College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Harbin 150030, China.
College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Harbin 150030, China.
Sci Total Environ. 2023 Sep 10;890:164172. doi: 10.1016/j.scitotenv.2023.164172. Epub 2023 May 16.
Arsenic (As) is a well-known pollutant in the environment, whose contamination in groundwater is a serious threat to animals and humans. Ferroptosis, a form of cell death caused by iron-dependent lipid peroxidation, is involved in various pathological processes. Ferritinophagy is the selective autophagy of ferritin and a crucial step in the induction of ferroptosis. However, the mechanism of ferritinophagy in poultry livers exposed to As remains unexplored. In this study, we investigated whether As-induced chicken liver injury is related to ferritinophagy-mediated ferroptosis at the cellular and animal levels. Our results showed that As exposure via drinking water induced hepatotoxicity in chickens, characterized by abnormal liver morphology and elevated liver function markers. Our data suggested chronic As exposure led to mitochondrial dysfunction, oxidative stress, and impaired cellular processes in chicken livers and LMH cells. Our results also showed that As exposure activated the AMPK/mTOR/ULK1 signaling pathway and significantly changed the levels of ferroptosis and autophagy-related proteins in chicken livers and LMH cells. Moreover, As exposure induced iron overload and lipid peroxidation in chicken livers and LMH cells. Interestingly, pretreatment with ferrostatin-1, chloroquine (CQ), and deferiprone alleviated these aberrant effects. Using CQ, we found that As-induced ferroptosis is autophagy-dependent. Our findings further suggested chronic As exposure induced chicken liver injury by promoting ferritinophagy-mediated ferroptosis, as evidence by activated autophagy, decreased mRNA expression of FTH1, increased intracellular iron content, and alleviation of ferroptosis through pretreatment with CQ. In conclusion, ferritinophagy-mediated ferroptosis is one of the critical mechanisms of As-induced chicken liver injury. Inhibiting ferroptosis may provide new insights for preventing and treating liver injury induced by environmental As exposure in livestock and poultry.
砷（As）是环境中一种众所周知的污染物，其对地下水的污染对动物和人类构成了严重威胁。铁死亡是一种由铁依赖性脂质过氧化引起的细胞死亡形式，涉及多种病理过程。自噬是铁蛋白选择性自噬，是诱导铁死亡的关键步骤。然而，砷暴露下禽类肝脏中铁蛋白自噬的机制仍不清楚。在这项研究中，我们研究了砷诱导的鸡肝脏损伤是否与细胞和动物水平的铁蛋白自噬介导的铁死亡有关。结果表明，通过饮水暴露于砷会导致鸡肝脏毒性，表现为肝脏形态异常和肝功能标志物升高。我们的数据表明，慢性砷暴露会导致鸡肝脏和 LMH 细胞中线粒体功能障碍、氧化应激和细胞过程受损。结果还表明，砷暴露激活了 AMPK/mTOR/ULK1 信号通路，并显著改变了鸡肝脏和 LMH 细胞中与铁死亡和自噬相关的蛋白质水平。此外，砷暴露会导致鸡肝脏和 LMH 细胞中铁过载和脂质过氧化。有趣的是，用铁抑素-1、氯喹（CQ）和去铁酮预处理可以减轻这些异常作用。使用 CQ，我们发现砷诱导的铁死亡是自噬依赖性的。我们的研究结果进一步表明，慢性砷暴露通过促进铁蛋白自噬介导的铁死亡诱导鸡肝脏损伤，这可以通过激活自噬、FTH1mRNA 表达降低、细胞内铁含量增加以及用 CQ 预处理减轻铁死亡来证明。总之，铁蛋白自噬介导的铁死亡是砷诱导鸡肝脏损伤的关键机制之一。抑制铁死亡可能为预防和治疗家畜和家禽环境砷暴露引起的肝脏损伤提供新的思路。
