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Development of and AOP network for the developmental effects of exposure to PFAS
Citation:
Gray, L., C. Lambright, N. Evans, M. Cardon, E. Medlock Kakaley, V. Wilson, AND J. Conley. Development of and AOP network for the developmental effects of exposure to PFAS. Virtual -Society of Toxicology Annual Meeting 2020, Anaheim, CA, March 15 - 20, 2020.
Impact/Purpose:
There is growing global concern about the health effects of PFAS due to widespread exposure from a variety of sources. We are developing an AOP network for PFAS from the literature and from our own developmental studies with rats. The goal is to link in vitro Molecular Initiating Events (MIEs) and in vivo Key Events (KEs) to adverse fetal and postnatal effects of individual PFAS and mixtures of PFAS. Development of a quantitative AOP network for PFAS would facilitate extrapolation of effects of individual PFAS and mixtures of PFAS in vitro and from in vivo studies with laboratory animals to potential adverse effects in humans.
Description:
L. E. Gray, Jr, C. Lambright, N. Evans, M. Cardon, E. M. Kakaley, V. Wilson, and J. Conley. USEPA, Durham, NC. Abstract: There is growing global concern about the health effects of PFAS due to widespread exposure from a variety of sources. We are developing an AOP network for PFAS from the literature and from our own developmental studies with rats. The goal is to link in vitro Molecular Initiating Events (MIEs) and in vivo Key Events (KEs) to adverse fetal and postnatal effects of individual PFAS and mixtures of PFAS. In vitro data demonstrate that the PFAS (HFPO-DA, PFNA, PFOS, PFOA, PFBS, PFMOAA and nafion byproduct 2 (NBP2)) and fatty acids (FA) oleic, linoleic, octanoic) are PPAR α and γ agonists but 6:2 FTOH is not. Only FA activated PPAR δ. None of the PFAS or FA are AR or GR agonists, whereas 6:2 FTOH appears to be a weak ER agonist. In order to identify KEs related to PFAS developmental toxicity, we dosed pregnant rats from gestational day (GD) 14 to 18, we found that HFPO-DA (GenX) altered fetal and maternal liver mRNA expression for genes in the PPAR and lipid pathways, increased maternal but not fetal liver weight, altered maternal serum lipid profiles, and reduced maternal serum T3 and T4. We also are examining the effects of PFAS on gene pathways in other fetal tissues including the thymus, heart, lung, brain and placenta. Although fetal viability and body and liver weight were unaffected by GD 14 to 18 exposure, in a pre-postnatal study dosed from GD 8 to postnatal day 2, HFPO-DA reduced pup weight and viability at dose levels that did not induce overt maternal toxicity. HFPO-DA also increased liver PPAR gene expression and liver weight in the dam and pups and reduced neonatal liver glycogen storage, which by itself could result in neonatal mortality. Similar studies on the effects of NBP2and a PFAS mixture (HFPO-DA, NBP2 and PFOS) are ongoing. To date, we have found that NBP2 and the mixture of PFAS (dose additive) also reduced neonatal survival and growth. Taken together, these data indicate that PFAS act via multiple MIEs, disrupting multiple KEs that result in diverse effects in fetal, neonatal and maternal tissues. MIEs include, but may not be not limited to, PPAR α and γ and ER agonism. The in vitro PPAR agonism EC50s did not correlate well with the reduced neonatal viability following in utero exposure and PFAS-induced hepatomegaly and induction of the liver PPAR pathways also were poorly correlated with neonatal mortality. In summary, tissue- and life-stage-specific AOP networks that account for multiple MIEs likely will be needed to accurately describe the developmental effects of in utero PFAS exposure.