Epigenome-Wide Assessment of DNA Methylation in the Placenta and Arsenic Exposure in the New Hampshire Birth Cohort Study (USA)

Abstract

Background: Arsenic is one of the most commonly encountered environmental toxicants, and research from model systems has suggested that one mode of its toxic activity may be through alterations in DNA methylation. In utero exposure to arsenic can affect fetal, newborn, and infant health, resulting in a range of phenotypic outcomes.

Objectives: This study examined variation in placental DNA methylation and its relationship to arsenic exposure in 343 individuals enrolled in the New Hampshire Birth Cohort Study.

Methods: Linear regression models using a reference-free correction to account for cellular composition were employed to determine CpG loci affected by arsenic levels.

Results: Total arsenic measured in maternal urine during the second trimester was not associated with methylation in the placenta, whereas arsenic levels quantified through maternal toenail collected at birth were associated with methylation at a single CpG locus (p = 4.1 × 10-8). Placenta arsenic levels were associated with 163 differentially methylated loci (false discovery rate < 0.05), with 11 probes within the LYRM2 gene reaching genome-wide significance (p < 10-8). Measurement of LYRM2 mRNA levels indicated that methylation was weakly to moderately correlated with expression (r = 0.15, p < 0.06). In addition, we identified pathways suggesting changes in placental cell subpopulation proportions associated with arsenic exposure.

Conclusions: These data demonstrate the potential for arsenic, even at levels commonly experienced in a U.S. population, to have effects on the DNA methylation status of specific genes in the placenta and thus supports a potentially novel mechanism for arsenic to affect long-term children's health.

Citation: Green BB, Karagas MR, Punshon T, Jackson BP, Robbins DJ, Houseman EA, Marsit CJ. 2016. Epigenome-wide assessment of DNA methylation in the placenta and arsenic exposure in the New Hampshire Birth Cohort Study (USA). Environ Health Perspect 124:1253-1260; http://dx.doi.org/10.1289/ehp.1510437.

Figure 1

Manhattan plots of epigenome-wide association results for arsenic concentrations within the placenta (A), maternal toenail (B), and maternal urine (C). The horizontal green dashed line represents unadjusted significance threshold (p < 0.05), and the blue dashed line represents Bonferroni-adjusted significance threshold (p = 1.0 × 10^–7).

Figure 2

Volcano plots of the associations between placenta DNA methylation at 344,348 loci and placental (A), toenail (B), and total urinary (C) arsenic levels following adjustment for sample cellular composition. The threshold for p < 0.05 is indicated by a dashed red line, and the threshold for Bonferroni significance (p = 1.0 × 10^–7) is indicated by a dashed blue line.

Figure 3

(A) Genomic tracks from the UCSC Genome Browser (University of California Santa Cruz 2015) for the region containing the 11 LYRM2 loci identified as significantly associated with placental arsenic levels. (B) Correlelogram of Pearson correlation test of methylation at these 11 CpG loci, with corresponding heatmap indicating the value of r between –1 and 1.

Figure 4

Scatter plot of the average methylation across the 11 significant LYRM2 sites and relative expression of LYRM2 mRNA for 93 individuals with the associated Pearson correlation. Individuals were selected from those within the highest and lowest tertiles of average LYRM2 methylation.