Alterations in DNA Methylation Resulting from Exposure to Chemical Carcinogens

Abstract

Continuous exposure to natural and man‐made chemicals is a major cause of noncommunicable human diseases, including cancer. Accumulated data indicate that an exposure to chemical carcinogens induces a range of genetic and epigenetic events, including alterations in the deoxyribonucleic acid (DNA) methylation pattern, which may be associated with cancer development and progression. Accumulated evidence indicates that the response of the DNA methylome to chemical carcinogens, especially lifestyle and food carcinogens, is critical in the carcinogenic process. The better understanding of mechanisms and processes associated with carcinogen‐induced DNA methylation abnormalities may be helpful for carcinogen hazard identification, carcinogen risk assessment and management, and the prevention of cancer.

Key Concepts:

  • Exposure to natural and man‐made chemicals is a major cause of human cancer.

  • Chemical carcinogens induce a range of genetic and epigenetic events, including alterations in the DNA methylation pattern.

  • Alteration of the DNA methylation status is one of the underlying mechanisms of the carcinogenicity of a number of established environmental and occupational carcinogenic agents.

  • Carcinogen‐induced DNA methylation changes consist of DNA and repetitive element demethylation, gene‐specific hypermethylation and gene silencing, gene‐specific hypomethylation and activation of gene transcription and altered expression or activity of DNA methyltransferases.

  • Epigenetic alterations may be used as biomarkers in the evaluation of the carcinogenic potential of chemicals.

  • The incorporation of epigenetic technologies in cancer risk assessment promises to enhance substantially the efficiency of carcinogenicity testing.

Keywords: chemical carcinogens; tobacco smoking; food carcinogens; DNA methylation; cancer development

Figure 1.

Alterations of the DNA methylome induced by chemical carcinogens. Exposure to chemical carcinogens induces genotoxic – for example, carcinogen‐DNA‐adduct formation at methylated CpG sites – and nongenotoxic – for example, inflammation, oxidative stress, metabolic alterations and increased cell proliferation – effects in the DNA methylome. The carcinogen‐induced DNA methylation changes consist of global loss of DNA methylation, gene‐specific hypermethylation and gene‐specific hypomethylation. These DNA methylation alterations compromise the expression of genetic information and the genome stability. Specifically, global DNA and repetitive elements demethylation lead to elevated mutation rates and genome instability. Gene‐specific DNA hypermethylation of critical tumour suppressor genes causes the loss of gene function and may also elevate mutation rates. In contrast, gene‐specific DNA hypomethylation induces activation of oncogenes and tumour‐promoting genes.

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Further Reading

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Wild CP, Scalbert A and Herceg Z (2013) Measuring the exposome: a powerful basis for evaluating environmental exposures and cancer risk. Environmental and Molecular Mutagenesis 54(7): 480–499.

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Pogribny, Igor P, Kobets, Tetyana, and Beland, Frederick A(Mar 2014) Alterations in DNA Methylation Resulting from Exposure to Chemical Carcinogens. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025456]