全氟辛酸
脂肪变性
过氧化物酶体
脂质代谢
全氟辛烷
化学
脂肪肝
生物信息学
生物化学
内科学
医学
疾病
基因
有机化学
磺酸盐
钠
作者
Yang Wang,Ling Xi,Shijun He,Haonan Cui,Zeyu Yang,Huihui An,Lihong Wang,Peng Zou,Qing Chen,Jinyi Liu,Lin Ao,Jia Cao
标识
DOI:10.1016/j.envint.2023.108138
摘要
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.This study aimed to explore PFAS-to-NAFLD link and the relevant molecular mechanisms.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.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.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.
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