Citation:

Conley, J., C. Lambright, N. Evans, M. Strynar, J. McCord, B. McIntyre, G. Tavlos, M. Cardon, E. Medlock Kakaley, P. Hartig, V. Wilson, AND L. Gray. Adverse effects of oral gestational exposure to hexafluoropropylene oxide dimer acid (GenX) in the Sprague-Dawley rat- Presentation. Society of Toxicology, Baltimore, MD, March 10 - 14, 2019.

Impact/Purpose:

There is a critical need for in vivo rodent toxicity data on several per- and polyfluoroalkyl substance (PFAS) compounds, including hexafluoropropylene oxide dimer acid (aka GenX), due to documented occurrence in treated drinking water and little to no available toxicity data. Within the context of our research plan, we asked whether GenX activates PPAR signaling pathways and leads to adverse effects on male reproductive development, as purported in the literature. Additionally we collected data on a range of effect endpoints on both maternal and fetal/neonatal tissues and paired that with internal dosimetry in order to more directly estimate human health effects from these laboratory rat studies. The data herein are highly valuable for the risk assessment community and health researchers at both the state and federal levels.

Description:

Hexafluoropropylene oxide dimer acid (HFPO-DA, aka GenX) is a member of the per- and polyfluoroalkyl substances (PFAS) chemical class and a high-profile contaminant of emerging concern. Elevated levels of HFPO-DA have been detected in multiple environmental matrices and treated drinking water in the United States and Europe indicating widespread exposure to human and ecological receptors. Our goal was to characterize the potential mammalian toxicity of HFPO-DA from oral administration during gestation to maternal and pre/postnatal rats. Initially, we dosed Sprague-Dawley rat dams daily via oral gavage with 1-500 mg HFPO-DA/kg/d during the critical window for male reproductive tract development (gestation day (GD) 14-18). We evaluated fetal testis testosterone production, expression of PPAR signaling pathway genes in maternal and fetal livers, maternal serum clinical chemistry, reproductive development of F1 animals, and internal dosimetry in maternal serum and fetal plasma. HFPO-DA exposure during gestation (GD 14-18) did not affect the fetal testis, but did produce significant dose-responsive increases in maternal liver weight (≥62.5 mg/kg), reduced maternal serum thyroid hormone and lipid profiles (≥30 mg/kg), and highly upregulated gene expression related to PPAR signaling pathways in maternal and fetal livers (≥1 mg/kg). A low sample size (n=3 per dose) pilot postnatal study at 125 mg/kg/d was largely negative for adverse effects but indicated potential reductions in female body weight and reduced weights of male reproductive tissues in F1 animals. However, a follow-up postnatal study covering a broader dosing interval (GD8 – postnatal day 3), greater sample size (n=5 per dose), and greater dose range (10-250 mg/kg/d) resulted in significant, dose-responsive neonatal mortality at ≥62.5 mg/kg/d and reduced body weight of surviving pups at all doses (≥10 mg/kg/d). This study is ongoing with evaluation of adult F1 animals that were exposed in utero. Overall, HFPO-DA exposure produced multiple adverse effects similar to previously published PFAS toxicity evaluations, such as PFOS and PFOA, and in vivo toxicokinetics seems to play a major role in the relative potency of these compounds for producing effects. The views presented here do not necessarily reflect the views or policy of the USEPA.

Record Details: