Adverse developmental effects of gestational exposure to emerging perfluoroalkyl ether acids: Mechanistic insights and potency comparisons to legacy PFAS

Perfluoroalkyl ether acids (PFEAs) are a sub-class of per- and polyfluoroalkyl substances (PFAS) and are currently used in the production of fluoropolymers following the phase-out of the legacy PFAS perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS). PFEA compounds such as hexafluoropropylene oxide dimer acid (GenX), Nafion byproduct 2 (NBP2), and perfluoro-2-methoxyacetic acid (PFMOAA) have been detected in surface water, drinking water, and/or human serum, yet little to no published toxicity data is available. We previously determined that oral GenX exposure to pregnant Sprague-Dawley rats produced similar adverse maternal and F1 effects to PFOS, but with lower potency. Here, we assessed the in utero toxicity of PFMOAA (0.01-200 mg/kg/d, gestation day (GD)14-18 and GD 9-13) and NBP2 (0.1-30 mg/kg/d from GD 14-18 and 0.3-30 mg/kg/d from GD 8-postnatal day (PND) 2) for comparison to GenX and the legacy PFAS. PFMOAA was negative for adverse maternal and F1 effects; however, NBP2 reduced maternal weight gain (GD14-18 and GD8-PND2 dosing), reduced neonatal survival (≥10 mg/kg), and reduced pup weight (GD8-PND2 dosing). Based on oral ED50s for neonatal mortality, NBP2 was only ~3-fold less potent than PFOS (3.1 mg/kg versus 9.5 mg/kg for PFOS and NBP2, respectively); whereas, GenX was ~35-fold less potent than PFOS. It appears that the spectrum of adverse developmental effects is similar between some of the PFEAs and the legacy PFAS and that the oral potency is also relatively similar for some compounds. Data from our GenX studies indicated that many genes associated with glucose metabolism were significantly downregulated in PND 0 pup livers and impaired liver glycogen deposition of the developing fetus/neonate may be a principle key event for reducing F1 survival and body weight. Ongoing research in our group is investigating the putative mechanism(s) of action (primarily activation of peroxisome proliferator-activated receptor subtypes) and additional key events that lead to adverse maternal and neonatal outcomes, comparison of internal dosimetry for extrapolation to human exposures, and mixture-based effects of in utero exposure to multiple PFAS. Abstract does not necessarily reflect USEPA policy.

Impact/Purpose

This is an abstract for an invited Symposium presentation at the 2020 SOT Annual Meeting in Anaheim, CA that is now being presented as a Virtual Session on May 7, 2020 due to cancellation of the in-person meeting. The data from this project will be useful to state, federal, and other regulatory agencies in the development of hazard assessments for perfluoromethoxy acetic acid (PFMOAA) and Nafion Byproduct 2 (NBP2), among other PFAS. This study characterizes the toxic effects of oral NBP2 and PFMOAA exposure during pregnancy to both the mother and the offspring (fetal and newborn) using a laboratory rat model. We found multiple, severe effects for NBP2 that were consistent with other PFAS, such as PFOS. Importantly, it appears that NBP2 is only slightly less potent than PFOS based on the orally administered dose. Continuation of this work will focus on characterizing the internal serum and liver doses for NBP2 and PFMOAA because toxicokinetics appears to be a major factor in the oral toxicity. The data presented here will be highly valuable for regulators to make scientifically based decisions on the potential adverse effects of NBP2 on human health and informing future toxicity studies of additional PFAS.

Citation

Conley, J. Adverse developmental effects of gestational exposure to emerging perfluoroalkyl ether acids: Mechanistic insights and potency comparisons to legacy PFAS. Virtual-Society of Toxicology Annual Meeting -, NA, Webinar, May 07, 2020.