PFAS and BPA exposures in utero and their alteration of DNA methylation at birth: the Hokkaido Study in collaboration with Taiwan cohorts

Abstract

Epigenetics is the study of heritable changes in gene expression that do not involve changes to the DNA sequence, and DNA methylation is one of the epigenetic modifications. Technologies make it possible to determine epigenome-wide DNA methylation (EWAS). Recent studies focus the environmental chemical exposures in utero and the DNA methylation levels at birth. Characterization of epigenetic changes may provide valuable insight into the mechanism by which our health is influenced by the environment and biomarkers of exposure. To minimize the influence of false positive results, application of a priori analysis in one study with validation to examine replication in another study is ideal to confirm the findings. In the Hokkaido Study on Environment and Children’s Health, Sapporo cohort, 514 pairs of pregnant women and their children were enrolled. Exposures to PFOS, PFOA, and bisphenol A (BPA) in maternal/cord blood were measured to determine in utero exposure. We assessed DNA methylation in cord blood samples and examined the associations between methylation and these exposure levels. We have collaborated with Taiwan Cohorts to conduct replication analysis. For PFOS and PFOA, we found that four differentially methylated positions (DMPs). Among the top five DMRs ranked by the lowest P-values that were associated with exposure to PFOS and PFOA, in addition to ZFP57, DMRs in the CYP2E1, SMAD3, SLC17A9, GFPT2, DUSP22, and TCERG1L genes showed the same direction of effect in the replication cohort. For BPA, we observed that a large portion of BPA-associated differentially methylated CpGs with hypomethylated among female infants (98%), and hypermethylated (88%) among males. Genes annotated to FDR-corrected CpGs clustered into an interconnected genetic network among males, whereas the female-specific genes were significantly enriched for gene ontology terms related to cell adhesion. Our epigenome-wide analysis of cord blood DNA methylation implies potential sex-specific epigenome responses to BPA exposure.