Abstract
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.