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, Fe²⁺ 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.

中文翻译：

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1,3-二氯-2-丙醇通过 Nrf2/ARE 信号通路诱导肝细胞铁死亡

1,3-二氯-2-丙醇 (1,3-DCP) 是具有多种毒性的具有代表性的氯丙烷环境污染物。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 Fe ^{2+的积累密切相关}和活性氧（ROS）。在本研究中，我们发现 1,3-DCP 可通过铁死亡诱导小鼠肝损伤。C57BL/6J小鼠经口灌胃给予12.5、25和50 mg/kg 1,3-DCP 4周，数据显示1,3-DCP暴露导致小鼠肝脏发生病理变化，显着诱导蓄积丙二醛 (MDA) 和铁含量降低，谷胱甘肽 (GSH) 减少，铁死亡标记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，我们还用 HepG2 细胞在体外证明了结果。数据显示，1,3-DCP 处理在体外显着引发了铁死亡。此外，我们发现在暴露于 1,3-DCP 的小鼠肝脏和 HepG2 细胞中，铁死亡相关的信号通路被显着激活。数据显示，1,3-DCP 通过抑制核因子红细胞 2 相关因子 2 (Nrf2) 易位进入细胞核，从而抑制其下游靶蛋白包括 GPX4、铁蛋白重链 (FTH)、铁转运蛋白 (FPN) 的表达来诱导铁死亡。 )、胱氨酸/谷氨酸转运蛋白 xCT (SLC7A11) 和血红素加氧酶 1 (HO-1)。总之，我们的研究结果证实，1,3-DCP 通过肝细胞中的 Nrf2/ARE 信号通路诱导铁死亡。我们的工作提供了 1,3-DCP 与铁死亡对肝细胞损伤的新毒性机制。