College of Food Science and Engineering, Jilin University, Changchun, People's Republic of China.
Key Laboratory of Zoonosis, Ministry of Education College of Veterinary Medicine, Jilin University, Changchun, People's Republic of China.
Environ Toxicol. 2022 Oct;37(10):2515-2528. doi: 10.1002/tox.23615. Epub 2022 Jul 23.
1,3-Dichloro-2-propanol (1,3-DCP) is a representative chloropropane environmental contaminant with multiple toxicities. Ferroptosis is a novel iron-dependent form of regulated cell death that is closely associated with the accumulation of lipid peroxides, Fe and reactive oxygen species (ROS). In this study, we found that 1,3-DCP could induce mouse liver injury via ferroptosis. Administrating of C57BL/6J mice with 12.5, 25, and 50 mg/kg 1,3-DCP for 4 weeks via oral gavage, the data showed that 1,3-DCP exposure led to the pathological changes in mouse livers, remarkably induced accumulation of malondialdehyde (MDA) and Iron, reduction of glutathione (GSH), and changed in the expression of ferroptosis marker proteins glutathione peroxidase 4 (GPX4) and acyl-CoA synthetase-4 (ACSL4). Then, we also proved the results with HepG2 cells in vitro. The data showed that treatment 1,3-DCP significantly triggered the ferroptosis in vitro. Furthermore, we found that the ferroptosis-related signal pathways were significantly activated in mice livers and HepG2 cells in response to 1,3-DCP exposure. The data showed that 1,3-DCP induced ferroptosis by inhibiting nuclear factor erythroid 2-related factor 2 (Nrf2) translocation into nuclear and thereby suppressing the expression of its downstream target proteins including GPX4, ferritin heavy chain (FTH), ferroportin (FPN), cystine/glutamate transporter xCT (SLC7A11), and heme oxygenase 1 (HO-1). Taken together, our findings confirmed that 1,3-DCP induced ferroptosis via the Nrf2/ARE signaling pathway in hepatocytes. Our works provide new toxicity mechanisms of 1,3-DCP with ferroptosis on hepatocytes injury.
1,3-二氯-2-丙醇（1,3-DCP）是一种具有多种毒性的代表性氯丙烷环境污染物。铁死亡是一种新型的铁依赖性调节细胞死亡形式，与脂质过氧化物、铁和活性氧（ROS）的积累密切相关。在这项研究中，我们发现 1,3-DCP 可以通过铁死亡诱导小鼠肝损伤。通过口服灌胃给予 C57BL/6J 小鼠 12.5、25 和 50mg/kg 的 1,3-DCP 4 周，数据显示 1,3-DCP 暴露导致小鼠肝脏发生病变，显著诱导丙二醛（MDA）和铁的积累，谷胱甘肽（GSH）减少，铁死亡标志物蛋白谷胱甘肽过氧化物酶 4（GPX4）和酰基辅酶 A 合成酶 4（ACSL4）的表达发生变化。然后，我们还在体外用 HepG2 细胞证明了这一结果。数据显示，1,3-DCP 处理显著触发了体外铁死亡。此外，我们发现 1,3-DCP 暴露后，小鼠肝脏和 HepG2 细胞中的铁死亡相关信号通路明显被激活。数据显示，1,3-DCP 通过抑制核因子红细胞 2 相关因子 2（Nrf2）向核内转位，从而抑制其下游靶蛋白包括 GPX4、铁蛋白重链（FTH）、亚铁转运蛋白（FPN）、胱氨酸/谷氨酸转运蛋白 xCT（SLC7A11）和血红素加氧酶 1（HO-1）的表达，诱导铁死亡。总之，我们的研究结果证实，1,3-DCP 通过 Nrf2/ARE 信号通路在肝细胞中诱导铁死亡。我们的工作为 1,3-DCP 引起肝细胞损伤的铁死亡提供了新的毒性机制。
