Effects of arsenic exposure on DNA methylation and epigenetic gene regulation

Abstract

Arsenic is a nonmutagenic human carcinogen that induces tumors through unknown mechanisms. A growing body of evidence suggests that its carcinogenicity results from epigenetic changes, particularly in DNA methylation. Changes in gene methylation status, mediated by arsenic, have been proposed to activate oncogene expression or silence tumor suppressor genes, leading to long-term changes in the activity of genes controlling cell transformation. Mostly descriptive, and often contradictory, studies have demonstrated that arsenic exposure is associated with both hypo- and hyper-methylation at various genetic loci in vivo or in vitro. This ambiguity has made it difficult to assess whether the changes induced by arsenic are causally involved in the transformation process or are simply a reflection of the altered physiology of rapidly dividing cancer cells. Here, we discuss the evidence supporting changes in DNA methylation as a cause of arsenic carcinogenesis and highlight the strengths and limitations of these studies, as well as areas where consistencies and inconsistencies exist.

Keywords: DNMT; S-adenosylmethionine; SAM; arsenate; arsenic; arsenite; cancer; carcinogenesis; epigenetics; glutathione; hypermethylation; hypomethylation; oxidative stress; transsulfuration.

Figure 1. Oxidative methylation of arsenite

Arsenate (As⁺⁵) reduction is catalyzed by several mammalian enzymes of various function. Methylation of trivalent arsenic is carried out by AS3MT. Methylation of arsenic by AS3MT also results in its oxidation from trivalent to pentavalent arsenic. Following oxidative methylation, pentavalent arsenic is reduced back to trivalent arsenic by GSTO. AS3MT: Arsenic (+3 oxidation state) methyltransferase; GSTO: Glutathione S-transferase Ω.

Figure 2. Biochemistry of one-carbon metabolism and interactions with arsenic metabolism

*Nutrients obtained through dietary sources. ^‡Enzymes with mRNA expression that is induced by arsenic. §Enzymes with mRNA expression that is repressed by arsenic. AHCY: Adenosylhomocysteinase; AS3MT: Arsenic (+3 oxidation state) methyltransferase; B6: Vitamin B6; B12: Vitamin B12; BHMT: Betaine-homocysteine methyltransferase; CBS: Cystathionine-b-synthase; CHDH: Choline dehydrogenase; CTH: Cystathionase; DNMT: DNA methyltransferase; gGCL: Glutamate-cysteine ligase; GSS: Glutathione synthetase; GSTO: Glutathione S-transferase W; HCY: Homocysteine; MAT: Methionine adenosyltransferase; MTHFR: 5,10-methylene-tetrahydrofolate reductase (NADPH); MTR: 5-methyltetrahydrofolatehomocysteine methyltransferase; SAM: S-adenosylmethionine; SAH: S-adenosylhomocysteine; SHMT: Serine hydroxymethyltransferase; THF: Tetrahydrofolate.