State Key Lab of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, PR China; Key Lab of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, PR China.
Key Lab of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, PR China.
Chemosphere. 2020 Mar;243:125336. doi: 10.1016/j.chemosphere.2019.125336. Epub 2019 Nov 9.
Fenvalerate (FEN), one of the most used synthetic pyrethroids, has the potential to interfere with human neural function. However, far too little attention was paid to the mechanism of FEN-induced neurotoxicity. Thus we exposed zebrafish to FEN from 4 to 120 h post fertilization (hpf), and analyzed the morphology and behavior of zebrafish. Our results showed that FEN decreased the survival rate of zebrafish, with increased malformation rates and abnormal behaviors. Furthermore, we found typical parkinson-like symptoms in FEN-exposed zebrafish with increases in parkinson's disease (PD), ubiquitin, and Lewy bodies-relevant genes. We also observed the loss of dopaminergic neurons in both FEN-exposed zebrafish and PC12 cells, which were all associated with PD-like symptoms. Besides, FEN activated autophagy by the enhanced expressions of p-mTOR, and LC3-II but the reduction of p62. Further, FEN initially activated p-p38 MAPK followed by p-mTOR, which triggered the transcription of genes responsible for autophagy process and prompted the Lewy bodies neuron generation leading to the PD-like symptoms. This process was inhibited by both 3-methyladenine (3-MA, an autophagy inhibitor) and SB203580 (a p38 MAPK selective inhibitor) in zebrafish and PC12 cells. These results suggest that FEN might cause parkinson-like symptom during zebrafish development through induction of autophagy and activation of p38 MAPK/mTOR signaling pathway. The study revealed the potential mechanism of FEN-induced neurotoxicity and should give new insights into a significant environmental risk factor of developing parkinson's disease.
氰戊菊酯（FEN）是最常用的合成拟除虫菊酯之一，具有干扰人类神经功能的潜力。然而，人们对 FEN 诱导神经毒性的机制关注甚少。因此，我们在受精后 4 至 120 小时（hpf）期间使斑马鱼暴露于 FEN 中，并分析了斑马鱼的形态和行为。结果表明，FEN 降低了斑马鱼的存活率，畸形率和异常行为增加。此外，我们发现暴露于 FEN 的斑马鱼中出现了典型的帕金森样症状，帕金森病（PD），泛素和路易体相关基因增加。我们还观察到在暴露于 FEN 的斑马鱼和 PC12 细胞中多巴胺能神经元丢失，这都与 PD 样症状有关。此外，FEN 通过增强 p-mTOR 和 LC3-II 的表达而激活自噬，但降低了 p62 的表达。进一步的研究表明，FEN 最初通过激活 p-p38 MAPK 然后激活 p-mTOR 来触发自噬过程相关基因的转录，并促使路易体神经元的产生，从而导致 PD 样症状。该过程在斑马鱼和 PC12 细胞中均被 3-甲基腺嘌呤（3-MA，自噬抑制剂）和 SB203580（p38 MAPK 选择性抑制剂）抑制。这些结果表明，FEN 可能通过诱导自噬和激活 p38 MAPK/mTOR 信号通路，在斑马鱼发育过程中引起帕金森样症状。该研究揭示了 FEN 诱导神经毒性的潜在机制，为开发帕金森病的重要环境风险因素提供了新的见解。
