Adverse maternal, fetal, and postnatal effects of hexafluoropropylene oxide dimer acid (GenX) from oral gestational exposure in Sprague-Dawley rats
Hexafluoropropylene oxide dimer acid ((HFPO-DA), GenX) is a member of the per- and polyfluoroalkyl substances (PFAS) chemical class and elevated levels have been detected in surface water, air, and treated drinking water in the United States and Europe.
Objectives: Characterize the potential maternal and postnatal toxicities of oral HFPODA in rats during sexual differentiation. Given that some PFAS activate peroxisome proliferator activated receptors (PPARs), assess if HFPO-DA affects androgendependent development or interferes with estrogen, androgen, or glucocorticoid receptor activity.
Methods: Steroid receptor activity was assessed with a suite of in vitro transactivation assays and Sprague-Dawley rats were used to assess maternal, fetal, and postnatal effects of HFPO-DA exposure. Dams were dosed daily via oral gavage during male reproductive development (gestation day 14-18). We evaluated fetal testes, maternal and fetal livers, maternal serum clinical chemistry, and reproductive development of F1 animals.
Results: HFPO-DA displayed negligible in vitro receptor activity and did not impact testosterone production or expression of genes key to male reproductive development in the fetal testis; however, in vivo exposure during gestation produced higher maternal liver weights (≥62.5 mg/kg), lower maternal serum thyroid hormone and lipid profiles (≥30 mg/kg), and upregulated gene expression related to PPAR signaling pathways in maternal and fetal livers (≥1 mg/kg). Further, the pilot postnatal study indicated lower female body weight and lower weights of male reproductive tissues in F1 animals.
Conclusions: HFPO-DA exposure produced multiple effects similar to prior toxicity evaluations on PFAS, such as PFOS and PFOA, but at higher oral doses. The mean dam serum concentration from the lowest dose group was 4-fold greater than the maximum serum concentration detected in a worker in a HFPO-DA manufacturing facility. Research is needed examining the mechanisms and downstream events linked to the adverse effects of PFAS, and mixture-based studies evaluating multiple PFAS.