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Hepatic Transcriptomic Responses in Pregnant and Non-pregnant Rats Exposed to HFPO-DA: Analyses to Inform the Role of Maternal Effects on Neonatal Toxicity

ABSTRACT: Like other per- and polyfluoroalkyl substances (PFAS), toxicity studies for short-chain HFPO-DA (ammonium, 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate) indicate the liver is the primary target of toxicity in rodents. However, neonatal mortality and decreased birth weight were also reported in rats following oral exposure to HFPO-DA in utero. Exposure-related effects in neonatal rats including hypoglycemia, decreased liver glycogen, and perturbed hepatic gene expression of glucose metabolism and peroxisome proliferator activated receptor (PPAR) pathways also accompanied these findings. A putative rodent-specific adverse outcome pathway (AOP) network was recently developed using these endpoints and assessed for its applicability to PFAS. AOP 1 in this putative AOP network consists of PPARα activation as one of multiple initiating events, and placental insufficiency, neonatal hepatic glycogen deficit, and hypoglycemia as key events leading to neonatal mortality and lower birth weight. To further inform AOP 1 of this putative AOP network and investigate whether this altered carbohydrate metabolism liver phenotype observed in rat neonates also occurs in HFPO-DA-exposed pregnant and non-pregnant adult rats, transcriptomic analysis and glycogen staining were performed on female rat livers from a 15-d developmental or 90-d subchronic toxicity study. HFPO-DA-mediated changes in hepatic gene expression in female rats were consistent with PPAR signaling. Changes in hepatic glycogen content and glucose metabolism-related gene expression were independent of HFPO-DA exposure, indicating that the altered carbohydrate metabolism phenotype observed in neonatal livers does not occur in adult female rats, regardless of pregnancy status. Therefore, key events in this AOP for neonatal mortality and lower birthweight are likely to directly affect the perinatal rat and are not expected to affect the maternal rat liver. Findings from this study were consistent with previous mechanistic studies supporting the rodent-specific PPARα mode of action for HFPO-DA-mediated liver effects in rodents.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE291412 | GEO | 2026/03/11

REPOSITORIES: GEO

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Project description:Nafion byproduct 2 (NBP2; CAS: 749836-20-2; Product #: 6164-3-3J; Lot: 512400; SynQuest Laboratories Alachua, FL, USA) is a polyfluoroalkyl ether sulfonic acid that was recently detected in surface water, drinking water, and human serum samples from monitoring studies in North Carolina, USA. We orally exposed pregnant Sprague-Dawley rats to NBP2 from gestation day (GD) 14–18 (0.1–30 mg/kg/d), GD17-21, and GD8 to postnatal day (PND) 2 (0.3–30 mg/kg/d) to characterize maternal, fetal, and postnatal effects. GD14-18 exposures were also conducted with perfluorooctane sulfonate (PFOS) for comparison to NBP2, as well as data previously published for hexafluoropropylene oxide-dimer acid (HFPO-DA or GenX). NBP2 produced stillbirth (30 mg/kg), reduced pup survival shortly after birth (10 mg/kg), and reduced pup body weight (10 mg/kg). Histopathological evaluation identified reduced glycogen stores in newborn pup livers and hepatocyte hypertrophy in maternal livers at ≥ 10 mg/kg. Exposure to NBP2 from GD14-18 reduced maternal serum total T3 and cholesterol concentrations (30 mg/kg). Maternal, fetal, and neonatal liver gene expression was investigated using RT-qPCR pathway arrays, while maternal and fetal livers were also analyzed using TempO-Seq transcriptomic profiling. Overall, there was limited alteration of genes in maternal or F1 livers from NBP2 exposure with significant changes mostly occurring in the top dose group (30 mg/kg) associated with lipid and carbohydrate metabolism. Metabolomic profiling indicated elevated maternal bile acids for NBP2, but not HFPO-DA or PFOS, while all three reduced 3-indolepropionic acid. Maternal and fetal serum and liver NBP2 concentrations were similar to PFOS, but ∼10–30-fold greater than HFPO-DA concentrations at a given maternal oral dose. NBP2 is a developmental toxicant in the rat, producing neonatal mortality, reduced pup body weight, reduced pup liver glycogen, reduced maternal thyroid hormones, and altered maternal and offspring lipid and carbohydrate metabolism similar to other studied PFAS, with oral toxicity for pup loss that is slightly less potent than PFOS but more potent than HFPO-DA.

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Hepatic Transcriptomic Responses in Pregnant and Non-pregnant Rats Exposed to HFPO-DA: Analyses to Inform the Role of Maternal Effects on Neonatal Toxicity

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