Transcriptomic Perturbations in Placental Gene Expression Following Developmental Exposure to Perfluorooctanoic Acid (PFOA) or Hexafluoropropylene Oxide-Dimer Acid (HFPO–DA or GenX) in CD-1 Mice Are Consistent with Placental Insufficiency

Per- and polyfluoroalkyl substances (PFAS) comprise a group of synthetic chemicals that are ubiquitous global contaminants. Exposure to certain PFAS has been associated with adverse pregnancy outcomes in humans and animal models including preeclampsia and low birth weight. The placenta is critical for a healthy pregnancy, and evidence suggests adverse pregnancy outcomes associated with exposure to certain PFAS may arise from aberrant placental development and/or function. To investigate the effects of two different PFAS on the placenta, samples collected from a prior study of pregnant CD-1 mice exposed to perfluorooctanoic acid (PFOA; 1 or 5 mg/kg) or hexafluoropropylene oxide-dimer acid (HFPO-DA, or GenX; 2 or 10 mg/kg) via oral gavage from embryonic day (E) 1.5 to E 11.5 or E 17.5 were used. Placentas were evaluated for morphometric, transcriptomic, and pathway-level effects. Although relatively few genes were significantly differentially expressed, multiple significantly enriched pathways were identified and were involved in biological processes related to hemostasis (e.g., coagulation and angiogenesis), the innate immune response (e.g., acute phase response signaling), and metabolism, synthesis, and transport of cholesterol, lipids, and bile acids (e.g., FXR/RXR activation and fatty acid metabolism). These pathway-level observations provide a mechanistic basis for observed morphometric changes, fetal:placental weight changes, and previously reported histopathological changes. Overall, these findings confirm proposed Adverse Outcome Pathways consistent with placental insufficiency and fetal nutrient restriction and PFAS-induced maternal vascular malperfusion of the placenta.