Identifying pesticide culprits in Parkinson’s disease

summary: Researchers have identified 10 pesticides that severely damage neurons involved in the development of Parkinson’s disease.

This study utilized California’s extensive pesticide use database and innovative testing methods to identify pesticides that are directly toxic to dopaminergic neurons that are essential for locomotor activity. Combinations of pesticides used in cotton cultivation were more harmful than single pesticides.

This study provides new insight into potential environmental triggers for Parkinson’s disease.

Important facts:

1. Researchers have identified 10 insecticides that are directly toxic to dopaminergic neurons. Dopaminergic neurons are important for voluntary movement and their death is a hallmark of Parkinson’s disease.
2. Combinations of multiple pesticides, especially those used in cotton cultivation, have been found to be more toxic than single pesticides.
3. Most of the 10 insecticides identified as directly toxic to dopaminergic neurons are still in use in the United States.

sauce: University of California, Los Angeles

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

Environmental factors such as exposure to pesticides have long been associated with Parkinson’s disease, but it has become more difficult to identify which pesticides may increase the risk of neurodegenerative disorders.

In California alone, the nation’s largest agricultural producer and exporter, there are approximately 14,000 registered pesticide products containing more than 1,000 active ingredients.

Through a novel combination of epidemiology and toxicology screening leveraging California’s extensive pesticide use database, researchers at UCLA and Harvard University were able to identify 10 pesticides that are directly toxic to dopaminergic neurons.

Neurons play an important role in voluntary movement, and the death of these neurons is a hallmark of Parkinson’s disease.

Furthermore, the researchers found that simultaneous exposure to pesticides commonly used in combination in cotton cultivation was more toxic than any single pesticide in the group.

The study was published on May 16th. Nature CommunicationsUCLA researchers looked at the history of exposure to 288 pesticides going back decades in Parkinson’s disease patients from the Central Valley who participated in an earlier study.

The researchers determined each person’s long-term exposure and tested each pesticide individually for association with Parkinson’s disease using what they termed a pesticide-wide association analysis.

From this non-targeted screen, the researchers identified 53 pesticides that may be associated with Parkinson’s disease. Most of them have never been studied for potential relevance and are still in use.

These results were shared for laboratory analysis led by Richard Krolewski, M.D., Ph.D., Lecturer in Neurology at Harvard University and Neurologist at Brigham and Women’s Hospital.

He tested most of the pesticides for their toxicity on dopaminergic neurons obtained from Parkinson’s disease patients via what is known as induced pluripotent stem cells. Induced pluripotent stem cells are a kind of ‘blank slate’ cells that can be reprogrammed into neurons much like those lost in Parkinson’s disease. Parkinson’s disease.

The 10 pesticides identified as being directly toxic to these neurons included four insecticides (dicofol, endosulfan, naled and propulgite), three herbicides (diquat, endohol and trifluralin), and 3 fungicides (copper sulfate). [basic and pentahydrate] and Folpet). Most pesticides are still in use in the United States today.

Little unifies these insecticides, except for their toxicity in dopaminergic neurons. They have a variety of uses, are structurally distinct, and share no previous toxicity classification.

The researchers also tested the toxicity of several pesticides commonly used in cotton fields during the same period, according to the California Pesticide Database. Combinations containing trifluralin, one of the most commonly used herbicides in California, produced the most toxicity.

Previous work in Agricultural Health Research, a large-scale research project involving pesticide applicators, Trifluralin has also been implicated in Parkinson’s disease.

Lead author and assistant professor of neurology at UCLA, Kimberly Pohl, Ph.D., said the study will allow their approach to screen a broad range of pesticides implicated in Parkinson’s disease and better understand the strength of these associations. said to have been proven.

“We were able to involve individual agents more than any previous study, and it was done in a completely agnostic way,” Paul said.

“Combining this kind of agnostic screening with a field-to-bench paradigm allows us to pinpoint pesticides that appear to be of critical importance to this disease.”

The researchers next used integrative omics to characterize exposure-related epigenetic and metabolomic features to explain which biological pathways are disrupted among Parkinson’s disease patients who experienced pesticide exposure. are planning to study

More detailed mechanistic studies of specific neural processes affected by pesticides such as trifluralin and copper are also underway at the Harvard/Brigham Institute and Women’s Research Institute.

Laboratory research focuses on differential effects on dopamine and cortical neurons that are important for motor and cognitive symptoms, respectively, in patients with Parkinson’s disease.

Basic science is also expanding into the study of pesticides on non-neuronal cells (glia) in the brain to better understand how pesticides affect the function of these important cells.

Other authors include Edinson Lukumi Moreno, Jack Blank, Christina M. Holton, Tim Arfelt, Melissa Furlong, Yu Yu, Miles Cockburn, Laura K. Thompson, Alexander Kramer Mann, Elizabeth M. Rich-Blair, Yu Jun Lee, and Heer B. Patel. , Richard T. Lee, Jeff Bronstein, Lee L. Rubin, Vikram Khurana, Beate Ritz.

About this Parkinson’s Disease Research News

author: Jason Millman
sauce: University of California, Los Angeles
contact: Jason Millman – UCLA
image: Image credited to Neuroscience News

Original research: open access.
“Pesticide and iPSC dopaminergic neuron screen to identify and classify pesticides associated with Parkinson’s diseaseWritten by Richard Krolewski et al. Nature Communications

overview

Pesticide and iPSC dopaminergic neuron screen to identify and classify pesticides associated with Parkinson’s disease

Parkinson’s disease (PD) is a complex neurodegenerative disease with an etiology rooted in genetic vulnerability and environmental factors.

Here we combine quantitative epidemiological studies of pesticide exposure and PD with toxicity screening in dopaminergic neurons derived from pluripotent stem cells (iPSCs) from PD patients to identify pesticides associated with Parkinson’s disease.

Agricultural records enable the 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.

Next, we employ a live-cell imaging screening paradigm and expose dopaminergic neurons to 39 PD-related insecticides. We found 10 pesticides to be directly toxic to these neurons.

In addition, we analyzed pesticides commonly used in combination in cotton cultivation and demonstrated that simultaneous exposure resulted in greater toxicity than single pesticides. We found that trifluralin is a driver of toxicity for dopaminergic neurons, causing mitochondrial dysfunction.

Our paradigm mechanistically analyzes pesticide exposures related to PD risk and may help guide agricultural policy.