Exposure to low-dose perfluorooctanoic acid promotes hepatic steatosis and disrupts the hepatic transcriptome in mice

Attema, Brecht; Janssen, Aafke W. F.; Rijkers, Deborah; Schothorst, Evert M. van; Hooiveld, Guido; Kersten, Sander

doi:10.1016/j.molmet.2022.101602

Cited by 45 publications

(38 citation statements)

References 91 publications

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“…Moreover, this study found that both TC and TG were elevated in the liver after GenX exposure, as confirmed by previously published literature. , But changes in TG and TC in plasma were not consistent, with no change in TG and an increase in TC with increasing GenX dose. Interestingly, our study was broadly similar to the population study, which found that serum TC was proportional but not linearly related to GenX concentration, whereas TG was not correlated with GenX concentration …”

Section: Discussionsupporting

confidence: 88%

“…Probably the experimental gradients used in our experiments span a wide range, and the substance may have different toxic effects at different concentration doses. GenX, as an alternative to PFOA, may have similar toxic effects to PFOA, and previous studies have shown that there is no linear relationship between the liver damage of PFOA at different concentration gradients . There are many substances that may indeed cause different toxic effects at different concentrations.…”

Section: Discussionmentioning

confidence: 99%

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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: 88%

Section: Discussionmentioning

confidence: 99%

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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“…Following Trp degradation, a portion of Kyn is ultimately converted to NAD through the 3-HAA pathway, while another fraction is converted to KA. , As an important site for Kyn pathway, the liver is responsible for 90% of Trp degradation under normal physiological conditions. , Previous study has confirmed that increase of KATs expression in skeletal muscle can be induced by selective PPARα agonists only under PGC-1α overexpression . In mice liver, although HFPO-DA can activate PPARα, ,, it results in down-regulation of PGC-1α mRNA levels, which may explain the decreased KATs expression and reduced KA observed in HFPO-DA treated mice in this study. In addition, studies by Gonzalez and Yue et al have revealed that Wy-14,643, a selective PPARα agonist, only disturbs the nicotinamide-NAD pathway and not the Kyn pathway, − suggesting that the effect of HFPO-DA on the hepatic Kyn pathway may not be not a consequence of PPAR activation.…”

Section: Discussionmentioning

confidence: 96%

Kynurenic Acid Plays a Protective Role in Hepatotoxicity Induced by HFPO-DA in Male Mice

Hu,

Dai,

Sheng

2024

Environ. Sci. Technol.

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Following its introduction as an alternative to perfluorooctanoic acid, hexafluoropropylene oxide dimer acid (HFPO-DA) has been extensively detected in various environmental matrices. Despite this prevalence, limited information is available regarding its hepatotoxicity biomarkers. In this study, toxicokinetic simulations indicated that under repeated treatment, HFPO-DA in mice serum reached a steady state by the 4th day. To assess its subacute hepatic effects and identify potential biomarkers, mice were administered HFPO-DA orally at doses of 0, 0.1, 0.5, 2.5, 12.5, or 62.5 mg/kg/d for 7 d. Results revealed that the lowest observed adverse effect levels were 0.5 mg/kg/d for hepatomegaly and 2.5 mg/kg/d for hepatic injury. Serum metabolomics analysis identified 34, 58, and 118 differential metabolites in the 0.1, 0.5, and 2.5 mg/kg/d groups, respectively, compared to the control group. Based on weighted gene coexpression network analysis, eight potential hepatotoxicity-related metabolites were identified; among them, kynurenic acid (KA) in mouse serum exhibited the highest correlation with liver injury. Furthermore, liver-targeted metabolomics analysis demonstrated that HFPO-DA exposure induced metabolic migration of the kynurenine pathway from KA to nicotinamide adenine dinucleotide, resulting in the activation of endoplasmic reticulum stress and the nuclear factor kappa-B signaling pathway. Notably, pretreatment with KA significantly attenuated liver injury induced by HFPO-DA exposure in mice, highlighting the pivotal roles of KA in the hepatotoxicity of HFPO-DA.

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“…11 Most PFAS hepatic toxicity is thought to be mediated by PPARα, since PPARα knockout in mice reduces the outcomes of PFOS and GenX (an alternative PFAS substance). 12 In our previous study, through in vitro binding assays, we found that perfluoroalkyl carboxylates (PFCAs) and perfluoroalkyl sulfonates (PFSAs) with various numbers of perfluorinated carbons directly bind to human PPARα and that a variety of PFAS may induce adverse effects through PPARα in humans. 13 To screen for PFAS that induce adverse effects via PPARα, it is necessary to determine the binding affinities between PPARα and various PFAS.…”

Section: Introductionmentioning

confidence: 99%

“…As PFAS are organofluorine analogs of fatty acids (the endogenous ligand for PPARα), binding and activation of PPARα is a logical molecular-initiating event in lipid destruction . Most PFAS hepatic toxicity is thought to be mediated by PPARα, since PPARα knockout in mice reduces the outcomes of PFOS and GenX (an alternative PFAS substance) . In our previous study, through in vitro binding assays, we found that perfluoroalkyl carboxylates (PFCAs) and perfluoroalkyl sulfonates (PFSAs) with various numbers of perfluorinated carbons directly bind to human PPARα and that a variety of PFAS may induce adverse effects through PPARα in humans …”

Section: Introductionmentioning

confidence: 99%

Elucidating Key Characteristics of PFAS Binding to Human Peroxisome Proliferator-Activated Receptor Alpha: An Explainable Machine Learning Approach

Maeda,

Hirano,

Hayashi

et al. 2023

Environ. Sci. Technol.

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Per- and polyfluoroalkyl substances (PFAS) are widely employed anthropogenic fluorinated chemicals known to disrupt hepatic lipid metabolism by binding to human peroxisome proliferator-activated receptor alpha (PPARα). Therefore, screening for PFAS that bind to PPARα is of critical importance. Machine learning approaches are promising techniques for rapid screening of PFAS. However, traditional machine learning approaches lack interpretability, posing challenges in investigating the relationship between molecular descriptors and PPARα binding. In this study, we aimed to develop a novel, explainable machine learning approach to rapidly screen for PFAS that bind to PPARα. We calculated the PPARα–PFAS binding score and 206 molecular descriptors for PFAS. Through systematic and objective selection of important molecular descriptors, we developed a machine learning model with good predictive performance using only three descriptors. The molecular size (b_single) and electrostatic properties (BCUT_PEOE_3 and PEOE_VSA_PPOS) are important for PPARα-PFAS binding. Alternative PFAS are considered safer than their legacy predecessors. However, we found that alternative PFAS with many carbon atoms and ether groups exhibited a higher affinity for PPARα. Therefore, confirming the toxicity of these alternative PFAS compounds with such characteristics through biological experiments is important.

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Exposure to low-dose perfluorooctanoic acid promotes hepatic steatosis and disrupts the hepatic transcriptome in mice

Cited by 45 publications

References 91 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

Kynurenic Acid Plays a Protective Role in Hepatotoxicity Induced by HFPO-DA in Male Mice

Elucidating Key Characteristics of PFAS Binding to Human Peroxisome Proliferator-Activated Receptor Alpha: An Explainable Machine Learning Approach

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