全氟烷基物质和多氟烷基物质 (PFAS)，例如全氟辛酸 (PFOA) 和全氟辛烷磺酸 (PFOS) 以及新的 PFAS 替代品全氟-2-甲基-3-氧己酸 (GenX)，是主要的环境污染物。在啮齿类动物中，这些 PFAS 会对肝脏产生多种不利影响，包括增殖增加、肝肿大、脂肪变性、高胆固醇血症、非酒精性脂肪肝和肝癌。 PFAS 激活过氧化物酶体增殖物受体 α 被认为是啮齿动物肝细胞诱导增殖的主要作用机制。然而，这种机制与人类的相关性尚不确定。我们使用 FRG 肝嵌合人源化小鼠（其肝脏重新填充了功能性人类肝细胞）研究了 PFAS 诱导的不良肝脏影响的人类相关机制。将雄性 FRG 人源化小鼠用饮用水中的 0.067 mg/L PFOA、0.145 mg/L PFOS 或 1 mg/L GenX 处理 28 天。 PFOS 导致血清总胆固醇和 LDL/VLDL 显着降低，而 GenX 导致 LDL/VLDL 显着升高，而总胆固醇和 HDL 没有变化。所有三种 PFAS 均诱导显着的肝细胞增殖。与人类基因组比对的 RNA 测序显示，在 PFOA、PFOS 和 GenX 暴露后，总共分别有 240、162 和 619 个差异表达基因。上游调节因子分析表明，所有三种 PFAS 都会诱导 p53 的激活以及雄激素受体和 NR1D1（一种在昼夜节律中重要的转录抑制因子）的抑制。进一步的生化研究证实了 NR1D1 的抑制作用，并且计算机模拟表明所有三种 PFAS 与 NR1D1 的 DNA 结合域存在潜在的相互作用。总之，我们使用 FRG 人源化小鼠的研究揭示了 PFAS 的新的人类相关分子机制，包括它们对昼夜节律的先前未知的影响。© 2024。作者获得 Springer-Verlag GmbH 德国（Springer 旗下公司）的独家许可自然。

Per- and polyfluoroalkyl substances (PFAS) such as perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) and perfluoro-2-methyl-3-oxahexanoic acid (GenX), the new replacement PFAS, are major environmental contaminants. In rodents, these PFAS induce several adverse effects on the liver, including increased proliferation, hepatomegaly, steatosis, hypercholesterolemia, nonalcoholic fatty liver disease and liver cancers. Activation of peroxisome proliferator receptor alpha by PFAS is considered the primary mechanism of action in rodent hepatocyte-induced proliferation. However, the human relevance of this mechanism is uncertain. We investigated human-relevant mechanisms of PFAS-induced adverse hepatic effects using FRG liver-chimeric humanized mice with livers repopulated with functional human hepatocytes. Male FRG humanized mice were treated with 0.067 mg/L of PFOA, 0.145 mg/L of PFOS, or 1 mg/L of GenX in drinking water for 28 days. PFOS caused a significant decrease in total serum cholesterol and LDL/VLDL, whereas GenX caused a significant elevation in LDL/VLDL with no change in total cholesterol and HDL. All three PFAS induced significant hepatocyte proliferation. RNA-sequencing with alignment to the human genome showed a total of 240, 162, and 619 differentially expressed genes after PFOA, PFOS, and GenX exposure, respectively. Upstream regulator analysis revealed that all three PFAS induced activation of p53 and inhibition of androgen receptor and NR1D1, a transcriptional repressor important in circadian rhythm. Further biochemical studies confirmed NR1D1 inhibition and in silico modeling indicated potential interaction of all three PFAS with the DNA-binding domain of NR1D1. In conclusion, our studies using FRG humanized mice have revealed new human-relevant molecular mechanisms of PFAS including their previously unknown effect on circadian rhythm.© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.