A study by UCLA Health and Harvard identified 10 pesticides in current use that are highly damaging to the neurons involved in Parkinson’s disease. The study used the California pesticide database to find pesticides that are toxic to dopaminergic neurons, which are important for voluntary movement. The research found 53 pesticides possibly linked to Parkinson’s, with a particular blend used in cotton farming showing increased toxicity. Future research will focus on the biological disruptions caused by these pesticides in Parkinson’s patients.
With thousands of pesticides in use, the researchers’ new screening technique could make it easier to identify which ones are linked to disease.
Researchers at the University of California, Los Angeles ([{” attribute=””>UCLA) Health and Harvard University have identified 10 pesticides that significantly damaged neurons implicated in the development of Parkinson’s disease, providing new clues about environmental toxins’ role in the disease.
While environmental factors such as pesticide exposure have long been linked to Parkinson’s, it has been harder to pinpoint which pesticides may raise risk for the neurodegenerative disorder. Just in California, the nation’s largest agricultural producer and exporter, there are nearly 14,000 pesticide products with over 1,000 active ingredients registered for use.
Through a novel pairing of epidemiology and toxicity screening that leveraged California’s extensive pesticide use database, UCLA and Harvard researchers were able to identify 10 pesticides that were directly toxic to dopaminergic neurons. The neurons play a key role in voluntary movement, and the death of these neurons is a hallmark of Parkinson’s.
Further, the researchers found that co-exposure of pesticides that are typically used in combinations in cotton farming were more toxic than any single pesticide in that group.
For this study, published on May 16 in the journal Nature Communications, UCLA researchers examined exposure history going back decades for 288 pesticides among Central Valley patients with Parkinson’s disease who had participated in previous studies. The researchers were able to determine long-term exposure for each person and then, using what they labeled a pesticide-wide association analysis, tested each pesticide individually for association with Parkinson’s. From this untargeted screen, researchers identified 53 pesticides that appeared to be implicated in Parkinson’s – most of which had not been previously studied for a potential link and are still in use.
Those results were shared for lab analysis led by Richard Krolewski, MD, PhD, an instructor of neurology at Harvard and neurologist at Brigham and Women’s Hospital. He tested the toxicity for most of those pesticides in dopaminergic neurons that had been derived from Parkinson’s patients through what’s known as induced pluripotent stem cells, which are a type of “blank slate” cell that can be reprogrammed into neurons that closely resemble those lost in Parkinson’s disease.
The 10 pesticides identified as directly toxic to these neurons included: four insecticides (dicofol, endosulfan, naled, propargite), three herbicides (diquat, endothall, trifluralin), and three fungicides (copper sulfate [basic and pentahydrate] and folpet). Most pesticides are still used today in the United States.
Aside from their toxicity to dopaminergic neurons, few of these pesticides are isolated. They have a range of uses, are structurally different, and do not share a prior toxicity classification.
The researchers also tested the toxicity of several pesticides commonly applied to cotton fields at the same time, according to the California pesticide database. Combinations involving trifluralin, one of the most commonly used herbicides in California, produced the most toxicity. Previous research in the Agricultural Health Study, a large research project involving pesticide applicators, also implicated trifluralin in Parkinson’s.
Kimberly Paul, PhD, a lead author and assistant professor of neurology at UCLA, said the study showed their approach could broadly screen for pesticides implicated in Parkinson’s and better understand strength of these associations.
“We were able to involve individual agents more than any other study done before, and it was done in a completely agnostic way,” Paul said. “When you combine this type of agnostic screening with the field-to-bench paradigm, you can identify pesticides that appear to be important to the disease.”
The researchers next plan to study epigenetic and metabolomic features associated with exposure using integrative omics to help delineate which biologic pathways are disrupted in Parkinson’s patients who have experienced pesticide exposure. More detailed mechanistic studies of specific neuronal processes affected by pesticides such as trifluralin and copper are also underway at the Harvard/Brigham and Women’s labs. The lab work focuses on unique effects on dopamine neurons and cortical neurons, which are important for movement and cognitive symptoms in Parkinson’s patients, respectively. Basic science is also expanding to study pesticides on non-neuronal cells in the brain – the glia – to better understand how pesticides influence the function of these critical cells.
Reference: “A pesticide and iPSC dopaminergic neuron screen identifies and classifies pesticides associated with Parkinson’s” by 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 , 16 May 2023, Communication in Nature.
DOI: 10.1038/s41467-023-38215-z
Other authors include 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.
