College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China.
College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China; Department of Veterinary Medicine, Heze Vocational College, Heze 274031, China.
Sci Total Environ. 2024 Apr 20;922:171234. doi: 10.1016/j.scitotenv.2024.171234. Epub 2024 Feb 29.
As a ubiquitous pollutant in the environment, hexafluoropropylene oxide trimer acid (HFPO-TA) has been proven to have strong hepatotoxicity. However, the underlying mechanism is still unclear. Consequently, in vivo and in vitro models of HFPO-TA exposure were established to investigate the detrimental effects of HFPO-TA on the liver. In vivo, we discovered that HFPO-TA enhanced endoplasmic reticulum (ER)-mitochondrial association, caused mitochondrial oxidative damage, activated ER stress, and induced apoptosis in mouse livers. In vitro experiments confirmed that IP3R overexpression on ER structure increased mitochondrial calcium levels, which led to mitochondrial damage and mitochondria-dependent apoptosis in HepG2 cells exposed to HFPO-TA. Subsequently, damaged mitochondria released a large amount of mitochondrial ROS, which activated ER stress and ER stress-dependent apoptosis. In conclusion, this study demonstrates that HFPO-TA can induce apoptosis by regulating the crosstalk between ER and mitochondria, ultimately leading to liver damage. These findings reveal the significant hepatotoxicity of HFPO-TA and its potential mechanisms.
六氟环氧丙烷三氟化物（HFPO-TA）作为环境中普遍存在的污染物，已被证明具有很强的肝毒性。然而，其潜在的作用机制尚不清楚。因此，本研究建立了 HFPO-TA 暴露的体内和体外模型，以研究 HFPO-TA 对肝脏的有害影响。在体内，我们发现 HFPO-TA 增强了内质网（ER）-线粒体的关联，导致线粒体氧化损伤，激活了 ER 应激，并诱导了小鼠肝脏细胞凋亡。体外实验证实，内质网结构上的 IP3R 过度表达增加了线粒体钙水平，导致暴露于 HFPO-TA 的 HepG2 细胞发生线粒体损伤和线粒体依赖性凋亡。随后，受损的线粒体释放大量的线粒体 ROS，激活了 ER 应激和 ER 应激依赖性凋亡。总之，本研究表明 HFPO-TA 可以通过调节 ER 和线粒体之间的串扰诱导细胞凋亡，最终导致肝脏损伤。这些发现揭示了 HFPO-TA 的显著肝毒性及其潜在机制。
