Department of Neurology, UCLA David Geffen School of Medicine, Los Angeles, CA, USA.
Division of Movement Disorders, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
Nat Commun. 2023 May 16;14(1):2803. doi: 10.1038/s41467-023-38215-z.
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.
帕金森病(PD)是一种复杂的神经退行性疾病,其病因根植于遗传易感性和环境因素。在这里,我们将定量流行病学研究农药暴露与 PD 与多巴胺能神经元毒性筛选相结合,这些神经元来自 PD 患者诱导多能干细胞(iPSC),以确定与帕金森病相关的农药。农业记录使我们能够在全面的、广泛的农药关联研究中调查 288 种特定农药和 PD 风险。我们将长期接触 53 种农药与 PD 联系起来,并确定共同暴露的情况。然后,我们采用活细胞成像筛选范式,将多巴胺能神经元暴露于 39 种与 PD 相关的农药中。我们发现 10 种农药对这些神经元有直接毒性。此外,我们还分析了棉花种植中常用的组合农药,证明共同暴露比任何单一农药的毒性都更大。我们发现氟乐灵是导致多巴胺能神经元毒性的原因,并导致线粒体功能障碍。我们的范式可能有助于从机制上剖析与 PD 风险相关的农药暴露,并指导农业政策。