Hexafluoropropylene oxide tetramer acid (HFPO-TeA)-induced developmental toxicities in chicken embryo: Peroxisome proliferator-activated receptor Alpha (PPARα) is involved

Dong, Qixuan; Guo, Yajie; Yuan, Junhua; Zhong, Shuping; Ni, Hao; Liu, Jingyi; Zhang, Mengzhen; Sun, Jiaqi; Yuan, Shuping; Yu, Huan; Zhong, Yuxu; Jiang, Qixiao

doi:10.1016/j.ecoenv.2023.114671

Cited by 6 publications

(6 citation statements)

References 60 publications

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“…Hepatic steatosis is the first response to numerous chronic liver diseases such as liver inflammation, fibrosis, and cancer . It was found that exposure of chicken embryos to hexafluoropropylene oxide tetramer acid caused developmental hepatic steatosis, whereas PPARα deficiency alleviated hepatic steatosis . In the present study, we found that GenX exposure could lead to hepatic lipid accumulation and steatosis by Oil Red O staining.…”

Section: Discussionsupporting

confidence: 90%

“…44 It was found that exposure of chicken embryos to hexafluoropropylene oxide tetramer acid caused developmental hepatic steatosis, whereas PPARα deficiency alleviated hepatic steatosis. 45 In the present study, we found that GenX exposure could lead to hepatic lipid accumulation and steatosis by Oil Red O staining. In addition, Bodipy staining showed that the formation of lipid droplets is less than GenX group after the addition of PPARα inhibitor.…”

Section: Discussionsupporting

confidence: 53%

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GenX Disturbs the Indicators of Hepatic Lipid Metabolism Even at Environmental Concentration in Drinking Water via PPARα Signaling Pathways

Shi,

Zhang,

et al. 2023

Chem. Res. Toxicol.

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Hexafluoropropylene oxide dimer acid (HFPO−DA; trade name GenX), as a substitute for perfluorooctanoic acid (PFOA), has been attracting increasing attention. However, its impact and corresponding mechanism on hepatic lipid metabolism are less understood. To investigate the possible mechanisms of GenX for hepatotoxicity, a series of in vivo and in vitro experiments were conducted. In in vivo experiment, male mice were exposed to GenX in drinking water at environmental concentrations (0.1 and 10 μg/L) and high concentrations (1 and 100 mg/L) for 14 weeks. In in vitro experiments, human hepatocellular carcinoma cells (HepG2) were exposed to GenX at 10, 160, and 640 μM for 24 and 48 h. GenX exposure via drinking water resulted in liver damage and disruption of lipid metabolism even at environmental concentrations. The results of triglycerides (TG) and total cholesterol (TC) in this study converged with the results of the population study, for which TG increased in the liver but unchanged in the serum, whereas TC increased in both liver and serum concentrations. KEGG and GO analyses revealed that the hepatotoxicity of GenX was associated with fatty acid transport, synthesis, and oxidation pathways and that Peroxisome Proliferator-Activated Receptor (PPARα) contributed significantly to this process. PPARα inhibitors significantly reduced the expression of CD36, CPT1β, PPARα, SLC27A1, ACOX1, lipid droplets, and TC, suggesting that GenX exerts its toxic effects through PPARα signaling pathway. In general, GenX at environmental concentrations in drinking water causes abnormal lipid metabolism via PPARα signaling pathway.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 53%

GenX Disturbs the Indicators of Hepatic Lipid Metabolism Even at Environmental Concentration in Drinking Water via PPARα Signaling Pathways

Shi,

Zhang,

et al. 2023

Chem. Res. Toxicol.

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“…Sun et al reported cardiotoxicity in zebrafish embryos following exposure to HFPO-TA [ 29 ]. The homologue HFPO-TeA has been associated with hepatic, cardiac, and developmental toxicity in chicken hatchlings [ 30 ]. Multiple forms of liver damage, including liver enlargement, lipid droplet accumulation, and steatosis, were observed in mice orally exposed to 1 mg/kg/day of HFPO-TeA over four weeks [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Many PFAS, including PFOA and the three HFPO-TeA homologues, are known to perturb the PPARα signaling pathway [ 28 , 30 , 38 ]. The PPARα nuclear receptor, which is highly expressed in the liver, heart, and kidney, regulates fatty acid metabolism and peroxisome proliferation [ 30 , 31 ]. Disruptions of this pathway have been implicated in several downstream adverse animal health outcomes, including developmental toxicities, altered lipid and glucose metabolism, decreased plasma thyroid hormone levels, and changes in liver weight [ 26 , 27 , 28 , 29 ].…”

Section: Introductionmentioning

confidence: 99%

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Dose Response, Dosimetric, and Metabolic Evaluations of Replacement PFAS Perfluoro-(2,5,8-trimethyl-3,6,9-trioxadodecanoic) Acid (HFPO-TeA)

Renyer,

Ravindra,

Wetmore

et al. 2023

Toxics

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Few studies are available on the environmental and toxicological effects of perfluoroalkyl ether carboxylic acids (PFECAs), such as GenX, which are replacing legacy PFAS in manufacturing processes. To collect initial data on the toxicity and toxicokinetics of a longer-chain PFECA, male and female Sprague Dawley rats were exposed to perfluoro-(2,5,8-trimethyl-3,6,9-trioxadodecanoic) acid (HFPO-TeA) by oral gavage for five days over multiple dose levels (0.3–335.2 mg/kg/day). Clinically, we observed mortality at doses >17 mg/kg/day and body weight changes at doses ≤17 mg/kg/day. For the 17 mg/kg/day dose level, T3 and T4 thyroid hormone concentrations were significantly decreased (p < 0.05) from controls and HFPO-TeA plasma concentrations were significantly different between sexes. Non-targeted analysis of plasma and in vitro hepatocyte assay extractions revealed the presence of another GenX oligomer, perfluoro-(2,5-dimethyl-3,6-dioxanonanoic) acid (HFPO-TA). In vitro to in vivo extrapolation (IVIVE) parameterized with in vitro toxicokinetic data predicted steady-state blood concentrations that were within seven-fold of those observed in the in vivo study, demonstrating reasonable predictivity. The evidence of thyroid hormone dysregulation, sex-based differences in clinical results and dosimetry, and IVIVE predictions presented here suggest that the replacement PFECA HFPO-TeA induces a complex and toxic exposure response in rodents.

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Developmental 6:2 FTCA exposure impairs renal development in chicken embryos via IGF signaling

Feng,

Tan,

Zhong

et al. 2024

Ecotoxicology and Environmental Safety

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Hexafluoropropylene oxide tetramer acid (HFPO-TeA)-induced developmental toxicities in chicken embryo: Peroxisome proliferator-activated receptor Alpha (PPARα) is involved

Cited by 6 publications

References 60 publications

GenX Disturbs the Indicators of Hepatic Lipid Metabolism Even at Environmental Concentration in Drinking Water via PPARα Signaling Pathways

GenX Disturbs the Indicators of Hepatic Lipid Metabolism Even at Environmental Concentration in Drinking Water via PPARα Signaling Pathways

Dose Response, Dosimetric, and Metabolic Evaluations of Replacement PFAS Perfluoro-(2,5,8-trimethyl-3,6,9-trioxadodecanoic) Acid (HFPO-TeA)

Developmental 6:2 FTCA exposure impairs renal development in chicken embryos via IGF signaling

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