Effects of arsenic exposure on DNA methylation and epigenetic gene regulation

John F Reichard, Alvaro Puga
2010 Epigenomics  
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 activate oncogene expression or silence tumor suppressor genes, leading to long-term changes in activity of genes controlling cell transformation. Mostly descriptive, and often contradictory, studies have
more » ... emonstrated 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 areas where consistencies and inconsistencies exist. Arsenic is an element of major health concern because substantial epidemiologic evidence links inorganic arsenic exposure to a variety of human cancers [201, 202] . Chronic low-dose dietary arsenic exposure is causally linked to cancers of the skin, bladder, liver and lung [1] [2] [3] [4] , and human exposures during gestation are associated with elevated incidence of lung and bladder cancer decades later during adulthood [4] [5] [6] . It is estimated that over 100 million people worldwide are exposed to carcinogenic levels of arsenic [201], the vast majority owing to the consumption of drinking water taken from arsenic contaminated aquifers. Populations affected by arsenic-contaminated drinking water span the globe with significant exposures identified in Bangladesh, India, Taiwan, China, Mexico, Argentina, Chile, Europe and regions of North America. The mechanism by which arsenic mediates carcinogenesis remains a subject of debate, with evidence supporting several plausible etiologies, including disruption of signaling cascades [7], elevated levels of oxidative stress [8, 9] , chromosomal aberrations [10] and epigenetic
doi:10.2217/epi.09.45 pmid:20514360 pmcid:PMC2877392 fatcat:y4xyyeqvnrew3jcwvx62awdnjm