Transcriptomic profiles of murine placental gene expression following developmental exposure to PFOA or GenX in CD-1 mice
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Per- and polyfluoroalkyl substances (PFAS) are a diverse class of chemicals that are persistent environmental contaminants. Perfluorooctanoic acid (PFOA), one of the legacy PFAS, is associated with adverse health outcomes in women including gestational hypertension, metabolic changes, and reduced fetal growth. The association between maternal exposure to PFOA and reduced fetal growth has been substantiated by systematic reviews of both the human and animal literature, however, the mechanism through which PFOA exerts its effects on fetal growth is not known. This study compares placenta morphology and transcriptomic profiles from in utero exposure to PFOA and its replacement, hexafluoropropylene oxide-dimer acid (HFPO-DA, known by the trade name GenX). Pregnant CD-1 mice were dosed with vehicle control (deionized water), PFOA (1.0 or 5.0 mg/kg/day), or GenX (2.0 or 10.0 mg/kg/day) from gestation day 1.5 to 17.5. Placentas were collected at two timepoints during gestation; E11.5 (immature/developing placenta) and E17.5 (mature/developed placenta). RNA was isolated from the placentas and transcriptomic analysis was performed using Affymetrix Mouse Clariom D transcriptome arrays. Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) were used to evaluate enriched pathways. GSEA hallmark analysis suggested PFOA and GenX disrupt placental pathways involved in fatty acid metabolism and adipogenesis, innate immune response (specifically inflammation), and hemostasis (specifically blood coagulation systems). IPA analysis showed pathway enrichment of LXR/RXR activation, FXR/RXR activation, and atherosclerosis signaling, suggesting maternal exposure to GenX disrupted the placental transcriptome via nutrient sensing, signaling, and transport pathways. Although these pathways were not as consistently enriched across treatment groups and timepoints, the clustering of enriched pathways in E17.5 female placenta suggests that this may be an important response to GenX exposure at 10 mg/kg. These pathways have translational relevance to human pregnancy conditions previously associated with maternal exposure to PFAS, including preeclampsia and other hypertensive disorders of pregnancy, and suggest a putative toxicological mechanism through which PFAS exerts adverse effects on the maternal-placental-fetal unit. These data may be highly relevant to ongoing human health risk evaluations by the US EPA and many states, including North Carolina. The views expressed are those of the authors and do not necessarily represent the views or policies of the U.S. EPA.