Concentrations of persistent organic pollutants in maternal plasma and epigenome-wide placental DNA methylation

Abstract

Background Prenatal maternal plasma persistent organic pollutant (POP) concentrations have been associated with neonatal outcomes. However, the underlying mechanisms remain unknown. Placental epigenetic mechanisms may be involved, but no prior epigenome-wide studies have investigated the impact of maternal POPs on placental DNA methylation. We studied the association between maternal plasma POP concentration in early pregnancy and epigenome-wide placental DNA methylation among 260 pregnant women from the NICHD Fetal Growth Studies. Results Our analysis focused on POPs with more than 80% plasma concentrations 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)). Using 5% false discovery rate, POPs were associated with a total of 214 differentially methylated CpG sites (nominal p values ranging from 2.61 × 10 −21 to 2.11 × 10 −7 ). Out of the 214 CpG sites, 24 (11%) were significantly correlated with placental expression of 21 genes. Notably, higher PFUnDA was associated with increased methylation at 3 CpG sites (cg13996963, cg12089439, cg18145877) annotated to TUSC3 , and increased methylation at those 3 CpG sites was correlated with decreased expression of TUSC3 in the placenta. Increased methylation at cg18145877 ( TUSC3 ) and decreased expression of TUSC3 were correlated with shorter birth length. Out of the 214 CpG sites, methylation at 44 CpG sites was correlated ( p value < 0.10) with at least one neonatal anthropometry measure (i.e., birth weight, birth length, and head circumference). Seven CpG sites mediated ( p value < 0.05) the association between PBDE 47 and neonatal anthropometry measures. Genes annotating the top differentially methylated CpG sites were enriched in pathways related to differentiation of embryonic cells (PBDE 47) and in pathways related to brain size and brain morphology (PFASs). Conclusions DNA methylation changes in the placenta were significantly associated with maternal plasma POPs concentration. The findings suggest that placental DNA methylation and gene expression mechanism may be involved in the prenatal toxicity of POPs and their association with neonatal anthropometry measures.

Gestational Perfluoroalkyl Substance Exposure and DNA Methylation at Birth and 12 Years of Age: A Longitudinal Epigenome-Wide Association Study

“…Few studies have examined the associations of gestational PFAS exposure with changes in epigenome-wide DNA methylation in cord blood or placenta (Miura et al 2018;Ouidir et al 2020;Starling et al 2020). Two studies found that higher serum perfluorooctanoate (PFOA) was significantly associated with lower cord blood DNA methylation at specific CpG sites (Miura et al 2018;Starling et al 2020), whereas one study found no significant associations (Ouidir et al 2020).…”

“…Few studies have examined the associations of gestational PFAS exposure with changes in epigenome-wide DNA methylation in cord blood or placenta (Miura et al 2018;Ouidir et al 2020;Starling et al 2020). Two studies found that higher serum perfluorooctanoate (PFOA) was significantly associated with lower cord blood DNA methylation at specific CpG sites (Miura et al 2018;Starling et al 2020), whereas one study found no significant associations (Ouidir et al 2020). Some of these studies have reported significant associations of DNA methylation with serum perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS) and perfluorononanoic acid (PFNA) concentrations (Miura et al 2018;Ouidir et al 2020).…”

Placenta and fetal brain share a neurodevelopmental disorder DNA methylation profile in a mouse model of prenatal PCB exposure

“…Human term placenta is therefore a potentially rich source of epigenetic biomarkers for prenatal exposures, such as PCBs. PCB exposure was previously shown to be associated with differential methylation at select CpG sites in human placenta in an array-based approach ( Ouidir et al, 2020 ). A low-pass, whole-genome bisulfite sequencing (WGBS) approach analyzing human placenta samples from the prospective high-risk MARBLES ASD cohort demonstrated that DNA methylation profiles distinguished ASD from control placenta and the top differentially methylated region (DMR) mapped to CYP2E1 ( Zhu et al, 2019 ).…”

A cross-cohort analysis of autosomal DNA methylation sex differences in the term placenta

“…Disease-related EWAS of the placenta include preeclampsia [ 17 – 21 ] (reviewed in [ 22 ]), acute chorioamnionitis [ 23 ], intrauterine growth restriction [ 20 , 24 ], and fetal birthweight [ 25 ], among others. Recent placental EWAS of environmental exposures and maternal phenotypes include investigations into heavy metals [ 26 , 27 ], pollution [ 28 , 29 ], maternal smoking [ 30 ], maternal stress [ 31 ], blood pressure [ 32 ], diabetes [ 33 ], body mass index, gestational weight gain, and dyslipidemia [ 34 , 35 ]. Understanding how biological sex is associated with autosomal DNAme is an underexplored facet of prenatal epigenetic research, and may shed light on the factors contributing to sex differences observed in growth and development throughout gestation.…”