Adverse Maternal, Fetal, and Postnatal Effects of Hexafluoropropylene Oxide Dimer Acid (GenX) from Oral Gestational Exposure in Sprague-Dawley Rats

Abstract

Background:Hexafluoropropylene oxide dimer acid [(HFPO-DA), GenX] is a member of the per- and polyfluoroalkyl substances (PFAS) chemical class, and elevated levels of HFPO-DA have been detected in surface water, air, and treated drinking water in the United States and Europe.Objectives:We aimed to characterize the potential maternal and postnatal toxicities of oral HFPO-DA in rats during sexual differentiation. Given that some PFAS activate peroxisome proliferator-activated receptors (PPARs), we sought to assess whether HFPO-DA affects androgen-dependent 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 days 14–18). We evaluated fetal testes, maternal and fetal livers, maternal serum clinical chemistry, and reproductive development of F1 animals.Results:HFPO-DA exposure resulted in 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 resulted in higher maternal liver weights (≥62.5mg/kg), lower maternal serum thyroid hormone and lipid profiles (≥30mg/kg), and up-regulated gene expression related to PPAR signaling pathways in maternal and fetal livers (≥1mg/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 that were similar to prior toxicity evaluations on PFAS, such as perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), but seen as the result of 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 an HFPO-DA manufacturing facility. Research is needed to examine the mechanisms and downstream events linked to the adverse effects of PFAS as are mixture-based studies evaluating multiple PFAS. https://doi.org/10.1289/EHP4372

Application of the Key Characteristics of Carcinogens to Per and Polyfluoroalkyl Substances

“…Consistent findings were observed following in utero exposure to PFOA [166]. Male reproductive toxicity, including effects on hormone levels and fertility was observed in PFNA treated mice [98] and gestational exposure to GenX and PFHxS resulted in lower testis weight and a weak but significant association with nipple retention in males, respectively [167,168].…”

“…Estrogenic activity was observed for PFOA, PFOS and PFHxS and antiandrogenic activity for PFHxS, PFOS, PFOA, PFNA and PFDA alone and in a mixture [181]. In another study, PFOA, PFOS, PFHxS, PFHxA, PFBS, PFBA, PMOH/GenX and PMPP/ADONA did not activate estrogen or androgen receptors at non-cytotoxic concentrations [182] and GenX, did not agonize or antagonize estrogen, androgen or glucocorticoid receptors in vitro [167]. PFOS exposure resulted in increased estradiol and decreased testosterone in in vitro steroidogenesis assays [183].…”

“…For example, most PFAS, but not fluorotelomers, bind thyroid hormone transport proteins such as transthyretin [188,189]. Exposure to PFOA and PFOS reduced T4 levels in adult rats as well as circulating T3 and T4 levels in pregnant dams and/or offspring exposed to PFOS, PFHxS, PFBS, and GenX [167,168,[190][191][192]. PFOA and PFHxA exposure also induced similar changes in T4, T3 and TSH in male rats [61].…”

“…Association: [61] Association: [175]; [188]; [189]; [179]; [180] No association: [182] PFBA Association: [175]; [189]; [179]; [180] No association: [182] PFPeA Association: [179]; [180] PFHpA Association: [188]; [189]; [179]; [180] GenX (HFPO-DA); PMOH Association: [167]; [171] Association: [178] No association: [182] PMPP/ADONA No association: [182] 4:2 FTOH Association: [175]; [185] 6:2 FTOH Association: [175]; [185] No association: [188] a The following long-chain PFAS are not presented in the table since no data were avaible to assess this key characteristic: PFOSA. b The following short-chain PFAS are not presented in the table since no data were avaible to assess this key characteristic: 4:2 diPAP, 6:2 diPAP.…”

Evaluation of Developmental Toxicity, Developmental Neurotoxicity, and Tissue Dose in Zebrafish Exposed to GenX and Other PFAS

“…From a developmental toxicity perspective, we and others have showed that exposure to sulfonic acid alkyl PFAS with at least five carbon atoms can cause developmental lethality and elicit conserved malformations at nonteratogenic concentrations consisting of swim bladder inflation failure and dorsoflexion of the tail (Hagenaars et al 2011;Huang et al 2010;Jantzen et al 2016;Padilla et al 2012;Truong et al 2014;Ulhaq et al 2013a). Similar to zebrafish, neonatal rodents exposed to PFOS die in the postnatal period (Conley et al 2019;Grasty et al 2005). Although humans do not have a swim bladder, the organ shares functional, structural, ontological, and transcriptional similarities with the human lung (Winata et al 2009).…”