DNA methylation in cord blood as mediator of the association between prenatal arsenic exposure and gestational age

Prenatal arsenic exposure is associated with adverse birth outcomes and disease risk later in life, which could be mediated through epigenetic dysregulation. We evaluated the association between arsenic and gestational age (GA) that was mediated through DNA methylation (DNAm) using data from a Bangladeshi birth cohort. Arsenic exposure was measured in maternal drinking water at 16weeks GA and maternal toenails collected 1month postpartum. Cord blood DNAm was measured using Infinium HumanMethylation450 arrays (n=44, discovery phase). Top loci identified in the discovery phase were then pyrosequenced in a second group (n=569, validation phase). Structural equation models (SEM) evaluated the direct and indirect effects of arsenic and DNAm on GA. In the discovery phase, arsenic was associated with differential DNAm of 139 loci that were associated with GA (P<1.10X10(-6); vertical bar beta regression vertical bar>0.10). Each doubling in water arsenic concentration decreased GA by 2days, which was fully mediated through the main principal component of the top-ten CpGs (P<0.001). In the validation phase, there were direct and indirect effects of miR214-3 and MCC DNAm on GA. In an adjusted SEM model, mediation of the association between arsenic and GA by miR124-3 was borderline significant (P=0.061). This study therefore identified DNAm at specific loci in cord blood that mediated the effect of arsenic exposure on GA. Specifically, prenatal arsenic exposure was associated with lower methylation of miR124-3 that mediated the exposure-response of arsenic on GA. Future research should evaluate if these epigenetic changes are persistent and associated with disease risk.