Dataset Information

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

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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:Production of PFAS has shifted from the most-studied PFAS, longer-chain perfluorinated alkyl acids, to shorter-chain or other alternative moieties including fluoroethers like HFPO-DA (“GenX chemicals”), Nafion Byproducts, and the PFOx homologous series that includes PFO4DA and PFO5DoA. In contaminated study areas, the fluoroethers PFO4DA and PFO5DoA, although detected at relatively low levels in surface water, have been detected in serum and/or tissues with high frequency in humans, wildlife including fish and alligators, and pets including horses. Although these compounds have been detected, there are extremely limited toxicity data available and no developmental toxicology studies that could be used to inform risk assessment or regulatory actions. To address these data gaps, Sprague-Dawley rat dams were exposed via oral gavage from GD18-22 to PFO4DA or PFO5DoA across a series of doses ranging from 0.1 to 62.5 mg/kg/day and, in conjunction with apical measures of toxicity, hepatic transcriptomics in both dam and offspring and serum metabolomics in dams were performed. Differential expression analysis was performed for transcriptomics and metabolomics, and pathway analysis, including a multi-omic integrative analysis, was performed. For PFO5DoA, overt toxicity (substantial body weight loss, fetal mortality) was observed at the highest dose, so data only include up to 30 mg/kg/day. Dimensionality reduction measures including principal components analysis and heatmaps revealed strong separation of clustering between maternal and fetal samples and between chemicals (PFO4DA vs PFO5DoA). Both dams and fetuses exhibited dose-responsive patterns of hepatic gene expression in response to PFO4DA or PFO5DoA. Of the 14,928 genes included in differential expression analysis, PFO4DA exposure in dams resulted in a maximum of 367 differentially expressed genes (DEG) at the highest dose (62.5 mg/kg/d) whereas PFO5DoA resulted in 4,506 DEG at the highest dose (30 mg/kg/d). Even at 10 mg/kg/d, PFO5DoA resulted in 1,915 DEG in dam liver. Fetuses were more affected at lower doses, but the pattern was similar, with PFO4DA resulting in 1,378 DEG at 62.5 mg/kg/d and PFO5DoA 3,653 DEG at 30 mg/kg/d. Several DEG were changed by every dose of PFO5DoA (≥ 0.3 mg/kg/d) in both maternal and fetal samples, including multiple acyl-coA thioesterases (Acot1, Acot2, Acot3, Acot4) and related enzymes that hydrolyze acyl-coA to free fatty acids, as well as Vnn1, a corticosteroid-responsive gene. Hallmark and Reactome pathway analyses of fetal and maternal livers revealed remarkable changes in metabolism of bile acids and salts, fatty acid metabolism, metabolism of lipids and lipoproteins, PPARα activation of gene expression, and phospholipid metabolism. In maternal serum metabolomics, PFO4DA did not result in significant changes at doses up to 62.5 mg/kg/d. In contrast, PFO5DoA exposure resulted in differential metabolite abundance for 149 unique metabolites, with 4 significantly altered at 0.3 mg/kg, 31 metabolites at 1 mg/kg, 51 at 3 mg/kg, 58 at 10mg/kg, and 119 at 30 mg/kg/d. Multi-omics KEGG and Reactome pathway analyses of integrated maternal liver transcriptomics and serum metabolomics revealed significant convergent pathway-level changes as low as 3 mg/kg/d PFO4DA and 0.3 mg/kg/d PFO5DoA exposure. Notable multi-omics pathway level changes include fatty acid metabolism at all doses of PFO5DoA and at PFO4DA ≥ 10 mg/kg/d, with PFO4DA changes driven by the magnitude of transcriptomic changes and low/null detection of metabolites. Striking pathway-level changes identified for hepatic transcriptome and serum metabolome in exposed dams included metabolism, metabolism of lipids, hemostasis, signaling by G-protein coupled receptors (GPCRs), neuronal system, immune and innate immune system, PPARα activation of gene expression, and regulation of lipid metabolism by PPARα. The transcriptomic and metabolomic effects of PFO4DA and PFO5DoA appear consistent with other carboxylic acid PFAS, with primary changes related to lipid metabolism, bile acids, cholesterol, and cellular stress. Although PFO4DA and PFO5DoA are structurally similar, separated by only a CF2O, the potency of transcriptomic and metabolomic effects of developmental exposure to each was significantly different, with 5-day exposure to PFO5DoA causing changes in glucose and lipid metabolism and stress signals at much lower doses than PFO4DA in both dams (~ 35-fold more potent at inducing hepatic DEG) and fetuses (~ 11.6-fold more potent at inducing hepatic DEG). Although it is likely that some differences in toxicity between PFO4DA and PFO5DoA are caused by accumulation differences resulting in different dosimetry, PFO5DoA demonstrated much greater transcriptomic and metabolomic toxicity at equivalent oral doses.

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.

Dataset Information

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

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets