Associations between Arsenic Exposure and Global Posttranslational Histone Modifications among Adults in Bangladesh

Abstract

Background Exposure to arsenic (As) is associated with an increased risk of several cancers, as well as, cardiovascular disease, and childhood neuro-developmental deficits. Arsenic compounds are weakly mutagenic, alter gene expression and post-translational histone modifications (PTHMs) in vitro. Methods Water and urinary As concentrations, as well as, global levels of histone 3 lysine 9 di-methylation and acetylation (H3K9me2 and H3K9ac), histone 3 lysine 27 trimethylation and acetylation (H3K27me3 and H3K27ac), histone 3 lysine 18 acetylation (H3K18ac) and histone 3 lysine 4 trimethylation (H3K4me3) were measured in peripheral blood mononuclear cells (PBMCs) from a subset of participants (N=40) of a folate clinical trial in Bangladesh (FACT study). Results Total urinary As (uAs) was positively correlated with H3K9me2 (r=0.36, p=0.02) and inversely with H3K9ac (r= -0.47, p=0.002). The associations between As and other PTHMs differed in a gender-dependent manner. Water As (wAs) was positively correlated with H3K4me3 (r=0.45, p=0.05) and H3K27me3 (r=0.50, p=0.03) among females and negatively correlated among males (H3K4me3: r= -0.44, p=0.05; H3K27me3: r= -0.34, p=0.14). Conversely, wAs was inversely associated with H3K27ac among females (r= -0.44, p=0.05) and positively associated among males (r=0.29, p=0.21). A similar pattern was observed for H3K18ac (females: r= -0.22, p=0.36; males: r=0.27, p=0.24). Conclusion Exposure to As is associated with alterations of global PTHMs; gender-specific patterns of association were observed between As exposure and several histone marks. Impact These findings contribute to the growing body of evidence linking As exposure to epigenetic dysregulation, which may play a role in the pathogenesis of As toxicity.

Epigenomic reprogramming in inorganic arsenic-mediated gene expression patterns during carcinogenesis

“…Furthermore, Chervona et al observed a variety of correlations between iAs exposure and this type of modification in peripheral blood mononuclear cells using a population-based study in Bangladesh. This study further revealed a positive correlation between urinary iAs and H3K9me2 (47,59).…”

“…Interestingly, these studies also showed that the iAs-induced changes in histone PTMs can be gender-specific. For instance, a decrease in H3K27ac and H3K18ac and increase in H3K4me3 and H3K27me3 was observed in iAs-exposed females, while the inverse trend was observed in iAs-exposed males (47).…”

“…These changes include increases in H3K9me2, H3K4me3, and H3S10, decreases in H2B ubiquitination, and either increases or decreases in H3K27me3 (47)(48)(49)(50)(51)(52). In addition, following iAs exposure in humans, blood cells exhibited an overall decrease in H3K9me3 and H3K9ac, with an increase in H3K9me2 (47,48).…”

Arsenic Induces Polyadenylation of Canonical Histone mRNA by Down-regulating Stem-Loop-binding Protein Gene Expression

“…Arsenic is a well established human carcinogen, and even today millions of people are exposed to dangerous levels of naturally occurring arsenic in drinking water throughout the world (1). Exposure to a carcinogenic metal, such as arsenic, has been associated with altered gene expression patterns both in vitro and in vivo, and it has been demonstrated that the arsenicinduced changes in gene expression may be epigenetically regulated (2)(3)(4)(5)(6)(7)(8)(9).…”

Environmental Epigenomics: Applications of Epigenetic Biomarkers to Investigate Epigenetic Alterations from Environmental Exposures

“…The miRNAs altered in response to As exposure were also involved in one-carbon metabolism (methylation) reactions. An epidemiologic study conducted in Bangladesh, reported signifi cant associations between As exposure and global post-translational histone modifi cation in peripheral blood mononuclear cell (PBMC) DNA from a subset of participants (N = 40) enrolled in a clinical trial of folate supplementation (Chervona et al 2012 ). Arsenic levels in drinking water were positively associated with several post-translational histone modifi cations that were uniquely observed in either exposed males or females.…”