Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
College of Life Sciences, Shanghai Normal University, Shanghai, 200234, China.
Chemosphere. 2020 Nov;259:127448. doi: 10.1016/j.chemosphere.2020.127448. Epub 2020 Jun 21.
Ivermectin (IVM), a broad-spectrum antiparasitic drug, is widely used in agriculture and animal husbandry. Due to widespread use and little metabolism in animals, the toxicity of IVM has received increasing attention. The accumulation of IVM in animal tissues and the excretion of urine and feces in the environment is the major source of potential toxicity. Human consumption of meat or milk contaminated with livestock can result in exposure to high levels of IVM exposure. The aim of this study was to reveal the cytotoxic mechanism of IVM in model cell HeLa in vitro, in order to provide a theoretical basis for the safe and rational use of IVM. Here we observed the γH2AX and 8-oxodG foci to detect the DNA damage in HeLa cells. As expected, we found that IVM can induce oxidative double-stranded damage in HeLa cells, indicating that IVM has potential genotoxicity to human health. In addition, we observed the formation of LC3-B in HeLa cells, the accumulation of Beclin1, the degradation of p62 and the activation of the AMPK/mTOR signal transduction pathway. This suggests that IVM confers cytotoxicity through autophagy mediated by the AMPK/mTOR signaling pathway. We conclude that IVM produces genotoxicity and cytotoxicity by inducing DNA damage and AMPK/mTOR-mediated autophagy, thereby posing a potential risk to human health.
伊维菌素（IVM）是一种广谱抗寄生虫药物，广泛应用于农业和畜牧业。由于在动物体内广泛使用且代谢较少，IVM 的毒性受到越来越多的关注。IVM 在动物组织中的积累以及在环境中随尿液和粪便的排泄，是其潜在毒性的主要来源。人类食用受牲畜污染的肉类或牛奶可能会导致摄入高水平的 IVM。本研究旨在揭示 IVM 在体外模型细胞 HeLa 中的细胞毒性机制，为 IVM 的安全合理使用提供理论依据。在这里，我们观察了γH2AX 和 8-oxodG 焦点，以检测 HeLa 细胞中的 DNA 损伤。正如预期的那样，我们发现 IVM 可以诱导 HeLa 细胞中的氧化双链损伤，表明 IVM 对人类健康具有潜在的遗传毒性。此外，我们观察到 HeLa 细胞中 LC3-B 的形成、Beclin1 的积累、p62 的降解以及 AMPK/mTOR 信号转导通路的激活。这表明 IVM 通过 AMPK/mTOR 信号通路介导的自噬产生细胞毒性。我们得出结论，IVM 通过诱导 DNA 损伤和 AMPK/mTOR 介导的自噬产生遗传毒性和细胞毒性，从而对人类健康构成潜在风险。
