Abstract
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.