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Targeted RNA-Seq analysis of the livers of male mice treated with the perfluorinated alkyl substance PFESA-BP2 (Nafion byproduct 2)

ABSTRACT: The perfluorinated alkyl substance PFESA-BP2 (1,1,2,2-tetrafluoro-2-[1,1,1,2,3,3-hexafluoro-3-(1,1,2,2-tetrafluoroethoxy)propan-2-yl]oxyethane-1-sulfonic acid; also known as nafion BP2) has been detected in the blood of people living in the North Carolina Cape Fear River basin downstream of an industrial manufacturing facility. Given that almost nothing is known about the potential toxicity of PFESA-BP2 and safe exposure levels have not yet been determined, we performed a benchmark dose analysis of phenotypic and genomic effects. Male mice were exposed to PFESA-BP2 at 0, 0.03, 0.3, 3, and 6 mg/kg-day each day for 7 days by oral gavage. Transcript profiling showed that PFESA-BP2 activates a number of transcription factors linked to liver toxicity including constitutive activated/androstane receptor, pregnane X receptor, and Nrf2, but unlike other long-chain PFAS, there was only weak activation of peroxisome proliferator-activated receptor α. Steatosis was coincident with activation of sterol response element binding proteins as well as increases in the expression of the very low density lipoprotein receptor.

ORGANISM(S): Mus musculus

PROVIDER: GSE147331 | GEO | 2022/12/01

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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Targeted RNA-Seq analysis of the livers of male mice treated with the perfluorinated alkyl substance PFESA-BP2 (Nafion byproduct 2)

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