Factors Affecting Differential Methylation of DNA Promoters in Arsenic-Exposed Populations
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The exposure/biotransformation of inorganic arsenic (iAs) may perturb DNA methylation patterns and subsequently influence disease risk by altering the expression of key genes. Interindividual variation in patterns of DNA methylation can be explained by the influence of environmental, genetic, and stochastic factors. Here, we examined promoter DNA methylation levels with urinary arsenical concentrations and investigated the genetic and nongenetic determinants of DNA methylation in 105 samples collected from populations in Shanxi Province, China, with high levels of arsenic in drinking water. Arsenic concentrations in water were determined by atomic absorption spectrophotometry (AA-6800, Shimadzu Co., Kyoto, Japan). Urine samples were measured using an atomic absorption spectrophotometer with an arsenic speciation pretreatment system (ASA-2sp, Shimadzu Co. Kyoto, Japan) for detection. Gene-specific (CDH1, EREG, ERCC2, GSTP1, and MGMT) DNA methylation was quantified by targeted bisulfite sequencing. Single-nucleotide polymorphism (SNP) genotyping was performed using a custom-by-design 2 × 48-Plex SNPscan™ Kit. These results revealed CDH1 with promoter DNA methylation levels associated with iAs. After the exclusion of confounding factors, age was correlated with increased methylation of the CDH1 gene. The susceptibility of the CDH1 and GSTP1 gene promoters to methylation was increased in individuals carrying the DNMT3B (SNP rs2424932) GA genotype, and the susceptibility of the CDH1 gene promoters to methylation was increased in individuals carrying the DNMT3B (SNP rs6087990) TC genotype. Although the above results must still be replicated in larger samples, the findings improve our understanding of the pathogenesis of arsenic and may highlight certain DNA methylation markers as attractive surrogate markers for prevention research.
KeywordsArsenic DNA methylation DNMT1 DNMT3B Single-nucleotide polymorphism
The authors thank the sample donors for making this work possible.
Yanting Zhang, Lanrong Luo, and Qian He extracted and selected samples and sent them for testing. Yanhui Gao, Yuanyuan Li, Hongqi Feng, Lijun Zhao, and Wei Wei collected all samples. Songbo Fu and Dianjun Sun guided and edited the article. Yanting Zhang performed the statistical analysis and wrote the manuscript. The manuscript was critically reviewed and approved by all authors.
The National Natural Science Foundation of China (grant no. 81372936) funded this study.
Compliance with Ethical Standards
The authors declare that they have no competing interests.
- 2.Smith AH, Marshall G, Yuan Y, Ferreccio C, Liaw J, von Ehrenstein O, Steinmaus C, Bates MN, Selvin S (2006) Increased mortality from lung cancer and bronchiectasis in young adults after exposure to arsenic in utero and in early childhood. Environ Health Perspect 114:1293–1296CrossRefPubMedPubMedCentralGoogle Scholar
- 5.IARC (2004) IARC monographs on the evaluation of the carcinogenic risk to humans. Lyon: IARC 84:39–267Google Scholar
- 17.Bailey KA, Wu MC, Ward WO, Smeester L, Rager JE, García-Vargas G, del Razo LM, Drobná Z, Stýblo M, Fry RC (2013) Arsenic and the epigenome: interindividual differences in arsenic metabolism related to distinct patterns of DNA methylation. J Biochem Mol Toxicol 27:106–115CrossRefPubMedPubMedCentralGoogle Scholar
- 34.Paul S, Banerjee N, Chatterjee A, Sau TJ, Das JK, Mishra PK, Chakrabarti P, Bandyopadhyay A, Giri AK (2014) Arsenic-induced promoter hypomethylation and over-expression of ERCC2 reduces DNA repair capacity in humans by non-disjunction of the ERCC2-Cdk7 complex. Metallomics 6:864–873CrossRefPubMedGoogle Scholar
- 35.Ml G, Cp P, Sm L et al (2003) Prostate cancer detection by GSTP1 methylation analysis of postbiopsy urine specimens. Clin Cancer Res 9:2673–2677Google Scholar
- 36.Ogino S, Hazra A, Tranah GJ, Kirkner GJ, Kawasaki T, Nosho K, Ohnishi M, Suemoto Y, Meyerhardt JA, Hunter DJ, Fuchs CS (2007) MGMT germline polymorphism is associated with somatic MGMT promoter methylation and gene silencing in colorectal cancer. Carcinogenesis 28:1985–1990CrossRefPubMedGoogle Scholar
- 62.Feil R, Fraga MF (2012) Epigenetics and the environment: emerging patterns and implications. Nat Rev Genet 13:97–109Google Scholar
- 63.Fd G, Hj H, Re C et al (2002) Glutathione S-transferase P1 and NADPH quinone oxidoreductase polymorphisms are associated with aberrant promoter methylation of P16(INK4a) and O(6)-methylguanine-DNA methyltransferase in sputum. Cancer Res 62:2248–2252Google Scholar
- 66.Heyn H, Li N, Ferreira HJ, Moran S, Pisano DG, Gomez A, Diez J, Sanchez-Mut JV, Setien F, Carmona FJ, Puca AA, Sayols S, Pujana MA, Serra-Musach J, Iglesias-Platas I, Formiga F, Fernandez AF, Fraga MF, Heath SC, Valencia A, Gut IG, Wang J, Esteller M (2012) Distinct DNA methylomes of newborns and centenarians. Proc Natl Acad Sci U S A 109:10522–10527CrossRefPubMedPubMedCentralGoogle Scholar