Abstract：
Pesticides represent a serious problem for agricultural workers due to their neurotoxic effects. The aim of this study was to evaluate the ability of pharmacological oxidative phosphorylation uncouplers to reduce the effect of the difenoconazole fungicide on mitochondrial DNA (mtDNA) of various organs in mice. Injections of difenoconazole caused cognitive deficits in mice, and the protonophore 2,4-dinitrophenol (2,4-DNP) and Azur I (AzI), a demethylated metabolite of methylene blue (MB), prevented the deterioration of cognitive abilities in mice induced by difenoconazole. Difenoconazole increased the rate of reactive oxygen species (ROS) production, likely through inhibition of complex I of the mitochondrial respiratory chain. After intraperitoneal administration of difenoconazole lungs, testes and midbrain were most sensitive to the accumulation of mtDNA damage. In contrast, the cerebral cortex and hippocampus were not tolerant to the effects of difenoconazole. The protonophore 2,4-DNP reduced the rate of ROS formation and significantly reduced the amount of mtDNA damage caused by difenoconazole in the midbrain, and partially, in the lungs and testes. MB, an alternative electron carrier capable of bypassing inhibited complex I, had no effect on the effect of difenoconazole on mtDNA, while its metabolite AzI, a demethylated metabolite of MB, was able to protect the mtDNA of the midbrain and testes. Thus, mitochondria-targeted therapy is a promising approach to reduce pesticide toxicity for agricultural workers.
摘要：
由于其神经毒性作用，农药对农业工人来说是一个严重的问题。这项研究的目的是评估药理学氧化磷酸化解偶联剂降低苯醚甲环唑杀菌剂对小鼠各种器官的线粒体DNA（mtDNA）的影响的能力。苯醚甲环唑的注射引起小鼠的认知缺陷，和质子基团2,4-二硝基苯酚（2,4-DNP）和AzurI（AzI），亚甲基蓝（MB）的去甲基化代谢物，预防苯醚甲环唑诱导的小鼠认知能力下降。苯醚环唑增加了活性氧（ROS）的产生速率，可能是通过抑制线粒体呼吸链的复合物I。腹膜内给予苯醚甲环唑肺后，睾丸和中脑对mtDNA损伤的积累最敏感。相比之下,大脑皮层和海马对苯醚甲环唑的影响不耐受。2,4-DNP的原位体降低了ROS的形成速率，并显着降低了苯醚甲环唑在中脑引起的mtDNA损伤量，部分地，在肺和睾丸。MB,一种能够绕过抑制复合物I的替代电子载体，对苯醚甲环唑对mtDNA的影响没有影响，而其代谢产物AzI，MB的去甲基化代谢产物,能够保护中脑和睾丸的mtDNA。因此，线粒体靶向治疗是降低农业工人农药毒性的一种有前途的方法。
