Cadmium is a human carcinogen of worldwide concern because it accumulates in the environment due to its extremely long half-life. Its compounds are classified as human carcinogens by several regulatory agencies. Cadmium affects cell proliferation, differentiation, apoptosis and other cellular activities and can cause numerous molecular lesions that would be relevant to carcinogenesis. For a long time cadmium has been considered as a non-genotoxic carcinogen, as it is only weakly mutagenic in bacterial and mammalian cell test systems. Recently, we presented evidence that when assayed in a test system, in which both intragenic and multilocus mutations can be detected, cadmium acts as a strong mutagen which induces predominantly multilocus deletions. In this review, we discuss two mechanisms that play an important role in cadmium mutagenicity: (i) induction of reactive oxygen species (ROS); and (ii) inhibition of DNA repair. Experimental evidence suggests that cadmium at low, for environmental exposure relevant concentrations, induces mutations by inducing oxidative DNA damage and that it decreases genetic stability by inhibiting the repair of endogenous and exogenous DNA lesions, which in turn increase the probability of mutations and consequently cancer initiation by this metal.
1 Irwin RJ , VanMouwerik M , Stevend L , Seese MD , Basham W . Environmental Contaminants Encyclopedia. National Park Service, Water Resources Division, Fort Collins, CO, 1997. Retrieved from http://www.nature.nps.gov/toxic/cadmium.pdf
2.
2 WHO . Cadmium. Environmental Health Criteria 134. World Health Organization , 1992.
3.
3 Goering PL , Waalkes MP , Klaassen CD . Toxicology of cadmium. In Goyer RA , Cherian MG eds. Handbook of experimental pharmacology: toxicology of metals, biochemical effects, Volume 115. Springer-Verlag , 1994: 189–214.
4.
4 IARC . Beryllium , cadmium , mercury , and exposures in the glass manufacturing industry . Monographs on the evaluation of carcinogenic risk to humans, Volume 58. Lyon, France , 1993: 119–238.
5.
5 National Toxicology Program. Tenth Report on Carcinogens, Department of Health and Human Services, III-42-III-44. Research Triangle Park, NC , 2000.
7 Pesch B , Haerting J , Ranft U , Klimpel , Oelschlagel B , Schill W , MURC Study Group . Occupational risk factors for renal cell carcinoma: agent-specific results from a case-control study in Germany . Int J Epidemiol2000; 29: 1014–1024 .
8.
8 Hu J , Mao Y , White P , Canadian Cancer Registries Epidemiology Research Group . Renal cell carcinoma and occupational exposure in Canada . Occup Med2002; 52: 157–164 .
9.
9 Waalkes MP , Misra RR . Cadmium carcinogenicity and genotoxicity. In Chang L ed. Toxicology of metals. CRC Press , 1996: 231–244.
10.
10 Schwartz GG , Reis IM . Is cadmium a cause of human pancreatic cancer . Cancer Epidemiol Biomark Prev2000; 9: 139–145 .
11.
11 Waalkes MP , Anver M , Diwan B . Carcinogenic effects of cadmium in the Noble (NBL/Cr) rat: induction of pituitary, testicular, and injection site tumors and intraepithelial proliferative lesions of the dorsolateral prostate . Toxicol Sci1999; 52: 154–161 .
12.
12 Waalkes MP , Anver M , Diwan B . Chronic toxic and carcinogenic effects of oral cadmium in the Noble (NBL/Cr) rat: induction of neoplastic and proliferative lesions of the adrenal, kidney, prostate and testes . J Toxicol Environ Health1999; 58: 199–214 .
13.
13 Rossman TG , Roy NK , Lin W . Is cadmium genotoxic? In GF Nordberg , Alessio L , Herber RFM eds. Cadmium in human environment: toxicity and carcinogenicity. International Agency for Research on Cancer , 1992: 367–375.
14.
14 Keshava N , Zhou G , Hubbs AF , Ensell M-X , Ong T . Transforming and carcinogenic potential of cadmium chloride in BALB/c-3T3 cells . Mutat Res2000; 448: 23–28 .
15.
15 Nakamura K , Yasunaga Y , Ko D , Xu LL , Moul JW , Peelh DM et al. Cadmium-induced neoplastic transformation of human prostate epithelial cells . Int J Oncol2002; 20: 543–547 .
16.
16 Achanzar WE , Bhalchandra AD , Liu J , Quader T , Webber MW , Waalkes MP . Cadmium-induced malignant transformation of human prostate epithelial cells . Cancer Res2001; 61: 455–458 .
17.
17 Ochi T , Oshawa M . Induction of 6-thioguanine-resistant mutants and single-strand scission of DNA by cadmium chloride in cultured Chinese hamster cells . Mutat Res1983; 111: 69–78 .
18.
18 Yang J-L , Chao J-I , Lin JG . Reactive oxygen species may participate in the mutagenicity and mutational spectrum of cadmium in Chinese hamster ovary-K1 cells . Chem Res Toxicol1996; 9: 1360–1367 .
19.
19 Oberly TJ , Piper CE , McDonald DS . Mutagenicity of metal-salts in the L5178Y mouse lymphoma assay .J Toxicol Environ Health1982; 9: 367–376 .
20.
20 Ochi T , Ohsawa M . Participation of active oxygen species in the induction of chromosomal aberrations by cadmium chloride in cultured Chinese hamster cells . Mutat Res1985; 143: 137–142 .
21.
21 Lin RH , Lee CH , Chen KW , Lin-Shiau SY . Studies on cytotoxic and genotoxic effects of cadmium nitrate and lead nitrate in Chinese hamster ovary cells . Environ Mol Mutagen1994; 23: 143–149 .
22.
22 Hartmann A , Speit G . Comparative investigations of the genotoxic effects of metals in the single cells gel (SCG) assay and the sister chromatide exchange (SCE) test . Environ Mol Mutagen1994; 23: 299–305 .
23.
23 Ochi T , Ishiguro T , Oshawa M . Participation of active singlet oxygen species in the induction of DNA single strand scission by cadmium chloride in cultured Chinese hamster cells . Mutat Res1983; 122: 169–175 .
24.
24 Misra RR , Smith GT , Waalkes MP . Evaluation of the direct genotoxic potential of cadmium in four different rodent cell lines . Toxicology1998; 126: 103–114 .
25.
25 Fatur T , Tušek M , Falnoga I , Šančar J , Lah TT , Filipič M . DNA damage and metallothionein synthesis in human hepatoma cells (HepG2) exposed to cadmium . Food Chem Toxicol2002; 40: 1069–1076 .
26.
26 Liu F , Jan K-Y . DNA damage in arsenite-and cadmium-treated bovine aortic endothelial cells . Free Rad Biol Med2000; 28: 55–63 .
27.
27 Yamada Y , Park MS , Okinaka RT , Chen DJ . Molecular analysis and comparison of radiation-induced large deletions of the HPRT locus in primary human skin fibroblasts . Radiat Res1996; 145: 481–490 .
28.
28 Puck TT , Wuchie P , Jones C , Kao FT . Genetics of somatic mammalian cells: lethal antigens as genetic markers for study of human linkage groups . Proc Nat Acad Sci USA1971; 68: 3102–3106 .
29.
29 Waldren CA , Jones C , Puck TT . Measurement of mutagenesis in mammalian-cells . Proc Nat Acad Sci USA1979; 76: 1358–1362 .
30.
30 Xu A , Wu LJ , Santella R , Hei TK . Role of oxyradicals in mutagenicity and DNA damage induced by crocidolite asbestos in mammalian cells . Cancer Res1999; 59: 5922–5926 .
31.
31 Filipič M , Hei TK . Mutagenicity of cadmium in mammalian cells: implication of oxidative DNA damage . Mutat Res2004; 546: 81–91 .
32.
32 Eckardt T , Haynes RH . Quantitative measures of mutagenicity and mutability based on mutant yield data . Mutat Res1980; 74: 439–458 .
33.
33 Puck TT , Waldren CA . Mutation in mammalian cells: theory and implications . Somat Cell Mol Gen1987; 13: 405–409 .
34.
34 Gustafson DL , Franz HR , Ueno AM , Smith CJ , Doolittle DJ , Waldren CA . Vanillin (3-methoxy-4-hydroxybenzaldehyde) inhibits mutation induced by hydrogen peroxide, N-methyl-N-nitrasoguanidine and mitomycin C but not Cs-137 gamma-radiation at the CD59 locus in human-hamster hybrid A(L) cells . Mutagenesis2000; 15: 207–213 .
35.
35 Hei TK , Piao CQ , He ZY , Vannais D , Waldren CA . Chrysotile fiber is a strong mutagen in mammaliancells . Cancer Res1992; 52: 6305–6309 .
36.
36 Hei TK , Liu SX , Waldren C . Mutagenicity of arsenic in mammalian cells: role of reactive oxygen species . Proc Nat Acad Sci USA1998; 95: 8103–8107 .
37.
37 Waalkes MP . Metal carcinogenesis. In Sarkar B ed. Handbook of heavy metals in the environment. Marcel Dekker , 2002: 121–146.
38.
38 Waalkes MP , Poirier LA . In vitro cadmium-DNA interactions: cooperativity of cadmium binding and competitive antagonism by calcium . Toxicol Appl Pharmacol1984; 75: 539–546 .
39.
39 Klaassen CD , Liu J , Choudhuri S . Metallothionein: an intracellular protein to protect against cadmium toxicity . Annu Rev Pharmacol Toxicol1999; 39: 267–294 .
40.
40 Kasprzak KS . Oxidative DNA and protein damage in metal-induced toxicity and carcinogenesis . Free Rad Biol Med2002; 32: 958–967 .
41.
41 Szuster-Ciesielska A , Stachura A , Slotwinska M , Kaminska T , Sniezko R , Paduch R et al. The inhibitory effect of zinc on cadmium-induced cell apoptosis and reactive oxygen species (ROS) production in cell cultures . Toxicology2000; 145: 159–171 .
42.
42 Waisberg M , Joseph P , Hale B , Beyersmann D . Molecular and cellular mechanisms of cadmium carcinogenesis . Toxicology2003; 198: 95–117 .
43.
43 Hussain T , Shukla GS , Chandra SV . Effects of cadmium on superoxide dismutase and lipid peroxidation in liver and kidney of growing rats: in vivo and in vitro studies . Pharmacol Toxicol1987; 60: 355–358 .
44.
44 Casalino E , Sblano C , Landriscina C . Enzyme activity alteration by cadmium administration to rats: the possibility of iron involvement in lipid peroxidation . Arch Biochem Biophys1997; 346: 37–50 .
45.
45 Koizumi T , Li ZG , Tatsumoto H . DNA damaging activity of cadmium in Leydig cells, a target cell population for cadmium carcinogenesis in rat testis . Toxicol Letts1992; 63: 211–220 .
46.
46 Hei TK , Gerard CR , Hall EJ . Effect of cellular non-protein sulfhydryl depletion in radiation-induced oncogenic transformation and genotoxicity in mouse C3H 10T1/2 cells . Int J Radiat Oncol Biol Phys1984; 10: 1255–1259 .
47.
47 Wu LJ , Randers-Pehrson G , Xu A , Waldren CA , Geard CR , Yu Z et al. Targeted cytoplasmic irradiation with alpha particles induces mutations in mammalian cells . Proc Nat Acad Sci USA1999; 96: 4959–4964 .
48.
48 Biaglow JE , Varnes ME , Clark EP , Epp ER . The role of thiols in cellular response to radiation and drugs . Radiat Res1983; 95: 437–455 .
49.
49 Cheng KC , Cahill DS , Kasai H , Nishimura S , Loeb LA . 8-Hydroxyguanine, an abundant form of oxidative DNA damage, causes G-T and A-C substitutions . J Biol Chem1992; 267: 166–172 .
50.
50 Yarborough A , Zhang YJ , Hsu TM , Santella RM . Immunoperoxidase detection of 8-hydroxydeoguano-sine in aflatoxin B-1-treated rat liver and human oral mucosal cells . Cancer Res1996; 56: 683–688 .
51.
51 Mikhailova MV , Littlefield NA , Hass BS , Poirier LA , Chou MW . Cadmium-induced 8-hydroxydeoxyguanosine formation, DNA strand breaks and antioxidant enzyme activities in lymphoblastoid cells . Cancer Letts1997; 115: 141–148 .
52.
52 Hartwig A . Current aspects in metal genotoxicity . Biometals1995; 8: 3–11 .
53.
53 Hartwig A . Carcinogenicity of metal compounds: possible role of DNA repair inhibition . Toxicol Letts1998; 102–103: 235–239 .
54.
54 Lindahl T . Instability and decay of the primary structure of DNA . Nature1993; 362: 709–715 .
55.
55 Friedberg EC , Walker GC , Siede W . DNA repair and mutagenesis. ASM Press , 1995.
56.
56 Potts RJ , Bespalov IA , Wallace SS , Melamede RJ , Hart BA . Inhibition of oxidative DNA repair in cadmium-adapted alveolar epithelial cells and the potential involvement of metallothionein . Toxicology2001; 161: 25–38 .
57.
57 Zharkov DO , Rosenquist TA . Inactivation of mammalian 8-oxoguanine-DNA glycosylase by cadmium(II): implications for cadmium genotoxicity . DNA Repair2002; 1: 661–670 .
58.
58 Tice RR , Agurell E , Anderson D , Burlinson B , Hartmann A , Kobayashi H et al. Single cell gel/comet assay: Guidelines for in vitro and in vivo genetic toxicology testing . Environ Mol Mutagen2000; 35: 206–221 .
59.
59 Fatur T , Lah TT , Filipič M . Cadmium inhibits repair of UV-, methyl methanesulfonate-and N-methyl-N-nitrosourea-induced DNA damage on Chinese hamster ovary cells . Mutat Res2003; 529: 109–116 .
60.
60 Hartmann M , Hartwig A . Disturbance of DNA damage recognition after UV-irradiation by nickel(II) and cadmium(II) in mammalian cells . Carcinogenesis1998; 19: 617–621 .
61.
61 Hartwig A , Asmuss M , Blessing H , Hoffman S , Jahnke G , Khandelwal S et al. Interference by toxic metal ions with zinc-dependent proteins involved in maintaining genomic stability . Food Chem Toxicol2002; 40: 1179–1184 .
62.
62 Tanaka K , Miura N , Satokata I , Miyamoto I , Yoshida MC , Satoh Y et al. Analysis of human DNA excision repair gene involved in group A Xeroderma pigmentosum and containing zinc-finger domain . Nature1990; 348: 73–76 .
63.
63 Wold MS . Replication protein A: a heterodimeric, single stranded DNA-binding protein required for eucaryotic DNA metabolism . Annu Rev Biochem1997; 66: 61–92 .
64.
64 Asmuss M , Mullenders LHF , Hartwig A . Interference by toxic metal compounds with isolated zinc-finger DNA repair proteins . Toxicol Letts2000; 112: 227–231 .
65.
65 Lynn S , Lai H-T , Kao S-M , Lai J , Jan KY . Cadmium inhibits DNA strand break rejoining in methyl methanesulfonate-treated CHO-K1 cells . Toxicol Appl Pharmacol1997; 144: 171–176 .
66.
66 Popenoe EA , Schmaeler MA . Interaction of human polymerase-b with ions of copper . Arch Biochem Biophys1979; 196: 109–120 .
67.
67 Dantzer F , Schreiber V , Niedergang C , Trucco C , Flatter E , De La Rubia G et al. Involvement of poly(ADP-ribose) polymerase in base excision repair . Biochimie1999; 81: 69–75 .
68.
68 Mandel R , Ryser HJ-P . Mutagenicity of cadmium in Salmonella typhimurium and its synergism with two nitrosamines . Mutat Res1984; 138: 9–16 .
69.
69 Takahashi K , Imaeda T , Kawazoe Y . Effect of metal ions on the adaptive response induced by N-methyl-N-nitrosourea in Escherichia coli . Biochem Biophys Res Commun1988; 157: 1124–1130 .
70.
70 Takahashi K , Suzuki M , Sekiguchi M , Kawazoe Y . Effect of metal ions on transcription of the ada gene which encodes O6-methylguanine DNA-methyltransferase of Escherichia coli . Chem Pharmacol Bull1992; 40: 2483–2486 .
71.
71 Peltomaki P . Role of DNA mismatch repair defects in the pathogenesis of human cancers . J Clin Oncol2003; 21: 1174–1179 .
72.
72 Boland CR . Molecular genetics of hereditary nonpolyposis colorectal cancer . Ann NY Acad Sci2000; 910: 50–59 .
73.
73 Jin YH , Clark AB , Slebos RJC , Al-Refai H , Taylor JA , Kunkel TA et al. Cadmium is a mutagen that acts by inhibiting mismatch repair . Nat Genet2003; 34: 326–329 .
74.
74 Satarug S , Baker JR , Urbenjapol S , Haswell-Elkins M , Reilly PEB , Williams DJ et al. A global perspective on cadmium pollution and toxicity in non-occupationally exposed population . Toxicol Letts2003; 137: 65–83 .
75.
75 Hengstler JG , Bolm-Audorff U , Faldum A , Janssen K , Reifenrath M , Götte W et al. Occupational exposure to heavy metals: DNA damage induction and DNA repair inhibition prove co-exposures to cadmium, cobalt and lead as more dangerous than hitherto expected . Carcinogenesis2003; 24: 63–73 .
76.
76 Abshire MK , Buzard GS , Shiraishi N , Waalkes MP . Induction of c-myc and c-jun proto-oncogene expression in rat L6 myoblasts by cadmium is inhibited by zinc preinduction of the metallothionein gene . J Toxicol Environ Health1996; 48: 359–377 .
77.
77 Zheng H , Liu J , Choo KH , Michalska AE , Klaassen CD . Metallothionein-I and-II knock-out mice are sensitive to cadmium-induced liver mRNA expression of c-jun and p53 . Toxicol Appl Pharmacol1996; 136: 229–235 .
78.
78 Takiguchi M , Achanzar WE , Qu W , Li G , Waalkes MP . Effects of cadmium on DNA-(cytosine-5) methyltransferase activity and DNA methylation status during cadmium-induced cellular transformation . Exp Cell Res2003; 286: 355–365 .
79.
79 Shimada H , Shiao Y-H , Shibata MA , Waalkes MP . Cadmium suppress apoptosis induced by chromium . J Toxicol Environ Health1998; 54: 159–168 .
80.
80 Kazantzis G , Blanks RG , Sullivan KR . Is cadmium a human carcinogen?IARC Sci Publ1992; 118: 435–446 .
81.
81 Sorahan T , Lancashire RJ . Lung cancer mortality in a cohort of workers employed at a cadmium recovery plant in the United States: an analysis with detailed job histories . Occupat Environ Med1997; 54: 194–201 .
82.
82 Stayner L , Smith R , Thun M , Schnorr T , Lemen R . A dose-response analysis and quantitative assessment of lung cancer risk and occupational cadmium exposure . Ann Epidemiol1992; 2: 177–194 .
83.
83 El-Maraghy SA , Gad MZ , Fahim AT , Hamdy MA . Effect of cadmium and aluminum intake on the antioxidant status and lipid peroxidation in rat tissues . J Biochem Mol Toxicol2001; 15: 207–214 .
84.
84 Liu J , Corton C , Dix DJ , Liu Y , Waalkes MP , Klaassen CD . Genetic background but not metallothionein phenotype dictates sensitivity to cadmium-induced testicular injury in mice . Toxicol Appl Pharmacol2001; 176: 1–9 .
85.
85 Park JD , Liu Y , Klaassen CD . Protective effect of metallothionein against the toxicity of cadmium and other metals (1) . Toxicology2001; 163: 93–100 .
86.
86 Kondo Y , Rusnak JM , Hoyt DG , Settineri CE , Pitt R , Lazo JS . Enhanced apoptosis in metallothionein null cells . Mol Pharmacol1997; 52: 195–201 .
87.
87 Coogan TP , Bare RM , Bjornson EJ , Waalkes MP . Enhanced metallothionein gene expression is associated with protection from cadmium-induced genotoxicity in cultured rat liver cells . J Toxicol Environ Health1994; 41: 233–245 .
88.
88 Waalkes MP , Coogan TP , Barter RA . Toxicological principles of metal carcinogenesis with special emphasis on cadmium . Crit Rev Toxicol1992; 22: 175–201 .
89.
89 Shimoda R , Achanzar WE , Qu W , Nagamine T , Takagi H , Mori M et al. Metallothionein is a potent negative regulator of apoptosis . Toxicol Sci2003; 73: 294–300 .
90.
90 Nordberg M . Studies on metallothionein and cadmium . Environ Res1978; 15: 381–404 .
