Chlorinated solvents associated with neurodegenerative disease induce neurotoxicity and impair autophagic flux

Abstract

Contributions of genetic heredity to neurodegenerative diseases have opened avenues of investigations into the interplay between environmental exposures and neurodegeneration. Epidemiological studies have identified some chlorinated solvents as potential modifiers of neurodegenerative disease risk, but not much is known about the molecular mechanisms underlying their neurotoxic potencies. To this end, we investigated how exposure to chlorinated solvents might induce neurotoxicity in wild-type and transgenic zebrafish. Chlorinated solvents were screened for neurotoxicity through a series of assays measuring changes in locomotion, neuron numbers, and autophagic flux. Decreased locomotion was observed in zebrafish larvae exposed to all chlorinated solvents and all but 1,2-dichloroethane (EDC) and 1,2-dichloropropane (PDC) led to monoaminergic neuron loss. Solvents that induced neuron loss, including carbon tetrachloride (Carbon Tet), dichloromethane (DCM), tetrachloroethylene (PCE), and trichloroethylene (TCE), also caused impairments in autophagic flux, as evidenced by decreased rates of autophagosome formation and increased p62 punctae. In summary, chlorinated methanes and ethenes induced neurotoxicity as evident by behavioral changes, neuronal loss, and reduced autophagic flux in the central nervous system, whereas chlorinated ethanes and propanes did not. This study lends further credence to the epidemiological associations connecting solvent exposure to neurodegenerative disease and highlights the importance of understanding mechanistic links that may cumulatively contribute to disease risk.