Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Emory University, Atlanta, Georgia 30322, USA.
Toxicol Sci. 2011 Jun;121(2):368-75. doi: 10.1093/toxsci/kfr058. Epub 2011 Mar 14.
Epidemiological and in vivo studies have demonstrated that exposure to the pesticides paraquat (PQ) and maneb (MB) increase the risk of developing Parkinson's disease (PD) and cause dopaminergic cell loss, respectively. PQ is a well-recognized cause of oxidative toxicity; therefore, the purpose of this study was to determine if MB potentiates oxidative stress caused by PQ, thus providing a mechanism for enhanced neurotoxicity by the combination. The results show that PQ alone at a moderately toxic dose (20-30% cell death in 24 h) caused increased reactive oxygen species (ROS) generation, oxidation of mitochondrial thioredoxin-2 and peroxiredoxin-3, lesser oxidation of cytoplasmic thioredoxin-1 and peroxiredoxin-1, and no oxidation of cellular GSH/GSSG. In contrast, MB alone at a similar toxic dose resulted in no ROS generation, no oxidation of thioredoxin and peroxiredoxin, and an increase in cellular GSH after 24 h. Together, MB increased GSH and inhibited ROS production and thioredoxin/peroxiredoxin oxidation observed with PQ alone, yet resulted in more extensive (> 50%) cell death. MB treatment resulted in increased abundance of nuclear Nrf2 and mRNA for phase II enzymes under the control of Nrf2, indicating activation of cell protective responses. The results show that MB potentiation of PQ neurotoxicity does not occur by enhancing oxidative stress and suggests that increased toxicity occurs by a combination of divergent mechanisms, perhaps involving alkylation by MB and oxidation by PQ.
流行病学和体内研究表明，接触农药百草枯（PQ）和代森锰（MB）分别会增加帕金森病（PD）的发病风险并导致多巴胺能细胞丢失。PQ 是公认的氧化毒性原因；因此，本研究旨在确定 MB 是否会增强 PQ 引起的氧化应激，从而为组合增强神经毒性提供机制。结果表明，单独使用 PQ （在 24 小时内造成 20-30%的细胞死亡）在中等毒性剂量下即可引起活性氧（ROS）生成增加、线粒体硫氧还蛋白-2 和过氧化物酶-3 的氧化、细胞质硫氧还蛋白-1 和过氧化物酶-1 的氧化减少，以及细胞内 GSH/GSSG 的氧化减少。相比之下，单独使用 MB 在类似的毒性剂量下不会引起 ROS 生成、硫氧还蛋白和过氧化物酶的氧化，并且在 24 小时后会增加细胞内 GSH。MB 一起使用会增加单独使用 PQ 时观察到的 GSH 和抑制 ROS 产生以及硫氧还蛋白/过氧化物酶氧化，同时导致更广泛的细胞死亡（>50%）。MB 处理导致核 Nrf2 的丰度增加和受 Nrf2 控制的 II 期酶的 mRNA 增加，表明细胞保护反应被激活。结果表明，MB 增强 PQ 的神经毒性不是通过增强氧化应激来实现的，这表明增加的毒性可能通过不同的机制共同作用，也许涉及 MB 的烷基化和 PQ 的氧化。
