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.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disease that is often manifested by tremors, rigidity, motor dysfunction, and cognitive impairment
Behavioral assessments revealed that Feninjected mice exhibited less distance traveled (Fig. 1a), less time spent on the rotarod (Fig. 1b), less grip strength (Fig. 1c), and weakened behavior in resisting arrest compared to these parameters in vehicle-treated mice, suggesting that chronic Fen treatment gradually reduced motor skills
We found that the production of tyrosine hydroxylase (TH) and the number of TH-positive cells were significantly decreased in the substantia nigra pars compacta (SNpc) of Fen-treated mice compared to these parameters in vehicle-treated mice (Fig. 1d, e), and TH expression was reduced in the striatum of Fen-treated mice (Supplementary Fig. 1)
Summary
Parkinson’s disease (PD) is a neurodegenerative disease that is often manifested by tremors, rigidity, motor dysfunction, and cognitive impairment. The pathological features of PD include progressive loss of dopaminergic (DA) neurons and generation of Lewy bodies in the substantia nigra pars compacta (SNpc). Official journal of the Cell Death Differentiation Association. Jiao et al Cell Death Discovery (2020)6:78. Mitochondrial function and dynamic networks are essential for maintaining the survival and development of neurons[7]. Previous studies have indicated that dysregulation of mitochondrial function and mismatches in dynamic networks are involved in the occurrence and progression of PD8,9, which include increased reactive oxygen species (ROS), impaired mitochondrial electron transport chains, loss of MMP, abnormal mitochondrial morphology, and abnormal mitochondrial dynamics[8,10,11].
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