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ARSENIC AND THE EPIGENOME: LINKED BY METHYLATION(Thailand)
Citation:
Bailey, K. A., L. Smeester, W. O. WARD, J. E. Rager, X. Guan, N. Smith, G. Garcia-Vargas, L. Del Razo, Z. Drobna, H. Kelkar, M. Styblo, AND R. Fry. ARSENIC AND THE EPIGENOME: LINKED BY METHYLATION(Thailand). Presented at 7th Princess Chulabhorn International Science Conference: Cancer: From Basic Research to Cure, Bancock, THAILAND, November 13 - 17, 2011.
Impact/Purpose:
Inorganic arsenic (iAs) is an environmental toxicant currently poisoning millions of people worldwide. The most common route of As exposure in humans is through the consumption of drinking water contaminated with iAs from natural, geologic sources
Description:
Inorganic arsenic (iAs) is an environmental toxicant currently poisoning millions of people worldwide. The most common route of As exposure in humans is through the consumption of drinking water contaminated with iAs from natural, geologic sources. Inorganic As exists in drinking water as a mixture of two oxidation states, namely trivalent arsenite (iAsIII) and pentavalent arsenate (iAsV), which predominate inanaerobic and aerobic conditions, respectively. Chronic arsenic poisoning is known as a series of clinical manifestations known as arsenicosis. The first signs of arsenicosis are often first observed in the skin, in which hyperkeratotic lesions and areas of hypo-and hyperpigmentation are often present. Individuals suffering from arsenicosis also have an increased risk of developing diseases such as diabetes mellitus, cardiovascular disease and cancers of the skin, lung, prostate, kidney and urinary bladder. In some exposed populations arsenicosis susceptibility is dependent in part on the capacity of individuals to biotransform iAsIII+V to a series of monomethylated and dimethylated forms (MMAs and DMAs, respectively). Each of these forms can exist as a mixture of trivalent and pentavalent oxidation states. Therefore, a total of six major forms of arsenic exist in the urine of chronically exposed humans: 10-30% total As content existing as trivalent and pentavalent iAs (iAsIII+V); 10-30% as trivalent monomethylated species, i.e. monomethylarsonous acid (MMAIII) and monomethylarsonic acid (MMAV), and 60-800/0 as trivalent/pentavalent dimethylated species, namely dimethylarsinous acid (DMAIII) and dimethylarsinic acid (DMAV). Importantly, these different forms of arsenic can differ considerably in their toxicities. In particular, the trivalent methylated forms of arsenic MMAIII and DMAIII are often the most toxic forms in human and animal cells in a variety of in vitro and in vivo systems and are considered to be potentially carcinogenic metabolites. In many exposed populations an increased risk of several arsenic-associated diseases (including skin and urinary bladder cancers) is observed in individuals with high ratios of MMAIII+V to DMAIII+V in their urine. These results suggest that iAs biotranformation capacity may determine the susceptibility of individuals to the toxic effects of arsenic. Considering iAs biotransformation and DNA methylation enzymes use the same methyl donor, s-adenosyl methionine (SAM), it is reasonable to speculate that iAs exposure may impact DNA methylation patterns. Alterations in DNA methylation status are believed to play a major role in the etiology ofmany environmentally-associated diseases, particularly those associated with metal/metalloid exposure. Therefore, we and others have sought to examine the relationship between iAs exposure, iAs biotransformation and DNA methylation status. In this study we set out to examine the DNA methylation patterns of 16 individuals from an arsenicosis endemic region in Zimapan, Hildago, Mexico. Eight of these individuals exhibited no clinical signs of chronic arsenic exposure; whereas, eight had characteristic skin lesions of arsenicosis. Using a state-of-the-art technique to map the methylome of peripheral blood lymphocytes (PBLs) isolated from these individuals, we identified 183 gene promoters that were differentially methylated between the two groups. All but one of these 183 genes was hypermethylated in the arsenicosis subjects. These 183 genes were enriched for functions related to arsenic-associated diseases such as cancer, heart disease, and diabetes. Notably, we have uncovered an arsenic-induced tumor suppressorome within these 183 genes that consists of 17 known/putative tumor suppressors previously demonstrated to be silenced in human cancers (Figure 1).