

Ji W, Yang L, Yu L, Yuan J, Hu D, Zhang W, Yang J,

Pang Y, Li W, Lu J, Fu J, Chen J, Lin Z, Chen

W, Zhuang Z (2008). Epigenetic silencing of

O6-methylguanine DNA methyltransferase

gene in NiS-transformed cells. Carcinogenesis

29(6):1267-1275.

Ji WD, CHen J, Lu J, Wu ZH, Yi F, Feng S (2006).

Alterations of FHIT Gene and P16 Gene in

Nickel Transformed Human Bronchial

Epithelial Cells. Biomedical And

Environmental Sciences 19:277-284.

Jiang G, Xu L, Song S, Zhu C, Wu Q, Zhang L, Wu L

(2008). Effects of longterm low-dose cadmium

exposure on genomic DNA methylation

inhuman embryo lung fibroblast cells.

Toxicology 244:49-55.

Johnson MD, Kenney N, Stoica A, Hilakivi-Clarke L,

Singh B, Chepko G, Clarke R, Sholler PF, Lirio

AA, Foss C, Reiter R, Trock B, Paik S, Martin

MB (2003). Cadmium mimics the in vivo

effects of estrogen in the uterus and mammary

gland. Nature Medicine 9:1081-1084.

Kabir E, Ray S, Kim KH, Yoon HO, Jeon EC, Kim

YS, Cho YS, Yun ST, Brown RJ (2012).

Current status of trace metal pollution in soils

affected by industrial activities. Scientific

World Journal. 2012: 916705.

Kang YJ (1992). Exogenous glutathione decreases

cellular cadmium uptake and toxicity. Drug

Metabolism and Disposition 20:714-718.

Karaczyn AA, Golebiowski F, Kasprzak KS (2006).

Ni(II) affects ubiquitination of core histones

H2B and H2A. Cell Research 312:3252-3259.

Kasprzak KS, Gabryel P, Jarczewska K (1983).

Carcinogenicity of nickel(II)hydroxides and

nickel(II)sulfate in Wistar rats and its relation to

the in vitro dissolution rates. Carcinogenesis.

4(3):275-9.

Kasprzak KS, Sunderman FW Jr, Salnikow K

(2003).Nickel carcinogenesis. Mutation

Research 533:67-97.

Ke Q, Davidson T, Chen H, Kluz T, Costa M (2006).

Alterations of histone modifications and

transgene silencing by nickel chloride.

Carcinogenesis 27(7):1481-1488.

Ke Q, Li Q, Ellen TP, Sun H, Costa M (2008). Nickel

compounds induce phosphorylation of histone

H3 at serine 10 by activating JNK-MAPK

pathway. Carcinogenesis 29(6):1276-1281.

Kerckaert GA, LeBoeuf RA, Isfort RJ (1996). Use of

the Syrian hamster embryo cell transformation

assay for determining the carcinogenic potential

of heavy metal compounds. Fundamental and

Applied Toxicology 34:67-72.

Kippler M, Engström K, Mlakar SJ, Bottai M, Ahmed

S, Hossain MB, RaqibR, Vahter M , Broberg K

(2013). Sex-specific effects of early life

cadmium exposure on DNA methylation and

implications for birth weight. Epigenetics

8:494-503.

Klein CB, Conway K, Wang XW, Bhamra RK, Lin

XH, Cohen MD, Annab L, Barrett JC, Costa M

(1991). Senescence of nickel-transformed cells

by an X chromosome: possible epigenetic

control. Science 251(4995):796-799.

Kondoh M, Araragi S, Sato K, Higashimoto M,

TakiguchiM , Sato M (2002). Cadmium induces

apoptosis partly via caspase-9 activation in HL-

60 cells. Toxicology 170:111-117.

Kowara R, Karaczyn A, Fivash MJ, Kasprzak KS

(2002). In vitroinhibition of the enzymatic

activity of tumor suppressor FHITgene product

by carcinogenic transition metals. Chemical

Research in Toxicology 15:319-325.

Landolph JR (1994). Molecular mechanisms of

transformation of C3H/10T1/2 C1 8 mouse

embryo cells and diploid human fibroblasts by

carcinogenic metal compounds. Environmental

Health Perspectives 102(3):119-25.

Lee YW, Klein CB, Kargacin B, Salnikow K,

Kitahara J, Dowjat K, Zhitkovich A, Christie

NT, Costa M (1995). Carcinogenic nickel

silences gene expression by chromatin

condensation and DNA methylation: a new

model for epigenetic carcinogens. Molecular

and Cellular Biology 15:2547-2557.

Lippmann M, Ito K, Hwang J.S, Maciejczyk P, Chen

L.C (2006). Cardiovascular effects of nickel in

International Journal of Scientific Research in Environmental Sciences (IJSRES), 1(8), pp. 202-216, 2013

212

ambient air. Environmental Health Perspectives

114:1662-1669.

Lloyd DR, Phillips DH (1999). Oxidative DNA

damage mediated by copper(II), iron(II) and

nickel(II) fenton reactions: evidence for site-

specifc mechanisms in the formation of double-

strand breaks, 8-hydroxydeoxyguanosine and

putative intrastrand crosslinks. Mutation

Research 424:23-36.

Lynn S, Yew FH, Chen KS, Jan KY (1997). Reactive

Oxygen Species are involved in Nickel

inhibition of DNA repair. Environmental and

Molecular Mutagenesis 29(2):208 -216.

M’Bemba-Meka P, Lemieux N, Chakrabarti SK

(2005). Nickel compound-induced DNA single-

strand breaks in chromosomal and nuclear

chromatin in human blood lymphocytes in

vitro: role of oxidative stress and intracellular

calcium. Mutation Research 586:124-137.

M’Bemba-Meka P, Lemieux N, Chakrabarti SK

(2007). Role of oxidative stress and

intracellular calcium in nickel carbonate

hydroxide-induced sister-chromatid exchange,

and alterations in replication index and mitotic

index in cultured human peripheral blood

lymphocytes. Archives of Toxicology 81:89-99.

Maehle L, Metcalf RA, Ryberg D, Bennett WP, Harris

CC, Haugen A (1992). Altered p53 gene

structure and expression in human epithelial

cells after exposure to nickel. Cancer Research

52(1):218-221.

Martin MB, Reiter R, Pham T, Avellanet YR, Camara

J, Lahm M, Pentecost E, Pratap K, Gilmore BA,

Divekar S, Dagata RS, Bull JL, Stoica A

(2003). Estrogen-like activity of metals in

MCF-7 breast cancer cells. Endocrinology

144(6):2425–2436.

Martinez-Zamudio R, Ha HC (2011). Environmental

epigenetics in metal exposure. Epigenetics

6(7):820-827.

MenoudPA and Schowing J (1987). A preliminary

study of the mechanisms of cadmium

teratogenicity in chick embryo after direct

action. Journal de toxicologie clinique et

expérimentale 7:77-84.

Méplan C, Mann K, Hainaut P (1999). Cadmium

induces conformational modifications of wild-

type p53 and suppresses p53 response to DNA

damage in cultured cells. The Journal of

Biological Chemistry 274(44):31663-31670.

Merian E (1984). Introduction on environmental

chemistry and global cycles of chromium,

nickel, cobalt, beryllium, arsenic, cadmium, and

selenium, and their derivatives. Toxicological

and Environmental Chemistry 8:9–38.

Minoru K, Naoki S, Akira O (1974). Toxic effect of

cadmium stearate on rat cerebellum in culture.

Bulletin of Environmental Contamination and

Toxicology 12(5):535-540.

Misra UK,Gawdi G, AkabaniG ,Pizzo SV (2002).

Cadmium-induced DNA synthesis and cell

proliferation in macrophages: the role of

intracellular calcium and signal transduction

mechanisms. Cell Signal 14:327-340.

Muñoz A, Costa M (2012).Elucidating the

mechanisms of nickel compound uptake: A

review of particulate and nano-nickel

endocytosis and toxicity. Toxicology and

Applied Pharmacology 260(1):1-16.

Nackerdien Z, Kasprzak KS, Rao G, Halliwell B,

Dizdaroglu M (1991). Peroxide to the DNA

Bases in Isolated Human Chromatin Nickel(II)-

and Cobalt(II)-dependent Damage by

Hydrogen. Cancer Research 51(21):5837-5842.

NTP; National Toxicology Program (1996).

Toxicology and Carcinogenesis Studies of

Nickel Subsulfide in F344/N Rats and B6C3F1

Mice. Tech Rep NTP Tech Rep 453. NTIS publ

no. PB 97–116784.

Oliveira H, Lopes T, Almeida T, Pereira Mde L,

Santos C (2012). Cadmium-induced genetic

instability in mice testis. Human and

Experimental Toxicology 31(12):1228-1236.

Oller AR, Kirkpatrick DT, Radovsky A, Bates HK.

(2008). Inhalation carcinogenicity study with

nickel metal powder in Wistar rats. Toxicology

and Applied Pharmacology 1;233(2):262-275.

Ohshima S (2003). Induction of genetic instability and

chromosomal instability by nickel sulfate in

V79 Chinese hamster cells. Mutagenesis

18:133–137.

Palecek E, Brazdova M, Cernocka H, Litsen D,

Brazda V, Vojtesek B (1999). Effect of

transition metals on binding of p53 protein to

supercoiled DNA and to consensus sequence in

DNA fragments. Oncogene 18:3617-3625.

Patra RC, Swarup D, Senapat SK (1999). Effects of

cadmium on lipid peroxides and superoxide

dismutasein hepatic, renal and testicular tissue

of rats.Veterinary and Human Toxicology

41:65-67.

Patricia MH, Patricia AK, Kevin CO (1987).Cadmium

uptake and toxicity via voltage-sensitive

calcium channels. BioChemistry 262: 16333-

16337.

Person RJ, Tokar EJ, Xu Y, Orihuela R, Ngalame NN,

Waalkes MP (2013). Chronic cadmium

exposure in vitro induces cancer cell

characteristics in human lung cells. Toxicology

and Applied Pharmacology pii: S0041-

008X(13)00286-X.

Saedi et al.

A Review of Genetic and Epigenetic Mechanisms in Heavy Metal Carcinogenesis: Nickel and Cadmium

213

Price DJ, Joshi JG (1983). Ferritin: Binding of

beryllium and other divalent metal ions. Journal

of Biological Chemistry 25;258(18):10873-

10880.

Refsvik T, Andreassen T (1995). Surface binding and

uptake of nickel(II) in human epithelial kidney

cells: modulation by ionomycin, nicardipine

and metals. Carcinogenesis 16:1107-1112.

Rusch GM, O’Grodnick JS, Rinehart WE (1986).

Acute inhalation study in rat of comparative

uptake, distribution and excretion of different

cadmium containing materials. American

Industrial Hygiene Association journal 47:754-

763.

Salnikow K, Cosentino S, Klein C, Costa M (1994).

Loss of thrombospondin transcriptional activity

in nickel-transformed cells. Molecular and

Cellular Biology 14:851–858.

Salnikow K, Costa M (2000) . Epigenetic mechanisms

of nickel carcinogenesis. Journal of

Environmental Pathology, Toxicology and

Oncology 19(3):307-318.

Salnikow K, Zhitkovich A (2008). Genetic and

epigenetic mechanisms in metal carcinogenesis

and cocarcinogenesis: nickel, arsenic, and

chromium. Chemical Research in Toxicology

21:28-44.

Sanders C L, Mahaffey J A (1984). Carcinogenicity of

single and multiple intratracheal instillations of

cadmium oxide in the rat. Environmental

Research 33: 227-233.

Schwerdtle T, Ebert F, Thuy C, Richter C, Mullenders

LH , Hartwig A (2010). Genotoxicity of soluble

and particulate cadmium compounds: impact on

oxidative DNA damage and nucleotide excision

repair. Chemical Research in Toxicology

23:432-442.

Schwerdtle T, Hartwig A (2006). Bioavailability and

genotoxicityof soluble and particulate nickel

compounds in cultured human lung cells.

MaterialwissWerkstofftech 37:521-525.

Schwerdtle T, Seidel A, Hartwig A (2002). Effect of

soluble and particulate nickel compounds in the

formation and repair of stable benzo[a]pyrene

DNA adducts in human lung cells.

Carcinogenesis 23:47–53.

Shih CM, Ko WC, Wu JS, Wei YH, Wang LF, Chang

EE, Lo TY, Cheng HH , Chen CT (2004).

Mediating of caspaseindependent apoptosis by

cadmium through the mitochondria- ROS

pathway in MRC-5 fibroblasts. Journal of

Cellular Biochemistry 91:384-397.

Siewit CL, Gengler B, Vegas E, Puckett R, Louie MC.

(2010). Cadmium promotes breast cancer cell

proliferation by potentiating the interaction

between ERalpha and c-Jun. Molecular

Endocrinology 24:981-92.

Smith TB, Dun MD, Smith ND, Curry BJ,

Connaughton HS, Aitken RJ (2013). The

presence of a truncated base excision repair

pathway in human spermatozoa that is mediated

by OGG1. Journal of Cell Science 126:1488-

1497.

Somji S, Garrett SH, Toni C, Zhou XD, Zheng Y,

Ajjimaporn A, SensMA ,Sens DA (2011).

Differences in the epigenetic regulation of MT-

3 gene expression between parental and Cd+2

or As+3 transformed human urothelial cells.

Cancer Cell International 11:2.

Stohs SJ, Bagchi D, Hassoun E, Bagchi M (2001).

Oxidative mechanisms in the toxicity of

chromium and cadmium ions. Journal of

Environmental Pathology, Toxicology and

Oncology 20: 77–88.

Sugiyama M (1994). Role of cellular antioxidants in

metal induced damage. Cell Biology and

Toxicology 10: 1–22.

Sunderman FW Jr (1984). Carcinogenicity of nickel

compounds in animals. IARC(International

Agency for Research on Cancer) scientific

publications 53:127-142.

Sunderman FW Jr, Hopfer SM, Nichols WW, Selden

JR, Allen HL, Anderson CA, Hill R, Bradt C,

Williams CJ (1990). Chromosomal

abnormalities and gene amplification in renal

cancers induced in rats by nickel subsulfide.

Annals of Clinical and Laboratory Science

20(1):60-72.

Sunderman FW Jr and McCully KS (1983).

Carcinogenesis Tests of Nickel Arsenides,

Nickel Antimonide, and Nickel Telluride in

Rats. Cancer Investigation 1(6):469-474.

Sutherland JE, Costa M (2003). Epigenetics and the

environment. Annals of the New York

Academy of Sciences 983:151–160.

Takenaka S, Oldiges H, König H, Hochrainer D,

Oberdörster G (1983). Carcinogenicity of

cadmium chloride aerosols in W rats. Journal of

the National Cancer Institute 70: 367-373.

Takiguchi M, Achanzar W, Qu W, Li G ,Waalkes M.

(2003). Effects of cadmium on DNA-(-

cytosine-5) methyltransferase activity and DNA

methylation status during cadmium induced

cellular transformation. Experimental Cell

Research, 286: 355-365.

Tchou-Wong KM, Kiok K, Tang Z, Kluz T, Arita

A, Smith PR, Brown S, Costa M (2011). Effects

of nickel treatment on H3K4 trimethylation and

gene expression. PLoS One, 6(3): e17728.

Thompson JM and Bannigan JG (2001). The effects

of cadmium on formation of the ventral body

International Journal of Scientific Research in Environmental Sciences (IJSRES), 1(8), pp. 202-216, 2013

214

wall in chick embryos and their prevention by

zinc pre-treatment. Teratology, 64: 87-97.

Tundermann JH, Tien JK, Howson TE (2005). Nickel

and nickel alloys. In: Kirk-Othmer

Encyclopedia of Chemical Technology.

Volume 17. (online edition)

Tvrdá E, Kňažická Z, Lukáčová J, Schneidgenová M,

Goc Z, Greń A, Szabó C, Massányi P, Lukáč N

(2013). The impact of lead and cadmium on

selected motility, prooxidant and antioxidant

parameters of bovine seminal plasma and

spermatozoa. Journal of Environmental Science

and Health, Part A. Toxic/Hazardous

Substances and Environmental Engineering, 48:

1292-1300.

Valko M, Morris H, Cronin MTD (2005). Metals,

toxicity and oxidative stress. Current Medicinal

Chemistry, 12: 1161-1208.

Waalkes M, Misra R (1996). Cadmium

carcinogenicity and genotoxicity. In: Chang, L.,

editor. Toxicology of metals. Boca Raton,

Florida: CRC Press 231-244.

Waalkes M (2003). Cadmium carcinogenesis.

Mutation Research, 533: 107-120.

Waalkes M.P (2000).Cadmium carcinogenesis in

review. Inorganic Biochemistry 79:241-244.

Wang B, Li Y, Shao C, Tan Y, Cai L (2012).

Cadmium and its epigenetic effects. Current

Medicinal Chemistry, 19: 2611-20.

Wang P, Guliaev AB, Hang B (2006). Metal

inhibition of human N-methylpurine-DNA

glycosylase activity in base excision repair.

Toxicology Letters, 166: 237-247.

Wang Y, Fang J, Leonard SS, Rao KM (2004).

Cadmium inhibits the electron transfer chain

and induces reactive oxygen species. Free

Radical Biology and Medicine, 36: 1434-1443.

Woźniak K, Błasiak J (2004). Nickel impairs the

repair of UV- and MNNG-damaged DNA.

Cellular and Molecular Biology Letters, 9: 83-

94.

Xu B, Chen S, Luo Y, Chen Z, Liu L, Zhou H, Chen

W, Shen T, Han X, Chen L, Huang S (2011).

Calcium signaling is involved in cadmium-

induced neuronal apoptosis via induction of

reactive oxygen species and activation of

MAPK/mTOR network. PloS ONE, 6:e19052.

Yan Y, Kluz T, Zhang P, Chen HB, Costa M.

(2003).Analysis of specific lysine histone H3

and H4 acetylation and methylation status in

clones of cells with a gene silenced by nickel

exposure. Toxicology and Applied

Pharmacology, 190: 272-277.

Yang JL, Chao JI, Lin JG (1996). Reactive oxygen

species may participate in the mutagenicity and

mutational spectrum of cadmium in Chinese

hamster ovary-K1 cells. Chemical Research in

Toxicology, 9(8): 1360–1367.

Youn CK, Kim SH, Lee DY, Song SH, Chang IY,

Hyun JW, Chung MH, You HJ (2005).

Cadmium downregulates human OGG1 through

suppression of Sp1 activity. The Journal of

Biological Chemistry, 280: 25185-25195.

Zglinicki T, Edwall C, Ostlund E, Lind B, Nordberg

M, Ringertz NR , Wroblewski J (1992). Very

low cadmium concentrations stimulate DNA

synthesis and cell growth. Journal of Cell

Science, 103: 1073-1081.

Zhang C, Liang Y, Lei L, Zhu G, Chen X, Jin T, Wu

Q (2013). Hypermethylations of RASAL1 and

KLOTHO is associated with renal dysfunction

in a Chinese population environmentally

exposed to cadmium. Toxicology and Applied

Pharmacology S0041-008X:00188-9

Zhang J, Zhou Y, Ma L, Huang S, Wang R, Gao R,

Wu Y, Shi H, Zhang J (2013). The Alteration of

MiR-222 and Its Target Genes in Nickel-

Induced Tumor. Biological Trace Element

Research 152(2):267-274.

Zhou X, Li Q, Arita A, Sun H, Costa M

(2009).Effects of nickel, chromate, and arsenite

on histone 3 lysine methylation. Toxicology

and Applied Pharmacology, 236(1): 78-84.

Zoroddu MA, Schinocca L, Kowalik-Jankowska T,

Kozlowski H, Salnikow K, Costa M (2002).

Molecular mechanisms in nickel

carcinogenesis: modeling Ni(II) binding site in

histone H4. Environmental Health Perspectives,

110(5): 719-723.

Saedi et al.

A Review of Genetic and Epigenetic Mechanisms in Heavy Metal Carcinogenesis: Nickel and Cadmium

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Table 2: toxicity and carcinogenicity of various cadmium species and compounds

Name Formula Solubility Reference Methods Results

Cadmium Cd Insoluble Person et al, 2013 exposing the peripheral

lung epithelia cell line,

HPL-1D, to a low level

of cadmium

induces cancer cell characteristics

in human lung cells

Cadmium

acetate

Cd(CH3COO)2 Soluble Yang, 1998 Exposing Chinese

hamster ovary (CHO)-

K1 cells to cadmium

acetate

decreased the colony-forming

ability of cells and induced

mutation frequency in the

hypoxanthine (guanine)

phosphoribosyltransferase (hprt)

gene

Cadmium

carbonate

CdCO3 Insoluble Rusch et al, 1986 Rats

exposed for 2 hours to

CdCO3

at the higher levels of 132 mg/m3

developed rales, rapid breathing,

and

2-3-fold increases in lung weight

Cadmium

chloride

CdCl2 high Takenaka et al,

(1983)

exposed male Wistar

rats to cadmium

chloride aerosol

(MMAD=0.55 μm)

increases in the incidence of lung

tumors , including

adenocarcinomas, squamous cell

carcinomas, and mucoepidermoid

carcinomas

Cadmium nitrate Cd (NO3)2 high Dote et al, 2007 intravenous

administration of CdN

in rats

hyperkalemia associated with

renal injury and hepatic damage

Cadmium

stearate

Cd(C36H72O4) Insoluble Minoru et al, 1974 cerebellar cells from

newborn rat in tissue

culture

inhibited the outgrowth of cells

and produced degenerative

changes at a concentration of 0.58

× 10−66 M

Cadmium sulfate CdSO4 Soluble Bassendowska-

Karska et al, 1987

sister chromatid

exchanges (SCEs) in

lymphocytes of human

peripheral blood

No significant increase was found

in the mean frequency of SCEs in

lymphocytes

Cadmium oxide CdO negligible Sanders and

Mahaffey, 1984

intratracheal instillation

of 25, 50, or 75 μg

cadmium oxide into

male F344 rats

induce d mammary gland tumors,

but not lung tumors

Cadmium sulfide CdS Insoluble Glaser et al, 1990 Inhalation exposure to

Cadmium sulfide

aerosol (90 μg Cd/m3)

observed lung tumors After 4

weeks

International Journal of Scientific Research in Environmental Sciences (IJSRES), 1(8), pp. 202-216, 2013

216

Zienab Saedi is MSc holder in Biotechnology, the Department of Biotechnology, Faculty of Advanced

Sciences and Technologies, University of Isfahan, Isfahan, Iran.

Shahin Gavanji is MSc holder in Biotechnology, the Department of Biotechnology, Faculty of

Advanced Sciences and Technologies, University of Isfahan, Isfahan, Iran. He has over 10 international

medals in invention. Shahin Gavanji's research has focused on Pharmacy and Pharmacology, Nano

Biotechnology, Bioinformatics, Biotechnology - Medical Biotechnology. He is editor in chief of

International Journal of Scientific Research in Inventions and New Ideas.

Sahar Davodi is MSc holder in Biotechnology, the Department of Biotechnology, Faculty of Advanced

Sciences and Technologies, University of Isfahan, Isfahan, Iran.