The synthetic pyrethroid derivative, fenpropathrin, is a widely used insecticide. However, a variety of toxic effects in mammals have been reported. In particular, fenpropathrin induces degeneration of dopaminergic neurons and parkinsonism. However, the mechanism of fenpropathrin-induced parkinsonism has remained unknown. In the present study, we investigated the toxic effects and underlying mechanisms of fenpropathrin on perturbing the dopaminergic system both in vivo and in vitro. We found that fenpropathrin induced cellular death of dopaminergic neurons in vivo. Furthermore, fenpropathrin increased the generation of reactive oxygen species, disrupted both mitochondrial function and dynamic networks, impaired synaptic communication, and promoted mitophagy in vitro. In mice, fenpropathrin was administered into the striatum via stereotaxic (ST) injections. ST-injected mice exhibited poor locomotor function at 24 weeks after the first ST injection and the number of tyrosine hydroxylase (TH)-positive cells and level of TH protein in the substantia nigra pars compacta were significantly decreased, as compared to these parameters in vehicle-treated mice. Taken together, our results demonstrate that exposure to fenpropathrin induces a loss of dopaminergic neurons and partially mimics the pathologic features of Parkinson’s disease. These findings suggest that fenpropathrin may induce neuronal degeneration via dysregulation of mitochondrial function and the mitochondrial quality control system.

合成拟除虫菊酯衍生物甲氰菊酯是一种广泛使用的杀虫剂。然而，已报道了对哺乳动物的多种毒性作用。特别地，甲氰菊酯诱导多巴胺能神经元变性和帕金森病。然而，甲氰菊酯诱发帕金森病的机制仍不清楚。在本研究中，我们研究了甲氰菊酯在体内和体外扰乱多巴胺能系统的毒性作用和潜在机制。我们发现甲氰菊酯在体内诱导多巴胺能神经元的细胞死亡。此外，甲氰菊酯增加了活性氧的产生，破坏了线粒体功能和动态网络，损害了突触通讯，并促进了体外线粒体自噬。在小鼠中，甲氰菊酯通过立体定位（ST）注射注入纹状体。与媒介物中的这些参数相比，注射ST的小鼠在第一次ST注射后24周时表现出较差的运动功能，并且黑质致密部中酪氨酸羟化酶（TH）阳性细胞的数量和TH蛋白水平显着降低- 治疗小鼠。综上所述，我们的结果表明，接触甲氰菊酯会导致多巴胺能神经元的丧失，并部分模仿帕金森病的病理特征。这些发现表明，甲氰菊酯可能通过线粒体功能和线粒体质量控制系统失调诱导神经元变性。