Evaluation of Maternal, Embryo, and Placental Effects in CD-1 Mice following Gestational Exposure to Perfluorooctanoic Acid

Background: Perfluorooctanoic acid (PFOA) is a poly- and perfluoroalkyl substance (PFAS) associated with adverse pregnancy outcomes in mice and humans, but little is known regarding one of its replacements, hexafluoropropylene oxide dimer acid (HFPO-DA, referred to here as GenX), both of which have been reported as contaminants in drinking water. Objectives: We compared the toxicity of PFOA and GenX in pregnant mice and their developing embryo-placenta units, with a specific focus on the placenta as a hypothesized target. Methods: Pregnant CD-1 mice were exposed daily to PFOA (0, 1, or 5 mg/kg) or GenX (0, 2, or 10 mg/kg) via oral gavage from embryonic day (E) 1.5 to 11.5 or 17.5 to evaluate exposure effects on the dam and embryo-placenta unit. Gestational weight gain (GWG), maternal clinical chemistry, maternal liver histopathology, placental histopathology, embryo weight, placental weight, internal chemical dosimetry, and placental thyroid hormone levels were determined. Results: Exposure to GenX or PFOA resulted in increased GWG, with increase in weight most prominent and of shortest latency with 10 mg/kg/d GenX exposure. Embryo weight was significantly lower after exposure to 5 mg/kg/d PFOA (9.4% decrease relative to controls). Effect sizes were similar for higher doses (5 mg/kg/d PFOA and 10 mg/kg/d GenX) and lower doses (1 mg/kg/d PFOA and 2 mg/kg/d GenX), including higher maternal liver weights, changes in liver histopathology, higher placental weights and embryo-placenta weight ratios, and greater incidence of placental abnormalities relative to controls. Histopathological features in placentas suggested that PFOA and GenX may exhibit divergent mechanisms of toxicity in the embryo-placenta unit, whereas PFOA- and GenX-exposed livers shared a similar constellation of adverse pathological features. Conclusions: Gestational exposure to GenX recapitulated many documented effects of PFOA in CD-1 mice, regardless of its much shorter reported half-life; however, adverse effects toward the placenta appear to have compound-specific signatures.