College of Chemistry Biological Engineering, University of Science and Technology Beijing, Beijing, 100083, PR China.
College of Chemistry Biological Engineering, University of Science and Technology Beijing, Beijing, 100083, PR China.
Chemosphere. 2019 Nov;234:328-337. doi: 10.1016/j.chemosphere.2019.06.031. Epub 2019 Jun 5.
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.
阿维菌素的广泛使用引起了人们对其安全性的关注，因为阿维菌素对非靶标生物产生了各种毒性。然而，阿维菌素诱导毒性的潜在机制在很大程度上仍不清楚。本研究旨在探讨阿维菌素对小鼠巨噬细胞（RAW264.7）的细胞毒性及其潜在机制。阿维菌素处理导致氧化应激，表现为 ROS 指示剂强度增加。阿维菌素还导致 DNA 损伤，即使在相对较低的剂量（NOAEL）下，细胞中的 8-OHdG/dG 比值也会增加。ROS 抑制剂 catalase-PEG 的预处理减轻了阿维菌素诱导的 DNA 损伤，表明 ROS 过度产生应该是阿维菌素诱导 DNA 损伤的原因。还研究了阿维菌素对 ROS 消除和产生的影响，结果表明阿维菌素诱导 CAT、SOD、GPx 酶和 GSH 水平（ROS 消除）的浓度依赖性改变，但对 RAW264.7 细胞中 NOX、线粒体复合物 I 和 III（ROS 产生）的表达和活性的影响有限。因此，阿维菌素对 ROS 消除的影响应该是阿维菌素诱导 RAW264.7 细胞氧化应激的主要原因。阿维菌素处理激活了 MAPK 和 ATM/ATR 信号通路，表现为 JNK、ATM 和 ATR 的磷酸化增加。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。这些发现应该有助于更全面地评估阿维菌素的毒性作用。
