Academic journal article Environmental Health Perspectives

Gene-Specific Differential DNA Methylation and Chronic Arsenic Exposure in an Epigenome-Wide Association Study of Adults in Bangladesh

Academic journal article Environmental Health Perspectives

Gene-Specific Differential DNA Methylation and Chronic Arsenic Exposure in an Epigenome-Wide Association Study of Adults in Bangladesh

Article excerpt


Millions of individuals worldwide are exposed to inorganic arsenic through drinking water as well as dietary sources (Smith et al. 2000). Arsenic is a well-established human carcinogen (International Agency for Research on Cancer 2012); however, the exact mechanism by which it causes cancer has not been established (Kitchin and Conolly 2010). There is in vitro and in vivo evidence to suggest that epigenetic alterations may mediate arsenic toxicity, as recently reviewed by Reichard and Puga (2010) and Ren et al. (2011).

Several human studies have examined global DNA methylation in blood in relation to arsenic exposure using surrogate markers of global DNA methylation, such as long interspersed nucleotide element-1 (LINE-1), Alu element methylation, methyl incorporation assays, or luminometric methylation assays. The findings from those studies have largely been inconsistent and included a number of differences in exposure measures and doses across studies (Hossain et al. 2012; Intarasunanont et al. 2012; Kile et al. 2012; Lambrou et al. 2012; Majumdar et al. 2010; Pilsner et al. 2007, 2009, 2012; Tajuddin et al. 2013; Wilhelm et al. 2010). Several other studies have evaluated arsenic in relation to gene-specific DNA methylation, most frequently assessing p16 and p53 promoter methylation (Chanda et al. 2006; Chen et al. 2007; Engstrom et al. 2013; Hossain et al. 2012; Intarasunanont et al. 2012; Marsit et al. 2006; Zhang et al. 2007). However, relatively few epigenome-wide DNA methylation studies have been conducted to investigate epigenetic alterations of arsenic toxicity in humans, evaluating associations with arsenical skin lesion status (Seow et al. 2014; Smeester et al. 2011), urinary arsenic species (Bailey et al. 2013), in utero arsenic exposure (Kile et al. 2014; Koestler et al. 2013a), toenail arsenic concentration (Liu et al. 2014), or arsenic-related urothelial carcinomas (Yang et al. 2014). Smeester et al. (2011) examined epigenome-wide promoter DNA methylation in peripheral blood leukocytes among 16 arsenic-exposed females from Mexico in relation to skin lesion status, and observed 183 differentially methylated genes, of which 182 were hypermethylated. Bailey et al. (2013) evaluated the data of Smeester et al. (2011) in relation to urinary arsenic species and observed nominally significant differential promoter DNA methylation in 812 unique genes, of which the majority were hypomethylated compared with relative urinary arsenic metabolite species. Koestler et al. (2013a) evaluated in utero arsenic exposure in relation to epigenome-wide cord blood methylation in 134 U.S.-based individuals and observed evidence of enrichment of hypermethylated loci in CpG islands, as well as a suggested indication of endocrine-disrupting effects of arsenic through hypomethylation of ESR1 (estrogen receptor 1) and PPARGC1A (peroxisome proliferator-activated receptor gamma, coactivator 1 alpha).

The evidence noted above warrants further investigation of arsenic exposure on genespecific DNA methylation in a comprehensive manner, and in a larger study population to identify potential mechanisms associated with arsenic-related toxicity. We conducted an epigenome-wide association study among 400 Bangladeshi individuals with manifest arsenical skin lesions to assess whether arsenic exposure level (as measured by blood arsenic and urinary total arsenic concentrations) is associated with differential white blood cell DNA methylation.


Study population. The Bangladesh Vitamin E and Selenium Trial is a 2 x 2 factorial randomized chemoprevention trial evaluating the long-term effects of vitamin E and selenium supplementation on nonmelanoma skin cancer risk (Argos et al. 2013). Participants were residents of rural communities in central Bangladesh. Eligibility criteria included age between 25 and 65 years, permanent residence in the study area, manifest arsenical skin lesions, and no prior cancer history. …

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