Longitudinal analysis of DNA methylation in relation to gestational perfluoroalkyl substance exposure: An epigenome-wide association study

Abstract

BACKGROUND AND AIM: Alterations to DNA methylation may underlie the association between gestational exposure to perfluoroalkyl substances (PFAS) and adverse health outcomes in children. However, few studies have examined the association between gestational PFAS exposure and DNA methylation, and no studies have repeated DNA methylation data across childhood. We examined associations between gestational PFAS exposure and repeated measures of offspring peripheral leukocyte DNA methylation among 266 mother-child pairs enrolled in the HOME Study (Cincinnati, OH). METHODS: We quantified serum concentrations of perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoate (PFNA), and perfluorohexane sulfonate (PFHxS) in mothers at ~16 weeks gestation. We measured DNA methylation at delivery (cord blood) and age 12 years using the Illumina HumanMethylation EPIC BeadChip. We analyzed the associations between log2-transformed PFAS concentrations and repeated DNA methylation measures using generalized estimating equations. Visit by PFAS interaction terms were used to test the stability of these differences across time. We performed Gene Ontology (GO) enrichment analysis to identify significant biological pathways. RESULTS:A total of 35 loci were significantly associated with PFAS (false discovery rate, q 0.05). Among the 5 loci for PFOS, 10 for PFOA, 7 for PFHxS, and 13 for PFNA (q 0.01), none overlapped. These loci mapped to genes (e.g., AGAP1, HPSE2, HABP2, RNF13, RADIL, and TMEM56) that are associated with cancers, cardiovascular disease, and cognitive function. We found little evidence that associations between PFAS and DNA methylation changed over time. The most significant GO pathways included homophilic cell adhesion, cell-cell adhesion and integral component of plasma membrane. CONCLUSIONS:Using longitudinal data, we identified loci associated with PFAS that have not been reported. Several loci were in genes linked to PFAS-associated health outcomes. Future studies are needed to confirm our findings and examine whether DNA methylation mediates associations between gestational PFAS exposure and offspring health. KEYWORDS: PFAS, Epigenomics, Biomarkers of exposure, Environmental epidemiology