Emerging evidence supports ambient fine particulate matter (PM2.5) exposure is associated with insulin resistance (IR) and hepatic lipid accumulation. In this study, we aimed to evaluate the sex-dependent vulnerability in response to PM2.5 exposure and investigate the underlying mechanism by which PM2.5 modulates hepatic lipid metabolism. Both male and female C57BL/6 mice were randomly assigned to ambient PM2.5 or filtered air for 24 weeks via a whole body exposure system. High-coverage quantitative lipidomics approaches and liquid chromatography-mass spectrometry techniques were performed to measure hepatic metabolites and hormones in plasma. Metabolic studies, histological analyses, as well as gene expression levels and molecular signal transduction analysis were applied to examine the effects and mechanisms by which PM2.5 exposure-induced metabolic disorder. Female mice were more susceptible than their male counterparts to ambient PM2.5 exposure-induced IR and hepatic lipid accumulation. The hepatic lipid profile was changed in response to ambient PM2.5 exposure. Levels of hepatic triacylglycerols (TAGs), free fatty acids (FFAs) and cholesterol were only increased in female mice from PM group compared to control group. Plasmalogens were dysregulated in the liver from PM2.5-exposed mice as well. In addition, exposure to PM2.5 led to enhanced hepatic ApoB and microsomal triglyceride transport protein expression in female mice. Finally, PM2.5 exposure inhibited hypothalamus-pituitary-adrenal (HPA) axis and decreased glucocorticoids levels, which may contribute to the vulnerability in PM2.5-induced metabolic dysfunction. Ambient PM2.5 exposure inhibited HPA axis and demonstrated sex-associated differences in its effects on IR and disorder of hepatic lipid metabolism. These findings provide new mechanistic evidence of hormone regulation in air pollution-mediated metabolic abnormalities of lipids and more personalized care should be considered in terms of sex-specific risk factors.

中文翻译：

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周围PM2.5污染对小鼠胰岛素敏感性和肝脂质代谢的性别依赖性影响。

越来越多的证据支持环境细颗粒物（PM2.5）暴露与胰岛素抵抗（IR）和肝脂质蓄积有关。在这项研究中，我们旨在评估应对PM2.5暴露的性别依赖性脆弱性，并研究PM2.5调节肝脂质代谢的潜在机制。通过全身暴露系统，将雄性和雌性C57BL / 6小鼠随机分配到环境PM2.5或过滤空气中，持续24周。进行了高覆盖率定量脂质组学方法和液相色谱-质谱分析技术来测量血浆中的肝代谢产物和激素。进行了代谢研究，组织学分析以及基因表达水平和分子信号转导分析，以检查PM2的作用和机制。5暴露引起的代谢紊乱。雌性小鼠比雄性小鼠更易受周围PM2.5暴露诱导的IR和肝脂质蓄积的影响。肝脂质谱随环境PM2.5暴露而变化。与对照组相比，PM组的雌性小鼠仅增加了肝脏三酰甘油（TAGs），游离脂肪酸（FFA）和胆固醇的水平。暴露于PM2.5的小鼠肝脏中的血浆致病菌也失调。此外，暴露于PM2.5导致雌性小鼠肝ApoB和微粒体甘油三酸酯转运蛋白表达增强。最后，暴露于PM2.5会抑制下丘脑-垂体-肾上腺（HPA）轴并降低糖皮质激素水平，这可能是PM2.5引起的代谢功能障碍的原因。环境PM2。5暴露抑制HPA轴，并证明其对IR和肝脂质代谢紊乱的影响具有性别相关差异。这些发现为空气污染介导的脂质代谢异常中激素调节的新机制提供了证据，应根据性别特异性危险因素考虑更多的个性化护理。