1. A pesticide and iPSC dopaminergic neuron screen identifies and classifies Parkinson-relevant pesticides
- Author
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Kimberly C. Paul, Richard C. Krolewski, Edinson Lucumi Moreno, Jack Blank, Kristina M. Holton, Tim Ahfeldt, Melissa Furlong, Yu Yu, Myles Cockburn, Laura K. Thompson, Alexander Kreymerman, Elisabeth M. Ricci-Blair, Yu Jun Li, Heer B. Patel, Richard T. Lee, Jeff Bronstein, Lee L. Rubin, Vikram Khurana, and Beate Ritz
- Subjects
Aging ,Multidisciplinary ,Parkinson's Disease ,Stem Cell Research - Induced Pluripotent Stem Cell ,Stem Cell Research - Induced Pluripotent Stem Cell - Human ,Dopaminergic Neurons ,Prevention ,Induced Pluripotent Stem Cells ,Neurosciences ,General Physics and Astronomy ,Parkinson Disease ,Neurodegenerative Diseases ,General Chemistry ,Rural Health ,Neurodegenerative ,Stem Cell Research ,General Biochemistry, Genetics and Molecular Biology ,Brain Disorders ,Neurological ,Humans ,2.1 Biological and endogenous factors ,Climate-Related Exposures and Conditions ,Pesticides ,Aetiology - Abstract
Parkinson’s disease (PD) is a complex neurodegenerative disease with etiology rooted in genetic vulnerability and environmental factors. Here we combine quantitative epidemiologic study of pesticide exposures and PD with toxicity screening in dopaminergic neurons derived from PD patient induced pluripotent stem cells (iPSCs) to identify Parkinson’s-relevant pesticides. Agricultural records enable investigation of 288 specific pesticides and PD risk in a comprehensive, pesticide-wide association study. We associate long-term exposure to 53 pesticides with PD and identify co-exposure profiles. We then employ a live-cell imaging screening paradigm exposing dopaminergic neurons to 39 PD-associated pesticides. We find that 10 pesticides are directly toxic to these neurons. Further, we analyze pesticides typically used in combinations in cotton farming, demonstrating that co-exposures result in greater toxicity than any single pesticide. We find trifluralin is a driver of toxicity to dopaminergic neurons and leads to mitochondrial dysfunction. Our paradigm may prove useful to mechanistically dissect pesticide exposures implicated in PD risk and guide agricultural policy.
- Published
- 2023