An emerging role for epigenetic dysregulation in arsenic toxicity and carcinogenesis

Abstract

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 epigenetic mechanisms may also mediate toxicity and carcinogenicity resulting from arsenic exposure.

Objective: We examined the evidence supporting the roles of the three major epigenetic mechanisms-DNA methylation, histone modification, and microRNA (miRNA) expression-in arsenic toxicity and, in particular, carcinogenicity. We also investigated future research directions necessary to clarify epigenetic and other mechanisms in humans.

Data sources and synthesis: We conducted a PubMed search of arsenic exposure and epigenetic modification through April 2010 and summarized the in vitro and in vivo research findings, from both our group and others, on arsenic-associated epigenetic 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 epigenetic end points. Systematic epigenomic 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, epigenetic dysregulation, and carcinogenesis and are becoming feasible because of recent technological advancements.

Figure 1

Simplified scheme of SAM synthesis and its involvement in arsenic and DNA methylation. The human arsenic metabolic pathway involves a series of methylation reactions; both arsenic metabolism and DNA methylation require SAM as the methyl donor. Here we show the intermediate steps of SAM synthesis and its involvement in the methylation of DNA and arsenic. Abbreviations: AS3MT, arsenic (+3 oxidation state) methyltransferase; ATP, Adenosine-5′-triphosphate; MAT1A, methionine adenosyltransferase I; MTR, 5-methyltetrahydrofolate-homocysteine methyltransferase; PPP, tripolyphosphate.

Figure 2

Histone modifications affected by As^III and MMA^III exposure. Major posttranscriptional histone modifications of the nucleosome are listed on the left. Modifications of specific histone proteins reported in the literature as altered by arsenic exposure are shown on the right.