A pesticide and iPSC dopaminergic neuron screen identifies and classifies Parkinson-relevant pesticides

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 ()
Additional contact information
Kimberly C. Paul: UCLA David Geffen School of Medicine
Richard C. Krolewski: Brigham and Women’s Hospital and Harvard Medical School
Edinson Lucumi Moreno: Brigham and Women’s Hospital and Harvard Medical School
Jack Blank: Prime Medicine, Inc
Kristina M. Holton: Harvard University
Tim Ahfeldt: Recursion Pharmaceuticals
Melissa Furlong: University of Arizona, Mel and Enid Zuckerman College of Public Health
Yu Yu: UCLA Center for Health Policy Research
Myles Cockburn: University of Southern California
Laura K. Thompson: University of Southern California
Alexander Kreymerman: Harvard University
Elisabeth M. Ricci-Blair: Harvard University
Yu Jun Li: Harvard University
Heer B. Patel: Harvard University
Richard T. Lee: Harvard University
Jeff Bronstein: UCLA David Geffen School of Medicine
Lee L. Rubin: Harvard University
Vikram Khurana: Brigham and Women’s Hospital and Harvard Medical School
Beate Ritz: UCLA David Geffen School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-38215-z

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