Science Inventory

Evaluation of Maternal, Embryo, and Placental Effects in CD-1 Mice following Gestational Exposure to Perfluorooctanoic Acid (PFOA) or Hexafluoropropylene Oxide Dimer Acid (HFPO-DA or GenX)

Citation:

Blake, B., H. Cope, S. Hall, R. Keys, B. Mahler, J. McCord, B. Scott, H. Stapleton, M. Strynar, S. Elmore, AND S. Fenton. Evaluation of Maternal, Embryo, and Placental Effects in CD-1 Mice following Gestational Exposure to Perfluorooctanoic Acid (PFOA) or Hexafluoropropylene Oxide Dimer Acid (HFPO-DA or GenX). ENVIRONMENTAL HEALTH PERSPECTIVES. National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC, 128(2):27006, (2020). https://doi.org/10.1289/EHP6233

Impact/Purpose:

Perfluorooctanoic acid (PFOA) is a 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 a contaminant in community drinking water systems in the US and Europe. This work aimed to compare the toxicity of PFOA and GenX in pregnant mice and their developing embryo-placental units by repeated dosing of pregnant CD-1 mice and measurement of various developmental endpoints. Exposure to GenX and PFOA was found to have similar, significant effects on several developmental processes, as measured by the chosen endpoints, but the mechanism of toxicity towards the embryo:placental unit differs for GenX and PFOA. Mechanisms of toxicity and the toxicological effects of the emerging chemical GenX are of significant concern to partners performing risk/toxicological assessment of replacement PFAS compounds.

Description:

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 5mg/kg) or GenX (0, 2, or 10mg/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 10mg/kg/d GenX exposure. Embryo weight was significantly lower after exposure to 5mg/kg/d PFOA (9.4% decrease relative to controls). Effect sizes were similar for higher doses (5mg/kg/d PFOA and 10mg/kg/d GenX) and lower doses (1mg/kg/d PFOA and 2mg/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.