Abstract

Background:

Perfluorooctane sulfonate (PFOS) is a persistent organic pollutant that can cause hepatotoxicity. The underlying toxicological mechanism remains to be investigated. Given the critical role of fecal microbiota in liver function, it is possible that fecal microbiota may contribute to the liver toxicity induced by PFOS.

Objectives:

We aimed to investigate the role of liver-fecal microbiota axis in modulating PFOS-induced liver injury in mice.

Methods:

Male and female mice were exposed to PFOS or vehicle for 14 d. In this investigation, 16S rDNA sequencing and metabolomic profiling were performed to identify the perturbed fecal microbiota and altered metabolites with PFOS exposure. In addition, antibiotic treatment, fecal microbiota transplantation, and bacterial administration were conducted to validate the causal role of fecal microbiota in mediating PFOS-induced liver injury and explore the potential underlying mechanisms.

Results:

Both male and female mice exposed to PFOS exhibited liver inflammation and steatosis, which were accompanied by fecal microbiota dysbiosis and the disturbance of amino acid metabolism in comparison with control groups. The hepatic lesions were fecal microbiota-dependent, as supported by antibiotic treatment and fecal microbiota transplantation. Mice with altered fecal microbiota in antibiotic treatment or fecal microbiota transplantation experiments exhibited altered arginine concentrations in the liver and feces. Notably, we observed sex-specific lower levels of key microbiota, including Lactobacillus, Enterococcus, and Akkermansia. Mice treated with specific bacteria showed lower arginine levels and lower expression of the phosphorylated mTOR and P70S6K, suggesting lower activity of the related pathway and mitigation of the pathological differences observed in PFOS-exposed mice.

Conclusions:

Our study demonstrated the critical role of the fecal microbiota in PFOS-induced liver injury in mice. We also identified several critical bacteria that could protect against liver injury induced by PFOS in male and female mice. Our present research provided novel insights into the mechanism of PFOS-induced liver injury in mice. https://doi.org/10.1289/EHP10281

中文翻译：

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粪便微生物群在全氟辛烷磺酸诱导雄性和雌性小鼠肝毒性中的作用

摘要

背景：

全氟辛烷磺酸 (PFOS) 是一种持久性有机污染物，可引起肝毒性。潜在的毒理学机制仍有待研究。鉴于粪便微生物群在肝功能中的关键作用，粪便微生物群可能有助于全氟辛烷磺酸引起的肝毒性。

目标：

我们旨在研究肝脏-粪便微生物群轴在调节 PFOS 诱导的小鼠肝损伤中的作用。

方法：

雄性和雌性小鼠暴露于 PFOS 或载体 14 天。在这项调查中，进行了 16S rDNA 测序和代谢组学分析，以识别受到 PFOS 暴露的粪便微生物群和代谢物的改变。此外，还进行了抗生素治疗、粪便微生物群移植和细菌管理，以验证粪便微生物群在介导 PFOS 诱导的肝损伤中的因果作用，并探索潜在的潜在机制。

结果：

与对照组相比，暴露于 PFOS 的雄性和雌性小鼠均表现出肝脏炎症和脂肪变性，并伴有粪便微生物群失调和氨基酸代谢紊乱。在抗生素治疗和粪便微生物群移植的支持下，肝脏病变是粪便微生物群依赖性的。在抗生素治疗或粪便微生物群移植实验中具有改变的粪便微生物群的小鼠表现出肝脏和粪便中精氨酸浓度的改变。值得注意的是，我们观察到关键微生物群的性别特异性较低水平，包括乳酸杆菌、肠球菌和阿克曼氏菌. 用特定细菌处理的小鼠显示出较低的精氨酸水平和较低的磷酸化 mTOR 和 P70S6K 表达，表明相关途径的活性较低，并减轻了在 PFOS 暴露小鼠中观察到的病理差异。

结论：

我们的研究证明了粪便微生物群在 PFOS 诱导的小鼠肝损伤中的关键作用。我们还发现了几种关键细菌，它们可以保护雄性和雌性小鼠免受 PFOS 引起的肝损伤。我们目前的研究为全氟辛烷磺酸诱导的小鼠肝损伤机制提供了新的见解。https://doi.org/10.1289/EHP10281