An epigenome-wide study of cord blood DNA methylations in relation to prenatal perfluoroalkyl substance exposure: The Hokkaido study

Background: Prenatal exposure to perfluoroalkyl substances (PFASs) influences fetal development and later in life. Objective: To investigate cord blood DNA methylation changes associated with prenatal exposure to PFASs. Methods: We assessed DNA methylation in cord blood samples from 190 mother-child pairs from the Sapporo cohort of the Hokkaido Study (discovery cohort) and from 37 mother-child pairs from the Taiwan Maternal and Infant Cohort Study (replication cohort) using the Illumina HumanMethylation 450 BeadChip. We examined the associations between methylation and PFAS levels in maternal serum using robust linear regression models and identified differentially methylated positions (DMPs) and regions (DMRs). Results: We found four DMPs with a false discovery rate below 0.05 in the discovery cohort. Among the top 20 DMPs ranked by the lowest P-values for perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) exposure, four DMPs showed the same direction of effect and P-value < 0.05 in the replication assay: cg16242615 mapped to ZBTB7A, cg21876869 located in the intergenic region (IGR) of USP2-AS1, cg00173435 mapped to TCP11L2, and cg18901140 located in IGR of NTN1. For DMRs, we found a region associated with PFOA exposure with family-wise error rate < 0.1 located in ZFP57, showing the same direction of effect in the replication cohort. 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. Conclusion: We suggest that prenatal exposure to PFASs may affect DNA methylation status at birth. Longitudinal studies are needed to examine whether methylation changes observed are associated with differential health outcomes.