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

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 (FDR)<0.05 and differentially methylated regions (DMRs) were identified using comb-p (Šidák-adjusted p<0.05). 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 (ρ=0.28−0.76). Methylation at one DMP (cg18587484), annotated to the gene TJAP1, was associated with perfluorooctanoate (PFOA) at FDR< 0.05. 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 (FDR< 0.1). 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


Table of Contents
Table S1.Concentrations (ng/mL) of 11 per-and polyfluoroalkyl substances measured in maternal pregnancy serum samples among 583 eligible participants enrolled in the Healthy Start study.
Table S2.Comparison of mother-infant pairs in this analysis to the potentially eligible Healthy Start population.
Table S4.Characteristics of previously published studies of perfluoroalkyl substance concentrations and epigenome-wide DNA methylation.

Figure S2 .
Figure S2.Directed acyclic graph a indicating hypothesized causal relationships among variables.

Table S1 .
Concentrations (ng/mL) of 11 per-and polyfluoroalkyl substances measured in maternal pregnancy serum samples among 583 eligible participants enrolled in the Healthy Start study.Limit of detection was 0.1 ng/mL for all analytes.b NHANES values are provided for the sum of PFOS and PFOA isomers, as branched and linear isomers were not reported in 2011-2012. a

Table S2 .
Comparison of mother-infant pairs in this analysis to the potentially eligible Healthy Start population.

Table S4 .
Characteristics of previously published studies of perfluoroalkyl substance concentrations and epigenome-wide DNA methylation.