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Developmental toxicity of Nafion byproduct 2 (NBP2) in the Sprague-Dawley rat

ABSTRACT: 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.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE192589 | GEO | 2022/01/10

REPOSITORIES: GEO

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Project description:Per- and polyfluoroalkyl substances (PFAS) are persistent pollutants known for their bio-accumulative properties and prevalence in water supplies and household products. Although legacy PFAS, such as perfluorooctanoic acid, are phased out in the U.S. due to public health concerns, a PFAS variant hexafluoropropylene oxide-dimer acid (HFPO-DA) is an emerging replacement. HFPO-DA is a potential neurotoxicant that has been shown to cause dopaminergic neurodegeneration. We investigated the bioaccumulative potential of HFPO-DA and its effects on lifespan, locomotor activity, and brain gene expression in female and male Drosophila melanogaster (fruit flies). Flies were collected less than 4 hours post-eclosion and exposed to 0, 10, 10^2, 10^3, or 10^4 mg/kg/day HFPO-DA. To measure the effect of HFPO-DA on lifespan, surviving flies from each exposure were recorded every 24 hours. Flies were subjected to a negative geotaxis assay at 3, 7, and 14 days of exposure to measure the effects of acute, sub-chronic, and chronic exposures on locomotor ability. To capture HFPO-DA-induced sexually dimorphic gene expression responses in the brain, we sequenced brain-specific mRNA from flies exposed for 3, 7, or 14 days. The Bioconcentration Factor was 0.031 for females, and 0.026 for males. Dose and median lifespan were negatively correlated in both female (R^2 adj = 0.77, p<0.0001) and male flies (R^2 adj = 0.77, p<0.0001). Log-rank Mantel-Cox tests and one-way ANOVAs revealed that median lifespan was reduced in females starting at 10 mg/kg/day and in males starting at 10^2 mg/kg/day (p< 0.01). Acute exposure at 10 mg/kg/day significantly decreased locomotor ability in females (p<0.0001) while acute exposures at 1 mg/kg/day decreased locomotor activity in males (p <0.0001). Among 7500 genes analyzed, pairwise gene expression comparison between controls and treatments identified 2496 differentially expressed genes. While HFPO-DA does not readily bioaccumulate in fruit fly bodies, high-dose exposures have sex-specific effects on lifespan, locomotor ability, and brain gene expression. LOAEL for median lifespan is 10 mg/kg/day in females, and 10^2 mg/kg/day in males. Both locomotor ability and brain gene expression exhibited non-conventional dose-response as seen in other endocrine disrupting chemical exposures.

Project description:Perfluorooctanesulfonate (PFOS) is a widespread environmental pollutant with a long half-life and clearly negative outcomes on metabolic diseases such as fatty liver and diabetes. Male and female Cyp2b-null and humanized CYP2B6-transgenic (hCYP2B6-Tg) mice were treated with 0, 1, or 10 mg/kg/day PFOS for 21 days, and surprisingly it was found that PFOS was retained at greater concentrations in the serum and liver of hCYP2B6-Tg mice than Cyp2b-null mice with greater differences in the females. Thus, Cyp2b-null and hCYP2B6-Tg mice provide new models for investigating individual mechanisms for PFOS bioaccumulation and toxicity. Overt toxicity was greater in hCYP2B6-Tg mice (especially females) as measured by mortality; however, steato-sis occurred more readily in Cyp2b-null mice despite the lower PFOS liver concentrations. Tar-geted lipidomics and transcriptomics from PFOS treated Cyp2b-null and hCYP2B6-Tg mouse livers were performed and compared to PFOS retention and serum markers of toxicity by PCA. Several oxylipins, including prostaglandins, thromboxanes, and docosahexaenoic acid metabo-lites are associated or inversely associated with PFOS toxicity. Both lipidomics and tran-scriptomics indicate PFOS toxicity is associated with PPAR activity in all models. GO terms as-sociated with reduced steatosis were sexually dimorphic with lipid metabolism and transport increased in females and circadian rhythm associated genes increased in males. However, we can rule out that steatosis was initially protective from PFOS toxicity. Moreover, several transporters are associated with increased retention probably due to increased uptake. The strongest associa-tions are the organic anion transport proteins (Oatp1a4-6) genes and a long-chain fatty acid transport protein (fatp1), enriched in female hCYP2B6-Tg mice. PFOS uptake was also reduced in cultured murine hepatocytes by OATP inhibitors. The role of OATP1A6 and FATP1 in PFOS transport has not been tested. In summary, Cyp2b-null and hCYP2B6-Tg mice provided unique models for estimating the importance of novel mechanisms in PFOS retention and toxicity.

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Project description:Perfluorooctane sulfonate (PFOS) is a perfluoroalkyl acid (PFAA) and a persistent environmental contaminant found in the tissues of humans and wildlife. Although blood levels of PFOS have begun to decline, health concerns remain because of the long half-life of PFOS in humans. Like other PFAAs, such as perfluorooctanoic acid (PFOA), PFOS is an activator of peroxisome proliferator-activated receptor-alpha (PPARα) and exhibits hepatocarcinogenic potential in rodents. PFOS is also a developmental toxicant in rodents where, unlike PFOA, it’s mode of action is independent of PPARα. Wild-type (WT) and PPARα-null (Null) mice were dosed with 0, 3, or 10 mg/kg/day PFOS for 7 days. Animals were euthanized, livers weighed, and liver samples collected for histology and preparation of total RNA. Gene profiling was conducted using Affymetrix 430_2 microarrays. In WT mice, PFOS induced changes that were characteristic of PPARα transactivation including regulation of genes associated with lipid metabolism, peroxisome biogenesis, proteasome activation, and inflammation. PPARα-independent changes were indicated in both WT and Null mice by altered expression of genes related to lipid metabolism, inflammation, and xenobiotic metabolism. Such results are similar to prior studies done with PFOA and are consistent with modest activation of the constitutive androstane receptor (CAR) and possibly PPARγ and/or PPARβ/δ. Unique treatment-related effects were also found in Null mice including altered expression of genes associated with ribosome biogenesis, oxidative phosphorylation and cholesterol biosynthesis. Of interest was up-regulation of Cyp7a1, a gene which is under the control of various transcription regulators. Hence, in addition to its ability to modestly activate PPARα, PFOS induces a variety of “off-target” effects as well. PPARalpha-null and wild-type male mice at 6-9 months of age were dosed by gavage for 7 consecutive days with either 0, 3, or 10 mg/kg PFOS (potassium salt) in 0.5% Tween 20. Five biological replicates consisting of individual animals were included in each dosage group. Data were compared to results previously published by our group for PFOA and Wy-14,643, a commonly used agonist of PPARalpha (Rosen et al., Toxicol Pathol. 36:592-607, 2008; GSE9796)

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Developmental toxicity of Nafion byproduct 2 (NBP2) in the Sprague-Dawley rat

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