2,3,7,8-四氯二苯并对二恶英(TCDD)是一种持久性环境污染物,可破坏肝功能,导致脂肪变性肝病(SLD)样病理,比如脂肪变性,脂肪性肝炎,和纤维化。这些作用是由基因表达变化后的芳烃受体介导的。尽管涉及多种细胞类型,基因表达的初始细胞特异性变化尚未报道。在这项研究中,在接受30µg/kgTCDD的雄性C57BL/6小鼠中,使用单核RNA测序检查了肝细胞类型中的差异基因表达。确定了十种肝细胞类型,大多数细胞类型的比例保持不变,除了嗜中性粒细胞在72小时时增加。基因表达表明TCDD诱导的与肝细胞中氧化应激相关的基因早在2小时。巨噬细胞,B细胞,T细胞,以诱导与脂质转运相关的基因为特征,类固醇激素生物合成,和β-氧化的抑制,而亚油酸代谢在肝星状细胞(HSC)中发生改变,B细胞,门静脉成纤维细胞,和浆细胞样树突状细胞。促纤维化过程也得到了丰富,包括HSC中的诱导视黄醇代谢基因和肝细胞中抗纤维化基因的早期诱导,内皮细胞,HSC,和巨噬细胞。肝细胞也有与肝细胞癌一致的基因表达变化。总的来说,这些发现强调了TCDD在启动SLD样表型中的作用,并确定了与氧化应激相关的细胞特异性基因表达变化,脂肪变性,纤维化,细胞增殖和肝癌的发展。
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant that disrupts hepatic function leading to steatotic liver disease (SLD)-like pathologies, such as steatosis, steatohepatitis, and fibrosis. These effects are mediated by the aryl hydrocarbon receptor following changes in gene expression. Although diverse cell types are involved, initial cell-specific changes in gene expression have not been reported. In this study, differential gene expression in hepatic cell types was examined in male C57BL/6 mice gavaged with 30 µg/kg of TCDD using single-nuclei RNA-sequencing. Ten liver cell types were identified with the proportions of most cell types remaining unchanged, except for neutrophils which increased at 72 h. Gene expression suggests TCDD induced genes related to oxidative stress in hepatocytes as early as 2 h. Lipid homeostasis was disrupted in hepatocytes, macrophages, B cells, and T cells, characterized by the induction of genes associated with lipid transport, steroid hormone biosynthesis, and the suppression of β-oxidation, while linoleic acid metabolism was altered in hepatic stellate cells (HSCs), B cells, portal fibroblasts, and plasmacytoid dendritic cells. Pro-fibrogenic processes were also enriched, including the induction retinol metabolism genes in HSCs and the early induction of anti-fibrolysis genes in hepatocytes, endothelial cells, HSCs, and macrophages. Hepatocytes also had gene expression changes consistent with hepatocellular carcinoma. Collectively, these findings underscore the effects of TCDD in initiating SLD-like phenotypes and identified cell-specific gene expression changes related to oxidative stress, steatosis, fibrosis, cell proliferation and the development of HCC.