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PPARα/ACOX1 as a novel target for hepatic lipid metabolism disorders induced by per- and polyfluoroalkyl substances: An integrated approach
- Source :
- Environment International, Vol 178, Iss , Pp 108138- (2023)
- Publication Year :
- 2023
- Publisher :
- Elsevier, 2023.
-
Abstract
- Background: Per- and polyfluoroalkyl substances (PFAS) are persistent and ubiquitous environmental contaminants with well-documented hepatotoxicity. However, the mechanistic linkage between PFAS exposure and non-alcoholic fatty liver disease (NAFLD) remains largely elusive. Objectives: This study aimed to explore PFAS-to-NAFLD link and the relevant molecular mechanisms. Methods: The cross-sectional analyses using National Health and Nutrition Examination Survey (NHANES) data were conducted to investigate the association between PFAS exposure and NAFLD. A combination of in silico toxicological analyses, bioinformatics approaches, animal experiments, and in vitro assays was used to explore the molecular initiating events (MIEs) and key events (KEs) in PFAS-induced hepatic lipid metabolism disorders. Results: The cross-sectional analyses with NHANES data revealed the significant association between PFAS exposure and hepatic steatosis/NAFLD. The in silico toxicological analyses showed that PPARα activation induced by perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS), prototypical representatives of PFAS, is the critical MIE associated with NAFLD-predominant liver diseases. Transcriptome-based bioinformatic annotation and analyses identified that transcriptional upregulation of hepatic acyl-CoA oxidase 1 (ACOX1) in PPARα-regulated peroxisomal β-oxidation pathway was the KE involved with PFOA/PFOS-perturbed hepatic lipid metabolic pathways in humans, mice and rats. The in vivo and in vitro assays further verified that ACOX1-mediated oxidative stress contributed to mitochondrial compromise and lipid accumulation in PFOA/PFOS-exposed mouse hepatocytes, which could be mitigated by co-treatment with ACOX1 inhibitor and mitochondria ROS scavenger. Additionally, we observed that besides PFOA and PFOS, hepatic ACOX1 exhibited good-fit response to short-term exposures of long-chain (C7-C10) perfluoroalkyl carboxylic acids (PFHpA, PFNA, PFDA) and perfluoroalkyl sulfonic acids (PFHpS, PFDS) in human hepatocyte spheroids through benchmark dose (BMD) modeling. Conclusion: Our study unveils a novel molecular target for PFAS-induced hepatic lipid metabolic disorders, shedding new light on prediction, assessment, and mitigation of PFAS hepatotoxicity.
- Subjects :
- Environmental sciences
GE1-350
Subjects
Details
- Language :
- English
- ISSN :
- 01604120
- Volume :
- 178
- Issue :
- 108138-
- Database :
- Directory of Open Access Journals
- Journal :
- Environment International
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.0857c45d2fe544548b5a719982f3b51b
- Document Type :
- article
- Full Text :
- https://doi.org/10.1016/j.envint.2023.108138