Skip to main content
SpringerLink
Log in

Mechanisms in cadmium-induced carcinogenicity: recent insights

  • Published:
BioMetals Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Achanzar WE, Webber MM, Waalkes MP (2002) Altered apoptotic gene expression and acquired apoptotic resistance in cadmium-transformed human prostate epithelial cells. Prostate 52:236–244

    Article  PubMed  Google Scholar 

  • 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 68:6435–6441

    Article  PubMed  Google Scholar 

  • 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 21:2097–2104

    Article  PubMed  Google Scholar 

  • 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 117:1847–1852

    Article  PubMed  Google Scholar 

  • Beneke S, Bürkle A (2007) Poly(ADP-ribosyl)ation in mammalian ageing. Nucleic Acids Res 35:7456–7465

    Article  PubMed  Google Scholar 

  • Beyersmann D, Hartwig A (2008) Carcinogenic metal compounds: recent insight into molecular and cellular mechanisms. Arch Toxicol 82:493–512

    Article  PubMed  Google Scholar 

  • 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 26:3194–3201

    Article  PubMed  Google Scholar 

  • 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 20:1621–1624

    Article  PubMed  Google Scholar 

  • 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 21:1051–1057

    Article  PubMed  Google Scholar 

  • Byrne C, Divekar SD, Storchan GB et al (2009) Cadmium—a metallohormone? Toxicol Appl Pharmacol 238:266–271

    Article  PubMed  Google Scholar 

  • Camenisch U, Naegeli H (2009) Role of DNA repair in the protection against genotoxic stress. EXS 99:111–150

    PubMed  Google Scholar 

  • Christmann M, Tomicic MT, Roos WP et al (2003) Mechanisms of human DNA repair: an update. Toxicology 193:3–34

    Article  PubMed  Google Scholar 

  • 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 42:2757–2763

    PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • de Boer J, Hoeijmakers JH (2000) Nucleotide excision repair and human syndromes. Carcinogenesis 21:453–460

    Article  PubMed  Google Scholar 

  • 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, Weinheim

  • 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 980:1–139

    Google Scholar 

  • 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 42:2729–2735

    PubMed  Google Scholar 

  • 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 529:109–116

    PubMed  Google Scholar 

  • Filipic M, Hei TK (2004) Mutagenicity of cadmium in mammalian cells: implication of oxidative DNA damage. Mutat Res 546:81–91

    PubMed  Google Scholar 

  • Filipic M, Fatur T, Vudrag M (2006) Molecular mechanisms of cadmium induced mutagenicity. Hum Exp Toxicol 25:67–77

    Article  PubMed  Google Scholar 

  • Genestra M (2007) Oxyl radicals, redox-sensitive signalling cascades and antioxidants. Cell Signal 19:1807–1819

    Article  PubMed  Google Scholar 

  • Giaginis C, Gatzidou E, Theocharis S (2006) DNA repair systems as targets of cadmium toxicity. Toxicol Appl Pharmacol 213:282–290

    Article  PubMed  Google Scholar 

  • Goyer RA, Liu J, Waalkes MP (2004) Cadmium and cancer of prostate and testis. Biometals 17:555–558

    Article  PubMed  Google Scholar 

  • Hainaut P, Hollstein M (2000) p53 and human cancer: the first ten thousand mutations. Adv Cancer Res 77:81–137

    Article  PubMed  Google Scholar 

  • Hakem R (2008) DNA-damage repair; the good, the bad, and the ugly. EMBO J 27:589–605

    Article  PubMed  Google Scholar 

  • Hart BA, Potts RJ, Watkin RD (2001) Cadmium adaptation in the lung—a double-edged sword? Toxicology 160:65–70

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Hartwig A (1994) Role of DNA repair inhibition in lead- and cadmium-induced genotoxicity: a review. Environ Health Perspect 102 Suppl 3:45–50

    Article  PubMed  Google Scholar 

  • Hartwig A (2001) Zinc finger proteins as potential targets for toxic metal ions: differential effects on structure and function. Antioxid Redox Signal 3:625–634

    Article  PubMed  Google Scholar 

  • 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 40:1179–1184

    Article  PubMed  Google Scholar 

  • Heinrich U (1992) Pulmonary carcinogenicity of cadmium by inhalation in animals. IARC Scientific Publications, Lyon, pp 405–413

    Google Scholar 

  • Hsieh P, Yamane K (2008) DNA mismatch repair: molecular mechanism, cancer, and ageing. Mech Ageing Dev 129:391–407

    Article  PubMed  Google Scholar 

  • IARC (1993) Beryllium, cadmium, mercury, and exposures in the glass manufacturing industry. IARC monographs on the evaluation of carcinogenic risks to humans. IARC, Lyon

    Google Scholar 

  • IARC (1997) Supplement: cadmium and cadmium compounds. IARC monographs on the evaluation of carcinogenic risks to humans. IARC, Lyon

    Google Scholar 

  • Jin YH, Clark AB, Slebos RJ et al (2003) Cadmium is a mutagen that acts by inhibiting mismatch repair. Nat Genet 34:326–329

    Article  PubMed  Google Scholar 

  • Joseph P (2009) Mechanisms of cadmium carcinogenesis. Toxicol Appl Pharmacol 238:272–279

    Article  PubMed  Google Scholar 

  • 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) 8:1139–1152

    Article  Google Scholar 

  • Klaassen CD, Liu J, Diwan BA (2009) Metallothionein protection of cadmium toxicity. Toxicol Appl Pharmacol 238:215–220

    Article  PubMed  Google Scholar 

  • 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 17:1452–1458

    Article  PubMed  Google Scholar 

  • 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 244:254–262

    Article  PubMed  Google Scholar 

  • Liu J, Qu W, Kadiiska MB (2009) Role of oxidative stress in cadmium toxicity and carcinogenesis. Toxicol Appl Pharmacol 238:209–214

    Article  PubMed  Google Scholar 

  • Lutzen A, Liberti SE, Rasmussen LJ (2004) Cadmium inhibits human DNA mismatch repair in vivo. Biochem Biophys Res Commun 321:21–25

    Article  PubMed  Google Scholar 

  • Mackay JP, Crossley M (1998) Zinc fingers are sticking together. Trends Biochem Sci 23:1–4

    Article  PubMed  Google Scholar 

  • Martelli A, Rousselet E, Dycke C et al (2006) Cadmium toxicity in animal cells by interference with essential metals. Biochimie 88:1807–1814

    Article  PubMed  Google Scholar 

  • McElroy JA, Shafer MM, Trentham-Dietz A et al (2006) Cadmium exposure and breast cancer risk. J Natl Cancer Inst 98:869–873

    Article  PubMed  Google Scholar 

  • 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 274:31663–31670

    Article  PubMed  Google Scholar 

  • 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 17:287–293

    Article  PubMed  Google Scholar 

  • O’Brien V, Brown R (2006) Signalling cell cycle arrest and cell death through the MMR System. Carcinogenesis 27:682–692

    Article  PubMed  Google Scholar 

  • 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 143:137–142

    PubMed  Google Scholar 

  • Petrucco S (2003) Sensing DNA damage by PARP-like fingers. Nucleic Acids Res 31:6689–6699

    Article  PubMed  Google Scholar 

  • Potts RJ, Watkin RD, Hart BA (2003) Cadmium exposure down-regulates 8-oxoguanine DNA glycosylase expression in rat lung and alveolar epithelial cells. Toxicology 184:189–202

    Article  PubMed  Google Scholar 

  • 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 1451:93–100

    Article  PubMed  Google Scholar 

  • 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 189:180–195

    Article  PubMed  Google Scholar 

  • 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 115:1094–1100

    Article  PubMed  Google Scholar 

  • 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 23:432–442

    Article  PubMed  Google Scholar 

  • Shrivastav M, De Haro LP, Nickoloff JA (2008) Regulation of DNA double-strand break repair pathway choice. Cell Res 18:134–147

    Article  PubMed  Google Scholar 

  • Silva E, Lopez-Espinosa MJ, Molina-Molina JM et al (2006) Lack of activity of cadmium in in vitro estrogenicity assays. Toxicol Appl Pharmacol 216:20–28

    Article  PubMed  Google Scholar 

  • 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 21:389–398

    Article  PubMed  Google Scholar 

  • Stohs SJ, Bagchi D, Hassoun E et al (2001) Oxidative mechanisms in the toxicity of chromium and cadmium ions. J Environ Pathol Toxicol Oncol 20:77–88

    PubMed  Google Scholar 

  • Stoica A, Katzenellenbogen BS, Martin MB (2000) Activation of estrogen receptor-alpha by the heavy metal cadmium. Mol Endocrinol 14:545–553

    Article  PubMed  Google Scholar 

  • Straif K, Benbrahim-Tallaa L, Baan R et al (2009) A review of human carcinogens—part C: metals, arsenic, dusts, and fibres. Lancet Oncol 10:453–454

    Article  PubMed  Google Scholar 

  • 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 286:355–365

    Article  PubMed  Google Scholar 

  • 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 678:59–64

    PubMed  Google Scholar 

  • Thevenod F (2010) Catch me if you can! Novel aspects of cadmium transport in mammalian cells. Biometals. doi:10.1007/s10534-010-9309-1

  • Valko M, Rhodes CJ, Moncol J et al (2006) Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact 160:1–40

    Article  PubMed  Google Scholar 

  • 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 16:265–270

    Article  PubMed  Google Scholar 

  • Waalkes MP (2003) Cadmium carcinogenesis. Mutat Res 533:107–120

    PubMed  Google Scholar 

  • Waisberg M, Joseph P, Hale B et al (2003) Molecular and cellular mechanisms of cadmium carcinogenesis. Toxicology 192:95–117

    Article  PubMed  Google Scholar 

  • Wieland M, Levin MK, Hingorani KS et al (2009) Mechanism of cadmium-mediated inhibition of Msh2-Msh6 function in DNA mismatch repair. Biochemistry 48:9492–9502

    Article  PubMed  Google Scholar 

  • Witkiewicz-Kucharczyk A, Bal W (2006) Damage of zinc fingers in DNA repair proteins, a novel molecular mechanism in carcinogenesis. Toxicol Lett 162:29–42

    Article  PubMed  Google Scholar 

  • Youn CK, Kim SH, Lee DY et al (2005) Cadmium down-regulates human OGG1 through suppression of Sp1 activity. J Biol Chem 280:25185–25195

    Article  PubMed  Google Scholar 

  • Zharkov DO, Rosenquist TA (2002) Inactivation of mammalian 8-oxoguanine-DNA glycosylase by cadmium(II): implications for cadmium genotoxicity. DNA Repair (Amst) 1:661–670

    Article  Google Scholar 

  • Zhou T, Jia X, Chapin RE et al (2004) Cadmium at a non-toxic dose alters gene expression in mouse testes. Toxicol Lett 154:191–200

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

  1. Institut für Lebensmitteltechnologie und Lebensmittelchemie, Fachgebiet Lebensmittelchemie und Toxikologie, Technische Universität Berlin, 13355, Berlin, Germany

    Andrea Hartwig

Authors
  1. Andrea Hartwig
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andrea Hartwig.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hartwig, A. Mechanisms in cadmium-induced carcinogenicity: recent insights. Biometals 23, 951–960 (2010). https://doi.org/10.1007/s10534-010-9330-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10534-010-9330-4

Keywords

Search

Navigation