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 posttranslational 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 tri-methylation 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 (PBMC) 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.

Figure 1

Median concentrations of histone marks by sex and water As category^a for (a) H3K18ac, (b) H3K27ac, (c) H3K27me3, and (d) H3K4me3^{b a} Low water As range = 50-81 μg/L, high water As range=150-500 μg/L, ^bBased on a Kruskal-Wallis test, there is a statistically significant overall difference among the four groups for H3K27Ac (p=0.049), H3K27me3 (p=0.048), and H3K4me3 (p=0.02). Using Wilcoxon rank-sum tests, we also tested for 1) differences in histone marks by high/low water As within gender and 2) differences in histone marks by gender within water As category (high/low) – p-values < 0.10 are indicated.