Identification of pesticides associated with an increased risk of Parkinson's disease using a multi-screen approach

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by aggregation and transmission of alpha-synuclein (α-syn) protein and loss of dopaminergic neurons. The etiology of PD is multifactorial, involving both genetic and environmental factors. Pesticide exposure has been associated with PD, and with thousands of registered pesticides in the United States, it is still unclear which of these chemically and structurally diverse pesticides confer this association. The population-based case-control Parkinson's, Environment, and Gene (PEG) study based in the California Central Valley, an agricultural hub servicing much of the nation, offers a promising opportunity to investigate this relationship and identify likely environmental risk factors contributing to PD risk. In this study, 62 pesticides with reported agricultural use in the Central Valley were independently evaluated in 2 cell-based assays testing for pesticides that promote α-syn transmission and alter autophagy. To further stratify and prioritize pesticide candidates, pesticides that were positive in the 2 cell-based screens (double hits) were filtered through a newly described pesticide-wide association analysis to agnostically identify relevant real-world exposures. Using these selection criteria, 6 pesticides were identified as triple hits and were tested for dopaminergic neurotoxicity in an in vivo zebrafish (ZF) model. Of these 6 pesticides, 4 pesticides contributed to aminergic neuron loss in ZF larvae. The majority of the pesticides identified in our screens have not previously been implicated as risk factors for PD but should be considered in future studies.