Gestational GenX Exposure Induces Maternal Hepatotoxicity by Disrupting the Lipid and Bile Acid Metabolism Distinguished from PFOA-Induced Pyroptosis

作者：Jin-Jin Zhang, Yu-Kui Chen, Yaqi Chen, Qin-Yao Zhang, Yu Liu, Qi Wang, Xiao‐Li Xie · 发表于：Toxics · 年份：2025 · DOI：10.3390/toxics13080617 · 被引用次数：6 · 研究领域：Per- and polyfluoroalkyl substances research、Birth, Development, and Health、Heme Oxygenase-1 and Carbon Monoxide

Perfluorooctanoic acid (PFOA) and its replacement, GenX, are per- and polyfluoroalkyl substances (PFASs) widely used in industrial and consumer applications. Pregnant women are a vulnerable population to environmental pollutants. The maternal effects of GenX and PFOA exposure during pregnancy have not been fully elucidated. In this study, pregnant mice received daily oral doses of GenX (2 mg/kg/day), PFOA (1 mg/kg/day), or Milli-Q water (control) throughout gestation. Histopathological analyses revealed significant liver abnormalities in both exposure groups, including hepatocyte swelling, cellular disarray, eosinophilic degeneration, karyopyknosis, lipid vacuolation, and increased inflammatory responses. Through transcriptomics analyses, it was found that multiple metabolic and inflammatory pathways were enriched in both exposure groups. In the GenX group, overexpression of CYP4A, c-Myc, and Oatp2 proteins and decreased expression of EGFR and β-catenin in the liver suggested disruption of lipid and bile acid metabolism. In the PFOA group, significantly upregulated protein levels of NLRP3, GSDMD, caspase-1, IL-18, and IL-1β indicated hepatic pyroptosis. Despite these distinct pathways, both compounds triggered inflammatory cytokine release in the liver, consistent with the results of the transcriptomics analysis, suggesting shared mechanisms of inflammatory liver injury. Taken together, our findings provided novel insights into the hepatotoxicity mechanisms of GenX and PFOA e...