Placental dysfunction in CD-1 mice following gestational exposure to per- and polyfluoroalkyl substances (PFAS)

Per- and polyfluoroalkyl substances (PFAS) comprise a vast universe of man-made chemicals that are ubiquitous environmental contaminants and have raised concerns regarding adverse effects on human health, including during pregnancy. The placenta has been hypothesized as an important target tissue of PFAS, however the specific mechanism(s) through which PFAS may disrupt placental function, and by extension both fetal and maternal health, are not known. To investigate placental genes and pathways altered following exposure to two different PFAS, transcriptomic and pathway analyses were performed on CD-1 mouse placenta following gestational exposure to perfluorooctanoic acid (PFOA; 1 or 5 mg/kg-d) or hexafluoropropylene oxide-dimer acid (HFPO-DA, or GenX; 2 or 10 mg/kg-d). We found dysregulation of biological pathways relating to hemostatic and thrombo-inflammatory processes and lipid homeostasis (e.g., fatty acid metabolism and oxidation). A quantitative adverse outcome pathway (AOP) analysis was performed using a previously published AOP for PFAS and low birth weight/neonatal mortality. Gene expression changes in the present study aligned with numerous Molecular Initiating Events in the AOP, namely PPARα/γ activation, CAR/PXR activation, and transthyretin binding. The Key Events of decreased trophoblast invasion/angiogenesis and perinatal hypoglycemia were also supported by the data. Placental morphometry measurements showed changes consistent with impaired trophoblast invasion and spiral artery remodeling, including decreased decidual area, increased labyrinth:decidua ratios, and increased vessel:luminal area in the spiral arteries. Further, qPCR validation of several prolactin genes revealed sex-specific dysregulation of expression levels. Prolactin plays a role in the epithelial-mesenchymal transition of extravillous trophoblasts and in regulating early decidual invasion. Taken together, these data improve our understanding of mechanistic processes underlying PFAS-mediated placental effects in mice and provide putative targets for future work.

Impact/Purpose

This product is an abstract for an invited presentation for the 2024 Birth Defects Research and Prevention annual meeting. The abstract describes research conducted in pregnant mice that were exposed to one of two different per- and polyfluoroalkyl substances (PFAS) during pregnancy. PFAS comprise a diverse group of man-made chemicals that are persistent environmental pollutants and human exposure to PFAS has been linked with adverse pregnancy outcomes such as low birth weight and hypertensive disorders of pregnancy. It has been hypothesized that exposure to PFAS may lead to these adverse health outcomes due to disrupted function of the placenta. In this study, placentas from the mice were collected at two different stages of pregnancy. We looked at changes in gene expression using transcriptomics and as well as changes in the placental tissues using histopathology plus morphometry. We found biological pathways relating to hemostatic and thrombo-inflammatory processes and lipid homeostasis were dysregulated in PFAS-exposed placentas. Placental morphometry measurements showed changes consistent with impaired placental trophoblast invasion and spiral artery remodeling, including decreased decidual area, increased labyrinth:decidua ratios, and increased vessel:luminal area in the spiral arteries. Further, qPCR validation of several prolactin genes revealed sex-specific dysregulation of expression levels. Prolactin plays a role in the epithelial-mesenchymal transition of extravillous trophoblasts and in regulating early decidual invasion. Taken together, these data improve our understanding of mechanistic processes underlying PFAS-mediated placental effects in mice and provide putative targets for future work. 

Citation

Blake, B., C. Miller, H. Nguyen, V. Chappell, D. Phadke, M. Balik-Meisner, R. Shah, AND S. Fenton. Placental dysfunction in CD-1 mice following gestational exposure to per- and polyfluoroalkyl substances (PFAS). Birth Defects Research and Prevention, Pittsburgh, PA, June 22 - 26, 2024.