An emerging role for epigenetic dysregulation in arsenic toxicity and carcinogenesis

Background: Exposure to arsenic, an established human carcinogen, through consumption of highly contaminated drinking water is a worldwide public health concern. Several mechanisms by which arsenical compounds induce tumorigenesis have been proposed, including oxidative stress, genotoxic damage, and chromosomal abnormalities. Recent studies have suggested that epi genetic mechanisms may also mediate toxicity and carcinogenicity resulting from arsenic exposure. objective: We examined the evidence supporting the roles of the three major epi genetic mecha-nisms-DNA methylation, histone modifcation, and microRNA (miRNA) expression-in arsenic toxicity and, in particular, carcinogenicity. We also investigated future research directions necessary to clarify epi genetic and other mechanisms in humans. data sources and synthesis: We conducted a PubMed search of arsenic exposure and epi genetic modifcation through April 2010 and summarized the in vitro and in vivo research fndings, from both our group and others, on arsenic-associated epi genetic alteration and its potential role in toxicity and carcinogenicity. Conclusions: Arsenic exposure has been shown to alter methylation levels of both global DNA and gene promoters; histone acetylation, methylation, and phosphorylation; and miRNA expression, in studies analyzing mainly a limited number of epi genetic end points. Systematic epi genomic studies in human populations exposed to arsenic or in patients with arsenic-associated cancer have not yet been performed. Such studies would help to elucidate the relationship between arsenic exposure, epi-genetic dysregulation, and carcinogenesis and are becoming feasible because of recent technological advancements.