, Volume 23, Issue 5, pp 951–960 | Cite as

Mechanisms in cadmium-induced carcinogenicity: recent insights



Cadmium is an environmental pollutant, with relevant exposures at workplaces and in the general population. The carcinogenicity has been long established, most evident for tumors in the lung and kidney, but with increasing evidence also for other tumor locations. While direct interactions with DNA appear to be of minor importance, the interference with the cellular response to DNA damage, the deregulation of cell growth as well as resistance to apoptosis have been demonstrated in diverse experimental systems. With respect to DNA repair processes, cadmium has been shown to disturb nucleotide excision repair, base excision repair and mismatch repair; consequences are increased susceptibility towards other DNA damaging agents and endogenous mutagens. Furthermore, cadmium induces cell proliferation, inactivates negative growth stimuli, such as the tumor suppressor protein p53, and provokes resistance towards apoptosis. Particularly the combination of these multiple mechanisms may give rise to a high degree of genomic instability in cadmium-adapted cells, relevant not only for tumor initiation, but also for later steps in tumor development. Future research needs to clarify the relevance of these interactions for low exposure conditions in humans.


Cadmium DNA repair Gene expression Cell cycle control Apoptosis Genomic instability 



The author gratefully acknowledges Nancy Sobier-Maier for critically proof-reading the manuscript. Research conducted in the author’s laboratory was supported by the Deutsche Forschungsgemeinschaft and by BWPLUS.


  1. Achanzar WE, Webber MM, Waalkes MP (2002) Altered apoptotic gene expression and acquired apoptotic resistance in cadmium-transformed human prostate epithelial cells. Prostate 52:236–244CrossRefPubMedGoogle Scholar
  2. Akesson A, Julin B, Wolk A (2008) Long-term dietary cadmium intake and postmenopausal endometrial cancer incidence: a population-based prospective cohort study. Cancer Res 68:6435–6441CrossRefPubMedGoogle Scholar
  3. Asmuss M, Mullenders LH, Eker A et al (2000) Differential effects of toxic metal compounds on the activities of Fpg and XPA, two zinc finger proteins involved in DNA repair. Carcinogenesis 21:2097–2104CrossRefPubMedGoogle Scholar
  4. Benbrahim-Tallaa L, Tokar EJ, Diwan BA et al (2009) Cadmium malignancy transforms normal human breast epithelial cells into a basal-like phenotype. Environ Health Perspect 117:1847–1852CrossRefPubMedGoogle Scholar
  5. Beneke S, Bürkle A (2007) Poly(ADP-ribosyl)ation in mammalian ageing. Nucleic Acids Res 35:7456–7465CrossRefPubMedGoogle Scholar
  6. Beyersmann D, Hartwig A (2008) Carcinogenic metal compounds: recent insight into molecular and cellular mechanisms. Arch Toxicol 82:493–512CrossRefPubMedGoogle Scholar
  7. 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 Res 26:3194–3201CrossRefPubMedGoogle Scholar
  8. Bialkowski K, Bialkowska A, Kasprzak KS (1999) Cadmium(II), unlike nickel(II), inhibits 8-oxo-dGTPase activity and increases 8-oxo-dG level in DNA of the rat testis, a target organ for cadmium(II) carcinogenesis. Carcinogenesis 20:1621–1624CrossRefPubMedGoogle Scholar
  9. Buchko GW, Hess NJ, Kennedy MA (2000) Cadmium mutagenicity and human nucleotide excision repair protein XPA: CD, EXAFS and (1)H/(15)N-NMR spectroscopic studies on the zinc(II)- and cadmium(II)-associated minimal DNA-binding domain (M98-F219). Carcinogenesis 21:1051–1057CrossRefPubMedGoogle Scholar
  10. Byrne C, Divekar SD, Storchan GB et al (2009) Cadmium—a metallohormone? Toxicol Appl Pharmacol 238:266–271CrossRefPubMedGoogle Scholar
  11. Camenisch U, Naegeli H (2009) Role of DNA repair in the protection against genotoxic stress. EXS 99:111–150PubMedGoogle Scholar
  12. Christmann M, Tomicic MT, Roos WP et al (2003) Mechanisms of human DNA repair: an update. Toxicology 193:3–34CrossRefPubMedGoogle Scholar
  13. Costa M, Heck JD, Robison SH (1982) Selective phagocytosis of crystalline metal sulfide particles and DNA strand breaks as a mechanism for the induction of cellular transformation. Cancer Res 42:2757–2763PubMedGoogle Scholar
  14. Dally H, Hartwig A (1997) Induction and repair inhibition of oxidative DNA damage by nickel(II) and cadmium(II) in mammalian cells. Carcinogenesis 18:1021–1026CrossRefPubMedGoogle Scholar
  15. de Boer J, Hoeijmakers JH (2000) Nucleotide excision repair and human syndromes. Carcinogenesis 21:453–460CrossRefPubMedGoogle Scholar
  16. DFG (2006) Cadmium and its compounds (in the form of inhable dusts/aerosols). The MAK collection for occupational health and safety, vol 22. D. Forschungsgemeinschaft, Wiley-VCH, WeinheimGoogle Scholar
  17. EFSA (2009) Scientific opinion of the panel on contaminants in the food chain on a request from the European Commission on cadmium in food. EFSA J 980:1–139Google Scholar
  18. Evans RM, Davies PJ, Costa M (1982) Video time-lapse microscopy of phagocytosis and intracellular fate of crystalline nickel sulfide particles in cultured mammalian cells. Cancer Res 42:2729–2735PubMedGoogle Scholar
  19. Fatur T, Lah TT, Filipic M (2003) Cadmium inhibits repair of UV-, methyl methanesulfonate- and N-methyl-N-nitrosourea-induced DNA damage in Chinese hamster ovary cells. Mutat Res 529:109–116PubMedGoogle Scholar
  20. Filipic M, Hei TK (2004) Mutagenicity of cadmium in mammalian cells: implication of oxidative DNA damage. Mutat Res 546:81–91PubMedGoogle Scholar
  21. Filipic M, Fatur T, Vudrag M (2006) Molecular mechanisms of cadmium induced mutagenicity. Hum Exp Toxicol 25:67–77CrossRefPubMedGoogle Scholar
  22. Genestra M (2007) Oxyl radicals, redox-sensitive signalling cascades and antioxidants. Cell Signal 19:1807–1819CrossRefPubMedGoogle Scholar
  23. Giaginis C, Gatzidou E, Theocharis S (2006) DNA repair systems as targets of cadmium toxicity. Toxicol Appl Pharmacol 213:282–290CrossRefPubMedGoogle Scholar
  24. Goyer RA, Liu J, Waalkes MP (2004) Cadmium and cancer of prostate and testis. Biometals 17:555–558CrossRefPubMedGoogle Scholar
  25. Hainaut P, Hollstein M (2000) p53 and human cancer: the first ten thousand mutations. Adv Cancer Res 77:81–137CrossRefPubMedGoogle Scholar
  26. Hakem R (2008) DNA-damage repair; the good, the bad, and the ugly. EMBO J 27:589–605CrossRefPubMedGoogle Scholar
  27. Hart BA, Potts RJ, Watkin RD (2001) Cadmium adaptation in the lung—a double-edged sword? Toxicology 160:65–70CrossRefPubMedGoogle Scholar
  28. Hartmann M, Hartwig A (1998) Disturbance of DNA damage recognition after UV-irradiation by nickel(II) and cadmium(II) in mammalian cells. Carcinogenesis 19:617–621CrossRefPubMedGoogle Scholar
  29. Hartwig A (1994) Role of DNA repair inhibition in lead- and cadmium-induced genotoxicity: a review. Environ Health Perspect 102 Suppl 3:45–50CrossRefPubMedGoogle Scholar
  30. Hartwig A (2001) Zinc finger proteins as potential targets for toxic metal ions: differential effects on structure and function. Antioxid Redox Signal 3:625–634CrossRefPubMedGoogle Scholar
  31. Hartwig A, Asmuss M, Blessing H et al (2002) Interference by toxic metal ions with zinc-dependent proteins involved in maintaining genomic stability. Food Chem Toxicol 40:1179–1184CrossRefPubMedGoogle Scholar
  32. Heinrich U (1992) Pulmonary carcinogenicity of cadmium by inhalation in animals. IARC Scientific Publications, Lyon, pp 405–413Google Scholar
  33. Hsieh P, Yamane K (2008) DNA mismatch repair: molecular mechanism, cancer, and ageing. Mech Ageing Dev 129:391–407CrossRefPubMedGoogle Scholar
  34. IARC (1993) Beryllium, cadmium, mercury, and exposures in the glass manufacturing industry. IARC monographs on the evaluation of carcinogenic risks to humans. IARC, LyonGoogle Scholar
  35. IARC (1997) Supplement: cadmium and cadmium compounds. IARC monographs on the evaluation of carcinogenic risks to humans. IARC, LyonGoogle Scholar
  36. Jin YH, Clark AB, Slebos RJ et al (2003) Cadmium is a mutagen that acts by inhibiting mismatch repair. Nat Genet 34:326–329CrossRefPubMedGoogle Scholar
  37. Joseph P (2009) Mechanisms of cadmium carcinogenesis. Toxicol Appl Pharmacol 238:272–279CrossRefPubMedGoogle Scholar
  38. Kerzendorfer C, O’Driscoll M (2009) Human DNA damage response and repair deficiency syndromes: linking genomic instability and cell cycle checkpoint proficiency. DNA Repair (Amst) 8:1139–1152CrossRefGoogle Scholar
  39. Klaassen CD, Liu J, Diwan BA (2009) Metallothionein protection of cadmium toxicity. Toxicol Appl Pharmacol 238:215–220CrossRefPubMedGoogle Scholar
  40. Kopera E, Schwerdtle T, Hartwig A et al (2004) Co(II) and Cd(II) substitute for Zn(II) in the zinc finger derived from the DNA repair protein XPA, demonstrating a variety of potential mechanisms of toxicity. Chem Res Toxicol 17:1452–1458CrossRefPubMedGoogle Scholar
  41. Kothinti RK, Blodgett AB, Petering DH et al (2010) Cadmium down-regulation of kidney Sp1 binding to mouse SGLT1 and SGLT2 gene promoters: possible reaction of cadmium with the zinc finger domain of Sp1. Toxicol Appl Pharmacol 244:254–262CrossRefPubMedGoogle Scholar
  42. Liu J, Qu W, Kadiiska MB (2009) Role of oxidative stress in cadmium toxicity and carcinogenesis. Toxicol Appl Pharmacol 238:209–214CrossRefPubMedGoogle Scholar
  43. Lutzen A, Liberti SE, Rasmussen LJ (2004) Cadmium inhibits human DNA mismatch repair in vivo. Biochem Biophys Res Commun 321:21–25CrossRefPubMedGoogle Scholar
  44. Mackay JP, Crossley M (1998) Zinc fingers are sticking together. Trends Biochem Sci 23:1–4CrossRefPubMedGoogle Scholar
  45. Martelli A, Rousselet E, Dycke C et al (2006) Cadmium toxicity in animal cells by interference with essential metals. Biochimie 88:1807–1814CrossRefPubMedGoogle Scholar
  46. McElroy JA, Shafer MM, Trentham-Dietz A et al (2006) Cadmium exposure and breast cancer risk. J Natl Cancer Inst 98:869–873CrossRefPubMedGoogle Scholar
  47. Meplan C, Mann K, Hainaut P (1999) Cadmium induces conformational modifications of wild-type p53 and suppresses p53 response to DNA damage in cultured cells. J Biol Chem 274:31663–31670CrossRefPubMedGoogle Scholar
  48. Mukherjee JJ, Gupta SK, Kumar S et al (2004) Effects of cadmium(II) on (+/−)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide-induced DNA damage response in human fibroblasts and DNA repair: a possible mechanism of cadmium’s cogenotoxicity. Chem Res Toxicol 17:287–293CrossRefPubMedGoogle Scholar
  49. O’Brien V, Brown R (2006) Signalling cell cycle arrest and cell death through the MMR System. Carcinogenesis 27:682–692CrossRefPubMedGoogle Scholar
  50. Ochi T, Ohsawa M (1985) Participation of active oxygen species in the induction of chromosomal aberrations by cadmium chloride in cultured Chinese hamster cells. Mutat Res 143:137–142PubMedGoogle Scholar
  51. Petrucco S (2003) Sensing DNA damage by PARP-like fingers. Nucleic Acids Res 31:6689–6699CrossRefPubMedGoogle Scholar
  52. Potts RJ, Watkin RD, Hart BA (2003) Cadmium exposure down-regulates 8-oxoguanine DNA glycosylase expression in rat lung and alveolar epithelial cells. Toxicology 184:189–202CrossRefPubMedGoogle Scholar
  53. Prozialeck WC, Lamar PC (1999) Interaction of cadmium (Cd(2+)) with a 13-residue polypeptide analog of a putative calcium-binding motif of E-cadherin. Biochim Biophys Acta 1451:93–100CrossRefPubMedGoogle Scholar
  54. Prozialeck WC, Lamar PC, Lynch SM (2003) Cadmium alters the localization of N-cadherin, E-cadherin, and beta-catenin in the proximal tubule epithelium. Toxicol Appl Pharmacol 189:180–195CrossRefPubMedGoogle Scholar
  55. Qu W, Ke H, Pi J et al (2007) Acquisition of apoptotic resistance in cadmium-transformed human prostate epithelial cells: Bcl-2 overexpression blocks the activation of JNK signal transduction pathway. Environ Health Perspect 115:1094–1100CrossRefPubMedGoogle Scholar
  56. Schwerdtle T, Ebert F, Thuy C et al (2010) Genotoxicity of soluble and particulate cadmium compounds: impact on oxidative DNA damage and nucleotide excision repair. Chem Res Toxicol 23:432–442CrossRefPubMedGoogle Scholar
  57. Shrivastav M, De Haro LP, Nickoloff JA (2008) Regulation of DNA double-strand break repair pathway choice. Cell Res 18:134–147CrossRefPubMedGoogle Scholar
  58. Silva E, Lopez-Espinosa MJ, Molina-Molina JM et al (2006) Lack of activity of cadmium in in vitro estrogenicity assays. Toxicol Appl Pharmacol 216:20–28CrossRefPubMedGoogle Scholar
  59. Snyder RD, Davis GF, Lachmann PJ (1989) Inhibition by metals of X-ray and ultraviolet-induced DNA repair in human cells. Biol Trace Elem Res 21:389–398CrossRefPubMedGoogle Scholar
  60. Stohs SJ, Bagchi D, Hassoun E et al (2001) Oxidative mechanisms in the toxicity of chromium and cadmium ions. J Environ Pathol Toxicol Oncol 20:77–88PubMedGoogle Scholar
  61. Stoica A, Katzenellenbogen BS, Martin MB (2000) Activation of estrogen receptor-alpha by the heavy metal cadmium. Mol Endocrinol 14:545–553CrossRefPubMedGoogle Scholar
  62. Straif K, Benbrahim-Tallaa L, Baan R et al (2009) A review of human carcinogens—part C: metals, arsenic, dusts, and fibres. Lancet Oncol 10:453–454CrossRefPubMedGoogle Scholar
  63. Takiguchi M, Achanzar WE, Qu W et al (2003) Effects of cadmium on DNA-(cytosine-5) methyltransferase activity and DNA methylation status during cadmium-induced cellular transformation. Exp Cell Res 286:355–365CrossRefPubMedGoogle Scholar
  64. Tapisso JT, Marques CC, Mathias Mda L et al (2009) Induction of micronuclei and sister chromatid exchange in bone-marrow cells and abnormalities in sperm of Algerian mice (Mus spretus) exposed to cadmium, lead and zinc. Mutat Res 678:59–64PubMedGoogle Scholar
  65. Thevenod F (2010) Catch me if you can! Novel aspects of cadmium transport in mammalian cells. Biometals. doi: 10.1007/s10534-010-9309-1
  66. Valko M, Rhodes CJ, Moncol J et al (2006) Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact 160:1–40CrossRefPubMedGoogle Scholar
  67. Valverde M, Trejo C, Rojas E (2001) Is the capacity of lead acetate and cadmium chloride to induce genotoxic damage due to direct DNA-metal interaction? Mutagenesis 16:265–270CrossRefPubMedGoogle Scholar
  68. Waalkes MP (2003) Cadmium carcinogenesis. Mutat Res 533:107–120PubMedGoogle Scholar
  69. Waisberg M, Joseph P, Hale B et al (2003) Molecular and cellular mechanisms of cadmium carcinogenesis. Toxicology 192:95–117CrossRefPubMedGoogle Scholar
  70. Wieland M, Levin MK, Hingorani KS et al (2009) Mechanism of cadmium-mediated inhibition of Msh2-Msh6 function in DNA mismatch repair. Biochemistry 48:9492–9502CrossRefPubMedGoogle Scholar
  71. Witkiewicz-Kucharczyk A, Bal W (2006) Damage of zinc fingers in DNA repair proteins, a novel molecular mechanism in carcinogenesis. Toxicol Lett 162:29–42CrossRefPubMedGoogle Scholar
  72. Youn CK, Kim SH, Lee DY et al (2005) Cadmium down-regulates human OGG1 through suppression of Sp1 activity. J Biol Chem 280:25185–25195CrossRefPubMedGoogle Scholar
  73. Zharkov DO, Rosenquist TA (2002) Inactivation of mammalian 8-oxoguanine-DNA glycosylase by cadmium(II): implications for cadmium genotoxicity. DNA Repair (Amst) 1:661–670CrossRefGoogle Scholar
  74. Zhou T, Jia X, Chapin RE et al (2004) Cadmium at a non-toxic dose alters gene expression in mouse testes. Toxicol Lett 154:191–200CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  1. 1.Institut für Lebensmitteltechnologie und Lebensmittelchemie, Fachgebiet Lebensmittelchemie und ToxikologieTechnische Universität BerlinBerlinGermany

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