With thousands of pesticides in use, researchers’ new screening approach could make it easier to determine which ones are linked to disease — ScienceDaily

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While environmental factors, such as pesticide exposure, have long been linked to Parkinson’s, it has been more difficult to determine which pesticides may increase the risk of the neurodegenerative disorder. In California alone, the nation’s largest agricultural producer and exporter, there are nearly 14,000 pesticide products with more than 1,000 active ingredients registered for use.

Through a novel combination of epidemiology and toxicity screening that tapped into California’s extensive database of pesticide use, the UCLA and Harvard researchers were able to identify 10 pesticides that were directly toxic to dopaminergic neurons. Neurons play a key role in voluntary movement, and the death of these neurons is a hallmark of Parkinson’s disease.

In addition, the researchers found that co-exposure of pesticides typically used in combination on cotton cultivation was more toxic than any single pesticide in that group.

For this study, published May 16 in nature communications, UCLA researchers examined exposure histories 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 each person’s long-term exposure and then, using what they called a pesticide association analysis, they tested each pesticide individually for association with Parkinson’s. From this untargeted screen, the 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 laboratory analysis led by Richard Krolewski, MD, PhD, an instructor in neurology at Harvard and a neurologist at Brigham and Women’s Hospital. He tested the toxicity of most of those pesticides in dopaminergic neurons derived from Parkinson’s patients through what are known as induced pluripotent stem cells, which are a type of “blank slate” cell that can be reprogrammed into neurons that resemble much to those who are 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 in the United States today.

Aside from their toxicity on dopaminergic neurons, there is little that unifies these pesticides. They have a variety of types of use, are structurally distinct, and do not share a prior toxicity classification.

The researchers also tested the toxicity of multiple pesticides that are commonly applied to cotton fields around the same time, according to the California Pesticide Database. Combinations of trifluralin, one of the most widely used herbicides in California, produced the highest toxicity. Previous research in the Agricultural Health Study, a large research project involving pesticide applicators, had also implicated trifluralin in Parkinson’s.

Kimberly Paul, PhD, lead author and assistant professor of neurology at UCLA, said the study demonstrated that their approach could broadly detect pesticides implicated in Parkinson’s and better understand the strength of these associations.

“We were able to involve individual agents more than any study before, and it was done completely agnostic,” Paul said. “When you combine this type of agnostic detection with a field-to-bank paradigm, you can identify the pesticides that appear to be quite important in the disease.”

Next, the researchers plan to study exposure-related epigenetic and metabolomic features using integrative omics to help describe which biological pathways are disrupted among Parkinson’s patients who experienced pesticide exposure. More detailed mechanistic studies of specific neural processes affected by pesticides such as trifluralin and copper are also underway at the Harvard/Brigham and Women’s Laboratories. The laboratory work focuses on different 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 studies of pesticides in non-neuronal cells in the brain, glia, to better understand how pesticides influence the function of these critical cells.

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.