Factors Affecting Differential Methylation of DNA Promoters in Arsenic-Exposed Populations

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.