Maternal plasma concentrations of persistent organic pollutants and placental DNA methylation

Abstract

Background/Aim: Prenatal maternal plasma persistent organic pollutants (POPs) concentrations have been associated with neonatal outcomes; however, the underlying mechanisms remain unknown. Placental epigenetics may be involved but no prior epigenome-wide studies have investigated such mechanisms. We studied the association between POPs in early pregnancy and epigenome-wide placental DNA methylation among 262 pregnant women from the NICHD Fetal Growth Studies. Methods: Epigenome-wide analyses using robust adjusted linear regression models were performed for each POP with more than 80% plasma concentration above the limit of quantification; including 3 organochlorine pesticides (hexachlorobenzene, trans-nonachlor, p,p’-dichlorodiphenyldichloroethylene), 1 polybrominated diphenyl ether (PBDE 47), 3 polychlorinated biphenyls (138/158, 153, 180) and 6 poly-and-perfluorinated alkyl substances (PFASs) (perfluorodecanoic acid, perfluorohexanesulfonic acid, perfluorononanoic acid, perfluorooctanesulfonic acid, perfluoroundecanoic acid (PFUnDA)). Genes annotated to the differentially methylated CpGs were tested for enrichment of molecular pathways. Results: At 5% false discovery rate, POPs concentrations were associated with a total of 193 differentially methylated CpGs in the placenta (nominal p-values ranging from 8.37x10-21 to 1.52x10-7). Among them, 21 CpGs were significantly correlated with placental expression of 18 unique genes (p-values<0.05). Notably, PFUnDA was associated with higher methylation of 3 CpGs (cg13996963, cg12089439, cg18145877) annotated to TUSC3. Higher methylation at the three CpGs was correlated with decreased expression of TUSC3 in placenta; and decreased expression of TUSC3 was correlated with smaller birth length. Pathway analysis found that genes annotated to CpGs differentially methylated with PBDE 47 were enriched in birthweight (p-value = 2.06x10-5) and differentiation of embryonic cells (p-value = 2.25x10-5), while genes annotated to CpGs associated with PFASs were enriched in brain size (p-value = 4.09x10-4) and morphology (p-value = 7.29x10-3). Conclusions: The findings give insight into the potential for placental DNA methylation and gene expression mechanism to be involved in the prenatal toxicity of POPs and their associations with fetal growth outcomes.