Abstract：
It has been proposed that pyrethroid exposure contributes to the increasing prevalence of neurodegenerative diseases. However, the potential mechanisms remain unclear. The current study aimed to investigate the effects of the widely used pyrethroid bifenthrin on Parkinson\'s disease (PD) risk. Bifenthrin (1S-cis-bifenthrin, 1R-cis-bifenthrin, raceme) was administered to male Parkin-/- mice and C57BL/6 mice by oral gavage at a dose of 10 mg/kg bw/day for 28 days. Bifenthrin exposure significantly increased the time of pole climbing and decreased the period of rotarod running, indicating that bifenthrin decreased motor coordination in Parkin-/- mice, which was more evident by 1S-cis-bifenthrin. Furthermore, administration of bifenthrin induced obvious decreases in tyrosine hydroxylase (TH)+ cell count and the protein expression of TH. Increased protein of mitochondrial autophagy LC3B and p62 was observed after exposure to bifenthrin. Increased iron deposition and protein expression of iron transport transferrin (Tf) and transferrin receptor 2 (TfR2) was detected. 1S-cis-bifenthrin bound with Tf, TfR2, and GPX4 with lower binding energies than 1R-cis-bifenthrin, resulting in stronger interactions with these proteins. These results show structure-dependent PD-like effects of bifenthrin on motor activity and coordination associated with the disturbed mitochondrial autophagy and ferroptosis-related pathway. These data demonstrate that pyrethroid exposure increases the potential of Parkinson\'s-like symptoms via the ferroptosis pathway in Parkin-/- mice that is more pronounced than in C57BL/6 mice, providing a prospective enantioselective toxic effect of environmental neurotoxins on PD risk.
摘要：
已经提出，拟除虫菊酯的暴露有助于神经退行性疾病的患病率增加。然而,潜在机制尚不清楚.本研究旨在探讨广泛使用的拟除虫菊酯对帕金森病（PD）风险的影响。联苯菊酯（1S-顺式联苯菊酯，1R-顺式-联苯菊酯,消旋）通过口服管饲法以10mg/kgbw/天的剂量对雄性Parkin-/-小鼠和C57BL/6小鼠施用28天。Bifenthrin暴露显着增加了爬杆的时间，并减少了旋转杆运行的时间，表明联苯菊酯降低了帕金森病-/-小鼠的运动协调性，1S-顺式联苯菊酯更明显。此外，联苯菊酯诱导酪氨酸羟化酶（TH）细胞计数和TH蛋白表达明显降低。暴露于联苯菊酯后，观察到线粒体自噬LC3B和p62的蛋白质增加。检测到铁沉积和铁转运转铁蛋白（Tf）和转铁蛋白受体2（TfR2）的蛋白质表达增加。1S-顺式联苯菊酯与Tf结合，TfR2和GPX4的结合能低于1R-顺式联苯菊酯，导致与这些蛋白质更强的相互作用。这些结果表明，联苯菊酯对与线粒体自噬和铁凋亡相关途径相关的运动活动和协调的结构依赖性PD样作用。这些数据表明，拟除虫菊酯暴露增加了帕金森样症状的潜力，通过在Parkin-/-小鼠中的铁凋亡途径，比在C57BL/6小鼠中更明显，提供环境神经毒素对PD风险的前瞻性对映选择性毒性作用。
