ROS generation and DNA damage contribute to abamectin-induced cytotoxicity in mouse macrophage cells
ROS generation and DNA damage contribute to abamectin-induced cytotoxicity in mouse macrophage cells
复制标题
ROS 的产生和 DNA 损伤导致阿维菌素诱导小鼠巨噬细胞的细胞毒性
DOI：
10.1016/j.chemosphere.2019.06.031
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发表时间：
2019-11-01
期刊：
影响因子：
8.8
通讯作者：
Hu, Jiye
中科院分区：
文献类型：
--
作者：
Liang, Yiran;Dong, Bizhang;Hu, Jiye
阿维菌素的广泛使用最近引起了安全性问题，因为阿维菌素对非靶生物产生了各种毒性。然而，阿维菌素诱导的毒性的潜在机制在很大程度上仍然未知。本研究旨在探讨阿维菌素对小鼠巨噬细胞（RAW 264. 7）的细胞毒作用及其机制。阿维菌素处理引起氧化应激，其特征在于ROS指示剂的强度增加。即使在相对较低的剂量（NOAEL）下，阿维菌素也会导致DNA损伤，表现为细胞中8-OHdG/dG比值增加。用过氧化氢酶-PEG预处理，ROS抑制剂，减弱阿维菌素诱导的DNA损伤，表明ROS的过度产生可能是阿维菌素诱导的DNA损伤的原因。结果表明，阿维菌素可诱导RAW 264. 7细胞CAT、SOD、GPx酶的表达和活性以及GSH水平（ROS清除）发生浓度依赖性变化，但对NOX、线粒体复合物I和III的表达和活性（ROS产生）影响有限。因此，阿维菌素对ROS清除的影响可能是阿维菌素诱导RAW264.7细胞氧化应激的主要原因。阿维菌素处理激活MAPK和ATM/ATR信号通路，如JNK、ATM和ATR磷酸化增加所示。此外，抑制JNK和ATM/ATR信号通路部分挽救了细胞活力的下降，表明阿维菌素诱导的ROS过度产生和DNA损伤可能最终通过JNK和ATM/ATR信号通路导致细胞毒性。这些发现将有助于更全面地评估阿维菌素的毒性效应。(C)2019爱思唯尔有限公司版权所有。
The widespread use of abamectin has recently raised safety concerns as abamectin has yielded various toxicities to non-target organisms. However, the underlying mechanisms of abamectin-induced toxicity are still largely unknown. The present study aimed to investigate the abamectin-induced cytotoxicity in mouse macrophage cells (RAW264.7) and its underlying mechanisms. Abamectin treatment caused oxidative stress as characterized by increased intensity of the ROS indicator. Abamectin also led to DNA damage as demonstrated by increased 8-OHdG/dG ratio in cells even at a relatively low dose (NOAEL). Pretreatment with catalase-PEG, a ROS inhibitor, attenuated abamectin-induced DNA damage, indicating that ROS overproduction should be the reason for abamectin-induced DNA damage. The effects of abamectin on ROS elimination and generation were also investigated, and the results showed that abamectin induced concentration-dependent alteration in the expression and activities of CAT, SOD, GPx enzymes and GSH level (ROS elimination), but had limited effects on the expression and activities of NOX, mitochondrial complex I and III (ROS production) in RAW264.7 cells. Therefore, the effects of abamectin on ROS elimination should be the main reason for abamectin-induced oxidative stress in RAW264.7 cells. Abamectin treatment activated MAPK and ATM/ATR signaling pathways as demonstrated by increased phosphorylation of JNK, ATM and ATR. In addition, inhibiting JNK and ATM/ATR signaling pathways partially rescued the decrease in cell viability, indicating that abamectin-induced ROS overproduction and DNA damage might finally lead to cytotoxicity through JNK and ATM/ATR signaling pathways. These findings should be useful for the more comprehensive assessment of the toxic effects of abamectin. (C) 2019 Elsevier Ltd. All rights reserved.