Untargeted Lipidomics Analysis of Prenatal Per- and Polyfluoroalkyl Substances (PFAS) Exposure and Small-for-Gestational Age (SGA) Delivery: An Exploratory Study in the Atlanta African American Maternal-Child Cohort, 2014–2020

Abstract

Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) is associated with small-for-gestational age (SGA), an adverse pregnancy outcome indicative of intrauterine growth restriction (IUGR). Evidence from previous environmental epidemiologic work suggests that lipids contribute to this association through oxidative stress and inflammation. Therefore, we conducted an exploratory study by analyzing the maternal lipidome with the meet-in-the-middle approach to identify potential intermediates. In the Atlanta African American Maternal–Child Cohort, pregnant participants provided serum samples between 6 and 17 weeks gestation, which underwent targeted PFAS analysis (N: total = 513, SGA = 61) and untargeted lipidomics analysis (N: total = 330, SGA = 36). A lipidome-wide association study (LWAS) was conducted for PFNA, PFOA, PFOS, and PFHxS with multivariable regression and their mixture with quantile g-computation. A separate LWAS was performed for SGA with multivariable regression. Lipid pathway analysis was performed in LIPEA (Lipid Pathway Enrichment Analysis). Lipidomic signatures that overlapped between any PFAS LWAS and the SGA LWAS were considered intermediates. A simultaneous, 1-quartile increase in serum concentrations of PFNA, PFOA, PFOS, and PFHxS at early pregnancy was associated with a 43% increase in delivery of an SGA newborn (Odds Ratio = 1.43; 95% Confidence Interval = 1.02, 2.00). The overall mixture effect was driven by PFNA (weight = 0.42). There were 321 features associated with the PFAS mixture and 25 features associated with SGA in the maternal lipidome (all p < 0.05, but none remained significant after false discovery rate correction). After confirmation and annotation, three intermediate metabolites were identified, including phosphatidylinositol 18:1–20:4, phosphatidylcholine 32:0, and monoacylglycerol 18:0. The pathways for glycerophospholipid metabolism, retrograde endocannabinoid signaling, insulin resistance, and long-term depression were also enriched in the LWAS for PFNA, PFOA, PFOS, PFHxS, the PFAS mixture, and SGA. Global analysis of the maternal lipidome during early pregnancy revealed diverse bioactive lipid involvement in the PFAS-SGA association. Additional research is warranted to understand if antioxidants and anti-inflammatory nutrients would attenuate exposure effects on adverse maternal–child health outcomes.