Investigating Placental Toxicity of PFAS in Mice and a Human Placental Cell Line
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The placenta is critical for establishing and maintaining pregnancy, and its function impacts both maternal and fetal health outcomes. However, it is understudied in the context of environmental exposures and recent research has implicated it may be a target of common contaminants, including per- and polyfluoroalkyl substances (PFAS). This presentation describes the impact of PFAS exposure on the placenta in vivo using the CD-1 mouse as a model system and in vitro using human-derived JEG-3 placental trophoblasts as a model for a high-throughput toxicity screen (HTTS). After gestational exposure to perfluoroctanoic acid (PFOA) or hexafluoropropylene oxide dimer acid (HFPO-DA), placental weight and fetal-placental weight ratios are disrupted in mice. Histopathological analyses confirmed a statistically significant increased incidence of multple placental abnormalities, including placental labyrinth congestion and atrophy. Lastly, placental thyroxine levels were disrupted by gestational exposure to HFPO-DA, but not PFOA. In the in vitro HTTS, forty two unique PFAS were tested for their impact on placental trophoblast viability, proliferation, and mitchondrial membrane potential. Concentration-response models were applied to the data to calculate EC50 values where possible. HTTS results were used to select a subset of PFAS for further investigation of their impact on JEG-3 migration using a scratch wound assay. HTTS concentration-response curve fitting determined EC50 values for 79% of tested compounds for at least one of the three endpoints. Trophoblast migratory potential was evaluated for a subset of six prioritized PFAS using a scratch wound assay. Migration, measured as the percent of wound closure after 72 h, was most severely inhibited by exposure to 100 µM perfluorooctanoic acid (PFOA; 72% closure), perfluorooctanesulfonic acid (PFOS; 57% closure), or ammonium perfluoro-2-methyl-3-oxahexanoate (GenX; 79% closure). PFOA and HFPO-DA were subsequently evaluated for disrupted expression of 46 genes reported to be vital to trophoblast health. Disrupted regulation of oxidative stress was suggested by altered expression of GPEX1 (300 µM HFPO-DA and 3 µM HFPO-DA), GPER1 (300 µM HFPO-DA), and SOD1 and altered cellular response to xenobiotic stress was indicated by upregulation of the placental efflux transporter, ABCG2 (300 µM HFPO-DA, 3 µM HFPO-DA, and 100 µM PFOA). Taken together, these studies suggest the placenta is vulnerable to PFAS-induced toxicity in mice and in vitro.