Parental arsenic exposure and tissue-specific DNA methylation in Bangladeshi infants with spina bifida

Abstract

An emerging hypothesis linking arsenic toxicity involves altered epigenetic mechanisms, such as DNA methylation. In this study, we examined the relationship between parents' arsenic exposure and DNA methylation in tissues obtained from 28 infants with spina bifida from Bangladesh. We analyzed arsenic in parents' toenails using inductively coupled plasma mass spectrometry (ICP-MS). DNA methylation was measured in infants' dural tissue, buccal swabs, and whole blood using the Illumina Infinium MethylationEPIC BeadChip. We performed epigenome-wide association analyses (EWAS) and tested differentially methylated regions (DMRs). In EWAS, DNA methylation at cg24039697 in dural tissue was positively associated (β = 0.59, p = 7.6 × 10^-9) with father's toenail arsenic concentrations, adjusting for covariates. We did not identify any CpG sites related to father's arsenic exposure in the other tissues, or any CpG sites related to mother's arsenic exposure. Gene ontology analysis identified many biological pathways of interest, including the Wnt signaling pathways. We identified several DMRs across the tissues related to arsenic exposure that included probes mapping to genes that have previously been identified in studies of neural tube defects. This study emphasizes the potential impact of arsenic exposure in fathers, often understudied in epidemiological studies, on DNA methylation in a unique neurological tissue specific to spina bifida.

Keywords: Arsenic; Bangladesh; environmental epidemiology; epigenetics; folate; neural tube defects.

Figure 1.

Manhattan plot of the epigenome-wide association between log₂transformed father’s toenail arsenic concentrations (μg/g) and DNA methylation levels (M-values) in dural tissue samples from infants with spina bifida, adjusting for infant age at collection (days), infant sex, maternal serum folate levels (ng/mL), and surrogate variables. The red horizontal line represents the Bonferroni threshold.

Figure 2.

Volcano plot of the epigenome-wide association between log₂transformed father’s toenail arsenic concentrations (μg/g) and DNA methylation levels (M-values) in dural tissue samples from infants with spina bifida, adjusting for infant age at collection (days), infant sex, maternal serum folate levels (ng/mL), and surrogate variables. The red horizontal line represents the Bonferroni threshold.

Figure 3.

Upset plot of the genes mapping to the differentially methylated regions (DMRs) of the epigenome-wide association between log₂transformed toenail arsenic concentrations (mother’s or father’s; μg/g) and DNA methylation levels (M-values) in dural tissue, whole blood, or buccal swab samples from infants with spina bifida, adjusting for infant age at collection (days), infant sex, mother’s serum folate levels (ng/mL), and surrogate variables.