Short-chain chlorinated paraffins (SCCPs) are pervasive organic pollutants recognized for their persistence and bio-toxicity. This study investigated the hepatotoxic mechanisms of SCCPs at environmentally relevant concentration (0.7 μg/kg). The results showed that SCCPs exposure in mice resulted in dysregulated blood and liver lipids, marked by elevated cholesterol levels. Additionally, liver function was compromised, as indicated by increased levels of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. Histopathological examination of liver tissue post-SCCPs exposure revealed hepatocyte enlargement, vacuolar degeneration, and mild ballooning degeneration. Mechanistically, SCCPs induced mitochondrial abnormalities, evidenced by heightened Hoechst 33258 fluorescence, and augmented reactive oxygen species and malondialdehyde levels in liver tissue. This was accompanied by a reduction in total antioxidant capacity, culminating in elevated apoptosis markers, including cytochrome C and caspase-3. Moreover, SCCPs perturbed hepatocellular energy metabolism, characterized by increased glycolysis, lactic acid, and fatty acid oxidation, alongside a disruption in the tricarboxylic acid cycle and a decline in mitochondrial energy metabolic function. Furthermore, SCCPs exposure downregulated the expression of genes involved in bile acid synthesis (cyp27a1, fxr, and shp), thereby precipitating the cholesterol-bile acid metabolism disorders and cholesterol accumulation. Collectively, these findings underscore that SCCPs, even at environmentally relevant levels, can induce lipid dysregulation, mitochondrial disorders and cholesterol deposition in the hepatocytes, contributing to liver damage. The study’s insights contribute to a comprehension of SCCPs-induced hepatotoxicity and may inform potential preventative and treatment targets for hepatic damage associated with SCCPs exposure.

中文翻译：

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短链氯化石蜡通过线粒体疾病和破坏胆固醇-胆汁酸途径诱导小鼠肝损伤


短链氯化石蜡 （SCCP） 是普遍存在的有机污染物，因其持久性和生物毒性而得到认可。本研究探讨了环境相关浓度 （0.7 μg/kg） 下 SCCPs 的肝毒性机制。结果表明，小鼠暴露于 SCCPs 导致血液和肝脂失调，以胆固醇水平升高为特征。此外，肝功能受损，如天冬氨酸氨基转移酶、丙氨酸氨基转移酶和碱性磷酸酶水平升高所示。SCCPs 暴露后肝组织的组织病理学检查显示肝细胞增大、空泡变性和轻度气球样变性。从机制上讲，SCCP 诱导线粒体异常，Hoechst 33258 荧光增强以及肝组织中活性氧和丙二醛水平增加证明了这一点。这伴随着总抗氧化能力的降低，最终导致细胞凋亡标志物升高，包括细胞色素 C 和 caspase-3。此外，SCCP 扰乱了肝细胞能量代谢，其特征是糖酵解、乳酸和脂肪酸氧化增加，同时三羧酸循环中断和线粒体能量代谢功能下降。此外，SCCPs 暴露下调了参与胆汁酸合成的基因 （cyp27a1 、 fxr 和 shp） 的表达，从而促进了胆固醇-胆汁酸代谢紊乱和胆固醇积累。总的来说，这些发现强调 SCCPs，即使在环境相关水平上，也会诱导肝细胞中的脂质失调、线粒体疾病和胆固醇沉积，从而导致肝损伤。 该研究的见解有助于理解 SCCPs 诱导的肝毒性，并可能为与 SCCPs 暴露相关的肝损伤的潜在预防和治疗目标提供信息。