Prenatal Exposure to Per- and Polyfluoroalkyl Substances, Umbilical Cord Blood DNA Methylation, and Cardio-Metabolic Indicators in Newborns: The Healthy Start Study

Abstract

Background: Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent chemicals widely detected in women of reproductive age. Prenatal PFAS exposure is associated with adverse health outcomes in children. We hypothesized that DNA methylation changes may result from prenatal PFAS exposure and may be linked to offspring cardio-metabolic phenotype. Objectives: We estimated associations of prenatal PFAS with DNA methylation in umbilical cord blood. We evaluated associations of methylation at selected sites with neonatal cardio-metabolic indicators. Methods: Among 583 mother–infant pairs in a prospective cohort, five PFAS were quantified in maternal serum (median 27 wk of gestation). Umbilical cord blood DNA methylation was evaluated using the Illumina HumanMethylation450 array. Differentially methylated positions (DMPs) were evaluated at a false discovery rate and differentially methylated regions (DMRs) were identified using comb-p (Šidák-adjusted ). We estimated associations between methylation at candidate DMPs and DMR sites and the following outcomes: newborn weight, adiposity, and cord blood glucose, insulin, lipids, and leptin. Results: Maternal serum PFAS concentrations were below the median for females in the U.S. general population. Moderate to high pairwise correlations were observed between PFAS concentrations ( ). Methylation at one DMP (cg18587484), annotated to the gene TJAP1 , was associated with perfluorooctanoate (PFOA) at . Comb-p detected between 4 and 15 DMRs for each PFAS. Associated genes, some common across multiple PFAS, were implicated in growth ( RPTOR ), lipid homeostasis ( PON1 , PON3 , CIDEB , NR1H2 ), inflammation and immune activity ( RASL11B , RNF39 ), among other functions. There was suggestive evidence that two PFAS-associated loci (cg09093485, cg09637273) were associated with cord blood triglycerides and birth weight, respectively ( ). Discussion: DNA methylation in umbilical cord blood was associated with maternal serum PFAS concentrations during pregnancy, suggesting potential associations with offspring growth, metabolism, and immune function. Future research should explore whether DNA methylation changes mediate associations between prenatal PFAS exposures and child health outcomes. https://doi.org/10.1289/EHP6888

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

“…Previous EWAS studies have found statistically significant associations between gestational PFAS concentrations and DNA methylation at birth or in newborns (Miura et al 2018;Ouidir et al 2020;Starling et al 2020;van den Dungen et al 2017). Specifically, two studies reported significant associations between higher pregnancy PFOA concentrations and lower cord blood DNA methylation at two CpGs (cg11260715: AC002480.3 and cg04461802: GPR126) in 190 Japanese mother-offspring pairs (Miura et al 2018), and at one CpG (cg18587484: TJAP1) in 583 mother-offspring pairs from Colorado.…”

“…Specifically, two studies reported significant associations between higher pregnancy PFOA concentrations and lower cord blood DNA methylation at two CpGs (cg11260715: AC002480.3 and cg04461802: GPR126) in 190 Japanese mother-offspring pairs (Miura et al 2018), and at one CpG (cg18587484: TJAP1) in 583 mother-offspring pairs from Colorado. (Starling et al 2020). A cross-sectional study reported that higher neonatal PFOA concentrations were significantly associated with lower DNA methylation at one CpG (cg15557840: SCRT2; SRXN1) in 597 newborns from New York.…”

“…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).…”

Maternal Glycemic Dysregulation During Pregnancy and Neonatal Blood DNA Methylation: Meta-analyses of Epigenome-Wide Association Studies

“…Seven cohorts with cord blood DNAm and fasting glycemic data in midpregnancy participated in the meta-analyses ( Table 1 and Supplementary Material ). These cohorts were from Southeast Asia (Singapore: Growing Up in Singapore Towards healthy Outcomes [GUSTO] [ 14 ]), North America (Canada: Genetics of Glucose regulation in Gestation and Growth [Gen3G] [ 15 ], U.S.: Healthy Start [ 16 ]), and Europe (Finland: the Finnish Gestational Diabetes [FinnGeDi] Study [ 7 , 17 ] and Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction [PREDO] study [ 18 ], France: EDEN [ 19 ], and Belgium: the ENVIRonmental influence ON early AGEing [ENVIRONAGE] [ 20 ]). One cohort, in the Generation R Study ( 21 ) (the Netherlands), had nonfasting glycemic data (included in a secondary analysis).…”