Yang Renjun, Yin Nuoya, Faiola Francesco
State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China.
State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China.
J Hazard Mater. 2025 Jul 15;492:138112. doi: 10.1016/j.jhazmat.2025.138112. Epub 2025 Apr 4.
Perfluorooctanoic acid and perfluorooctane sulfonate are well-known eight-carbon per- and polyfluoroalkyl substances (8C-PFAS) potentially toxic for the human liver. However, direct experimental evidence demonstrating their toxicity on the human liver remains limited. Consequently, this study aimed to extrapolate the 8C-PFAS liver toxicity mechanisms by leveraging omics data to integrate mouse and human findings. Through integration analyses of nine datasets (one human, six murine, and two rat), we identified 199 genes with known biological functions that are commonly affected by 8C-PFAS across species. We delineated a comprehensive regulatory network of 8C-PFAS toxicity, demonstrating that 8C-PFAS may trigger fatty liver disease by up-regulating CD36 and PPARα pathway; dysregulate xenobiotic metabolism by disrupting CAR and CYP family genes; and induce cancer by dysregulating WNT, TGFβ, FGF21, and P53 pathways. We also identified ATF3, EGR1, ESR1, NFATC4, SNAI2, TP53, and EZH2 as transcriptionally regulated by 8C-PFAS, along with PPARα, RXRα, FGFR1, TCF3, and SMAD3 as potentially functionally impacted. Collectively, these factors account for over 90 % of 8C-PFAS-affected key genes. This study not only developed a novel method for extrapolating human toxicity risks by integrating scattered toxicity evidence based on transcriptomics data, but also proposes new mechanisms by which 8C-PFAS contributes to fatty liver disease and cancer.
全氟辛酸和全氟辛烷磺酸是众所周知的具有八个碳原子的全氟和多氟烷基物质（8C-PFAS），可能对人类肝脏有毒性。然而，证明它们对人类肝脏毒性的直接实验证据仍然有限。因此，本研究旨在通过利用组学数据整合小鼠和人类的研究结果，推断8C-PFAS的肝脏毒性机制。通过对九个数据集（一个人类、六个小鼠和两个大鼠数据集）的整合分析，我们确定了199个具有已知生物学功能的基因，这些基因在不同物种中普遍受到8C-PFAS的影响。我们描绘了一个全面的8C-PFAS毒性调控网络，表明8C-PFAS可能通过上调CD36和PPARα途径引发脂肪肝疾病；通过破坏CAR和CYP家族基因来失调外源性物质代谢；并通过失调WNT、TGFβ、FGF21和P53途径诱导癌症。我们还确定了ATF3、EGR1、ESR1、NFATC4、SNAI2、TP53和EZH2受8C-PFAS转录调控，以及PPARα、RXRα、FGFR1、TCF3和SMAD3可能在功能上受到影响。总的来说，这些因素占8C-PFAS影响的关键基因的90%以上。本研究不仅开发了一种通过整合基于转录组学数据的分散毒性证据来推断人类毒性风险的新方法，还提出了8C-PFAS导致脂肪肝疾病和癌症的新机制。
