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Hexafluoropropylene oxide-dimer acid (HFPO-DA or GenX) alters maternal and fetal glucose and lipid metabolism and produces neonatal mortality, low birthweight and hepatomegaly in the Sprague-Dawley rat
Citation:
Conley, J., C. Lambright, N. Evans, J. McCord, M. Strynar, D. Hill, E. MedlockKakaley, V. Wilson, AND E. Gray. Hexafluoropropylene oxide-dimer acid (HFPO-DA or GenX) alters maternal and fetal glucose and lipid metabolism and produces neonatal mortality, low birthweight and hepatomegaly in the Sprague-Dawley rat. ENVIRONMENT INTERNATIONAL. Elsevier B.V., Amsterdam, Netherlands, 146:106204, (2021). https://doi.org/10.1016/j.envint.2020.106204
Impact/Purpose:
Per- and poly-fluoroalkyl substance (PFAS) research is of critical importance to USEPA and other health and regulatory organizations across the US and globally due to the nearly ubiquitous human and environmental exposure to multiple compounds in this chemical class. The legacy PFAS, PFOA, was replaced in manufacturing with hexafluoropropylene oxide dimer acid (HFPO-DA or GenX); however, there are only a few peer-reviewed studies on GenX toxicity and none, to date, that examine exposure during pregnancy and subsequent effects on the offspring after delivery. GenX is currently being evaluated by USEPA OW, NC DHHS/DEQ, the Netherlands National Institute for Public Health and the Environment, and other organizations due to recent reports of elevated concentrations detected in surface water and drinking water near manufacturing facilities. There is a critical need to more thoroughly evaluate the toxicology of GenX and other emerging perfluoroalkyl ether acids (PFEA, such as Nafion byproduct 2 and perfluoromethoxyacetic acid) to generate relevant, in vivo toxicity data for risk assessment and for identifying critical molecular initiating events and key events to characterize PFAS Adverse Outcome Pathways. Based on our previously published research on GenX, we hypothesized that short-term gestational exposure would produce adverse liver effects and activate PPAR signaling pathways considerably higher doses than the more potent, legacy PFAS. Further, we expected that longer exposure during gestation would lead to some subtle effects on offspring after birth at higher oral doses. The data from this project will be useful to state, federal, and international regulatory agencies in the development of hazard and risk assessments on GenX. This study clearly identifies GenX as a developmental toxicant. We found multiple, severe effects that were consistent with other PFAS, such as perfluorooctane sulfonate (PFOS). Importantly, although it appears that GenX is less potent than other PFAS (like PFOS) based on the orally administered dose, it is more potent based on the internal dose. Overall, GenX produces toxic effects in the lab rat similar to other PFAS and 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 GenX on human health and informing future toxicity studies of additional PFAS.
Description:
Hexafluoropropylene oxide dimer acid (HFPO-DA or GenX) is an industrial replacement for the straight-chain perfluoroalkyl substance (PFAS), perfluorooctanoic acid (PFOA). Previously we reported maternal, fetal, and postnatal effects from gestation day (GD) 14-18 oral dosing in Sprague-Dawley rats. Here, we further evaluated the perinatal toxicity of HFPO-DA by orally dosing rat dams with 1–125 mg/kg/d (n = 4 litters per dose) from GD16-20 and with 10–250 mg/kg/d (n = 5) from GD8 – postnatal day (PND) 2. Effects of GD16-20 dosing were similar to those previously reported for GD14-18 dosing and included increased maternal liver weight, altered maternal serum lipid and thyroid hormone concentrations, and altered expression of peroxisome proliferator-activated receptor (PPAR) pathway genes in maternal and fetal livers. Dosing from GD8-PND2 produced similar effects as well as dose-responsive decreased pup birth weight (≥30 mg/kg), increased neonatal mortality (≥62.5 mg/kg), and increased pup liver weight (≥10 mg/kg). Histopathological evaluation of newborn pup livers indicated a marked reduction in glycogen stores and pups were hypoglycemic at birth. Quantitative gene expression analyses of F1 livers revealed significant alterations in genes related to glucose metabolism at birth and on GD20. Maternal serum and liver HFPO-DA concentrations were similar between dosing intervals, indicating rapid clearance, however dams dosed GD8 – PND2 had greater liver weight and gestational weight gain effects at lower doses than GD16-20 dosing, indicating the importance of exposure duration. Comparison of neonatal mortality dose–response curves between HFPO-DA and previously published perfluorooctane sulfonate (PFOS) data indicated that, based on serum concentration, the potency of these two PFAS are similar in the rat. Overall, HFPO-DA is a developmental toxicant in the rat and the spectrum of adverse effects is consistent with prior PFAS toxicity evaluations, such as PFOS and PFOA.
