Researchers identify 10 pesticides toxic to neurons involved in Parkinson’s

Researchers at UCLA Health and Harvard have identified 10 pesticides that significantly damaged neurons involved in the development of Parkinson’s disease, providing new clues about the role of environmental toxins in the disease.

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

A novel combination of epidemiology and toxicity screening that leveraged California’s extensive pesticide use database allowed researchers at UCLA and Harvard 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.

Furthermore, the researchers found that simultaneous exposure of pesticides typically used in combinations in cotton farming was more toxic than a single pesticide in that group.

For this study, published May 16 in Nature communicationUCLA researchers examined decades of exposure history for 288 pesticides among Central Valley Parkinson’s disease patients who had participated in previous studies.

The researchers were able to determine the long-term exposure for each person and then, using what they called 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 involved in Parkinson’s — most of which had not previously been investigated for a possible link and are still in use.

Those results were shared for lab analysis led by Richard Krolewski, MD, Ph.D., a neurology instructor at Harvard and neurologist at Brigham and Women’s Hospital. He tested the toxicity of most of those pesticides in dopaminergic neurons derived from Parkinson’s patients using what are known as induced pluripotent stem cells. Parkinson’s disease.

The 10 pesticides identified as directly toxic to these neurons were: four insecticides (dicofol, endosulfan, naled, propargite), three herbicides (diquat, endothal, trifluralin), and three fungicides (copper sulfate). [basic and pentahydrate] and folpet). Most pesticides are still used in the United States.

Aside from their toxicity in dopaminergic neurons, there is little that unites these pesticides. They have a range of uses, are structurally different, and have no prior toxicity classification.

Researchers also tested the toxicity of multiple pesticides commonly applied in cotton fields around the same time, according to California’s pesticide database. Combinations with trifluralin, one of California’s most commonly used herbicides, produced the most toxicity. Previous research in the Agricultural Health Study, a large pesticide-applied research project, had also linked trifluralin to Parkinson’s disease.

Kimberly Paul, Ph.D., a lead author and assistant professor of neurology at UCLA, said the study showed that their approach can broadly screen for pesticides involved in Parkinson’s and better understand the power of these associations.

“We were able to involve individual agents more than any other study before, and it was done in a completely agnostic way,” Paul said. “When you put this kind of agnostic screening together with a field-to-bench paradigm, you can pinpoint pesticides that look like they’re pretty important in the disease.”

The researchers next plan to study epigenetic and metabolomic features associated with exposure using integrative omics to help describe which biological pathways are disrupted in Parkinson’s patients who have experienced pesticide exposure. More detailed mechanistic studies of the specific neuronal processes affected by pesticides such as trifluralin and copper are also underway in the Harvard/Brigham and Women’s labs.

The lab work focuses on different effects on dopamine neurons and cortical neurons, which are important for movement and cognitive symptoms in Parkinson’s patients, respectively. The basic science is also expanding to studies of pesticides on non-neuronal cells in the brain – the glia – to better understand how pesticides affect the function of these critical cells.