Fetal and maternal liver expression post gestational exposure to perfluorooctanoic acid (PFOA) or hexafluoropropylene oxide-dimer acid (HFPO-DA or GenX) in CD-1 mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE199233 | GEO | 2022/11/29
REPOSITORIES: GEO
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Project description:Perfluoroalkyl substances (PFAS) are man-made chemicals with suspected endocrine-disrupting properties. Exposure to perfluorooctanoic acid (PFOA) has been linked to disturbed metabolism via the liver, although the exact mechanism is not clear. Moreover, information on the metabolic effects of the new PFAS alternative GenX is limited. We tested whether low-dose exposure to PFOA and GenX induces metabolic disturbances, including NAFLD, dyslipidemia, and glucose tolerance in mice and studied the involvement of PPARα. To this end, male C57BL/6J wildtype and PPARα−/− mice were given 0.05 or 0.3 mg/kg bw/day PFOA, or 0.3 mg/kg bw/day GenX next to a high-fat diet for 20 weeks. RNA sequencing was performed on liver, next to thorough assesment of metabolic parameters. RNA sequencing revealed that whereas the effects of GenX are entirely dependent on PPARα, effects of PFOA are mostly dependent on PPARα. In the absence of PPARα, the involvement of PXR/CAR becomes more prominent. Exposure to high-dose PFOA in mice decreased body weights and increased liver weights in wildtype and PPARα−/− mice. High-dose but not low-dose PFOA reduced plasma triglycerides and cholesterol, which for triglycerides, showed PPARα dependency. PFOA and GenX increased hepatic triglycerides in a PPARα-dependent manner. Overall, we show that long-term and low-dose exposure to PFOA and GenX disrupts lipid metabolism in mice. Whereas the effects of PFOA are mediated by multiple nuclear receptors, effects of GenX are entirely mediated by PPARα. Our data underscore the potential of PFAS to disrupt metabolism by altering signaling pathways in the liver.
2022-09-02 | GSE212294 | GEO
Project description:HFPO-DA (ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate; CASRN 62037-80-3; trade name “GenX”) is an alternative to environmentally persistent per- and poly-fluorinated alkyl substances (PFAS). The liver is the primary target of toxicity for HFPO-DA in rodents and previous examination of hepatic transcriptomic responses in mice following oral exposure to HFPO-DA for 90 days showed induction of peroxisome proliferator-activated receptor (PPAR) signaling pathways, predominantly by PPAR alpha, as well as increased gene expression of both peroxisomal and mitochondrial fatty acid metabolism. To further investigate the mechanism of liver toxicity, transcriptomic analysis was conducted on liver tissue from mice orally exposed to 0, 0.1, 0.5 or 5 mg/kg-bw/day HFPO-DA in a reproduction/developmental toxicity study. Hepatic gene expression changes were consistent with the previous 90-day mouse study, demonstrating activation of the PPAR alpha signaling pathway. Peroxisomal and mitochondrial fatty acid beta-oxidation gene sets were enriched at lower HFPO-DA concentrations, and complement cascade, cell cycle and apoptosis related gene sets were enriched at higher HFPO-DA concentrations. These results support the reported histopathological findings in livers of mice from this study and indicate that these effects are mediated through rodent-specific PPAR alpha signaling mechanisms.
2022-06-08 | GSE202302 | GEO
Project description: Not available
| S-EPMC7064328 | biostudies-literature
Project description:Like many per- or polyfluorinated alkyl substances (PFAS), toxicity studies with HFPO-DA (ammonium, 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate; CASRN 62037-80-3), a short-chain PFAS used in the manufacture of some types of fluorinated polymers, indicate that the liver is the primary target of toxicity in rodents following oral exposure. Although the current weight of evidence supports the PPARa mode of action (MOA) for liver effects in HFPO-DA-exposed mice, alternate MOAs have also been hypothesized including PPARg or cytotoxicity. To further evaluate the MOA for HFPO-DA in rodent liver, transcriptomic analyses were conducted on samples from primary mouse, rat and pooled human hepatocytes treated for 12, 24 or 72 hours with various concentrations of HFPO-DA, or established agonists of PPARa (GW7647), PPARg (rosiglitazone), or cytotoxic agents (i.e., acetaminophen or d-galactosamine). Concordance analyses of enriched pathways across chemicals within each species demonstrated greatest concordance between HFPO-DA and PPARa agonist GW7647-treated hepatocytes compared to the other chemicals evaluated. These findings were supported by benchmark concentration modeling and predicted upstream regulator results. In addition, transcriptomic analyses across species demonstrated a greater transcriptomic response in rodent hepatocytes treated with HFPO-DA or agonists of PPARa or PPARg, indicating rodent hepatocytes are more sensitive to HFPO-DA or PPARa/g agonist treatment. These results are consistent with previously published transcriptomic analyses and further support that liver effects in HFPO-DA-exposed rodents are mediated through rodent-specific PPARa signaling mechanisms as part of the MOA for PPARa activator-induced rodent hepatocarcinogenesis.
2024-04-30 | GSE248251 | GEO
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.
2022-06-17 | GSE206119 | GEO
Project description:Per- and polyfluoroalkyl substances (PFAS) are chemicals that are relatively resistant to degradation. While such features are desirable in a variety of consumer and industry products, such as firefighting foams and non-stick cookware coating, some PFAS, including perfluorooctanoic acid (PFOA), are toxic and bioaccumulate. Hexafluoropropylene oxide dimer acid (HFPO-DA) is an emerging PFAS developed to replace PFOA and has not been extensively studied. To evaluate the potential toxicity of HFPO-DA with a cost- and time-efficient approach, we exposed C. elegans larvae to 4×10-9–4 g/L HFPO-DA in liquid media and performed assays measuring developmental, behavioral, locomotor, and transcriptional effects at various exposure levels. After 48 hours of 1.5–4 g/L HFPO-DA exposure, acute developmental toxicity was observed as developmental delay; statistically significantly delayed (p < 0.05) progeny production was observed in worms exposed to 2–4 g/L HFPO-DA. After 48 hours of 4×10-9–0.4 g/L exposure, no significant behavioral or locomotor effect was observed relative to the 0 g/L control group. Statistically significant differential gene expression was identified with over 99% confidence via the R-package NOISeq in all fourteen 48-hour 1.25×10¬-5–4 g/L HFPO-DA exposure groups, except for 6.25×10¬-5 g/L. Among 10298 genes analyzed, 2624 differentially expressed genes (DEGs) were identified in the developmentally delayed 4 g/L group only, and 78 genes were differentially expressed in at least one of the thirteen exposure groups testing 1.25×10¬-5–2 g/L HFPO-DA exposures. Genes encoding for detoxification proteins such as cytochrome P450 enzymes and UDP glucuronosyltransferases are upregulated in 0.25–4 g/L acute exposure groups. In the lower exposure concentration groups, statistically significant gene expression changes were also observed, though these DEGs did not share any biological functions, except for six ribosomal protein-coding genes. While our transcriptional data is insufficient for conclusive mechanistic explanation, the statistically significant gene expression differences detected at 1.25×10¬-5 g/L, the lowest concentration tested for transcriptional changes, is concerning and calls for further targeted analyses that focus on low-dose HFPO-DA exposure effects.
2022-06-09 | GSE205582 | GEO
Project description:The objective of our study is to investigate the effect of PFOA and GenX on the gene expression levels in Monodelphis domestica whole blood cultures by RNA-seq and identify the major susceptible genes. We identified 578 differentially expressed genes (DEGs) in the PFOA treatment group and 148 DEGs in the GenX treatment group. 10 genes were selected for qRT-PCR validation and were confirmed to be DEGs. Pathway enrichment analysis revealed that several developmental processes were altered after PFOA exposure and showed an up-regulated pattern. And down-regulated DEGs after PFOA exposure were enriched for metabolic process and immune system process. GenX exposure is associated with up-regulated fatty acid transport pathways and inflammatory process. Our study is the first one to investigate the effects of PFASs on marsupial animals, providing supportive evidence of the similar transcriptomic alterations caused by PFOA and a fluorinated alternative GenX, which can work as a complement of the previous studies of PFASs effects on rodent or human.
2022-10-15 | GSE208237 | GEO
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.
2022-01-10 | GSE192589 | GEO
Project description: Not available
| S-EPMC7490830 | biostudies-literature
Project description: Not available
| S-EPMC8794304 | biostudies-literature