Epigenome-wide analyses of prenatal perfluoroalkyl acids exposure on cord blood DNA methylation: the Hokkaido study

Abstract

Prenatal exposure to perfluoroalkyl acids (PFAAs) can modify fetal metabolic pathways leading to obesity in later years. One possible mechanism is through epigenetic modification in utero. However, whether prenatal PFAA exposure can influence infant DNA methylation has not been rigorously evaluated in epidemiological studies. Here, we assessed epigenome–wide cord blood DNA methylation changes in relation to prenatal PFAA exposure. Mother-child pairs (N=164) from the Hokkaido Study on Environment and Children’s Health were included in the study. Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) levels in maternal serum during pregnancy were measured by liquid chromatography-tandem mass spectrometry. Cord blood methylation was determined by Illumina HumanMethylation 450 BeadChip. Robust linear regression was applied for the associations between DNA methylation and PFAAs. We selected CpGs with either i) false–discovery rate < 0.05, or ii) partial regression coefficient ≥ 0.075 (PFOS) or ≥ 0.05 (PFOA), and then identified genes that showed coherent hypo– or hypermethylation at more than 3 CpGs on a locus. Among 368 and 616 CpGs associated, 26 CpGs on 7 genes and 43 CpGs on 11 genes were identified in relation to PFOS and PFOA exposure, respectively. We found several genes associated with energy metabolism: i.e. In association with PFOS, RPH3AL cg17193961 (β=0.09, p=0.01) and 2 other CpGs on the locus were hypermethylated, which encodes a protein playing a key role in insulin secretion; With PFOA, GALNT2 cg24250902 (β=-0.06, p= 1.3x10-6) and 3 CpGs were hypomethylated, which encodes glycosyltransferase and may influence triglyceride levels. We also found hypomethylation of a histone deacetylase gene, HDAC4 cg20784693 (β=-0.10, p= 2.9x10-3) and 3 CpGs, which involves glucose homeostasis. Our results suggest prenatal PFAA exposure can epigenetically modify genes involved in energy metabolism. Further study is required to replicate our findings.