With thousands of pesticides in use, researchers’ new screening approach could make it easier to determine which ones are linked to disease.
Summary Parkinson’s disease ( PD) is a complex neurodegenerative disease with an etiology rooted in genetic vulnerability and environmental factors. Here we combine the quantitative epidemiological study of pesticide exposure and PD with the detection of toxicity in dopaminergic neurons derived from induced pluripotent stem cells in PD patients (iPSCs) to identify pesticides relevant to Parkinson’s disease. Agricultural records allow investigation of 288 specific pesticides and PD risk in a comprehensive pesticide association study. We associated long-term exposure to 53 pesticides with PD and identified co-exposure profiles. We then employed a live-cell imaging screening paradigm that exposes dopaminergic neurons to 39 pesticides associated with Parkinson’s disease. We found that 10 pesticides are directly toxic to these neurons . Additionally, we analyzed pesticides typically used in combinations in cotton cultivation, demonstrating that co-exposures result in greater toxicity than either pesticide alone. We found that trifluralin is a driver of toxicity to dopaminergic neurons and leads to mitochondrial dysfunction. Our paradigm may be useful to mechanistically dissect pesticide exposures implicated in PD risk and guide agricultural policy. |
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Through a novel combination of epidemiology and toxicity screening, the researchers were able to identify 10 pesticides that were directly toxic to key neurons.
Researchers from UCLA Health and Harvard 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, 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 leveraged California’s extensive pesticide use database, researchers at UCLA and Harvard 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.
Additionally, the researchers found that joint exposure to pesticides typically used in combination in cotton cultivation was more toxic than any individual pesticide in that group.
For this study, published in 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 each person’s long-term exposure and then, using what they called a pesticide association analysis, tested each pesticide individually for an 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" cells that can be reprogrammed into neurons that look like much to 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, there is little to unify 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 commonly applied to cotton fields at around the same time, according to the California Pesticide Database. Combinations of trifluralin , one of the most widely used herbicides in California, produced the greatest 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, senior author and assistant professor of neurology at UCLA, said the study showed that their approach could broadly screen for pesticides implicated in Parkinson’s and better understand the strength of these associations.
"We were able to involve individual agents more than any other study before, and it was done in a completely agnostic manner," Paul said. "When you combine this type of agnostic screening with a field-to-bench paradigm, you can identify 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 the specific neural processes affected by pesticides such as trifluralin and copper are also underway in 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.
