UCLA & Harvard Researchers Identify 10 Neurotoxic Pesticides
By UNIVERSITY OF CALIFORNIA - LOS ANGELES HEALTH SCIENCES
Researchers at the University of California, Los Angeles (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 of the pesticides are still
in use today in the United States.
Aside from their toxicity in dopaminergic neurons, there
is little that unifies these pesticides. They have a range of use types, are
structurally distinct, and do not share a prior toxicity classification.
Researchers also tested the toxicity of multiple
pesticides that are commonly applied in cotton fields around the same time,
according to California’s 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, had also implicated
trifluralin in Parkinson’s.
Kimberly Paul, PhD, a lead author and assistant professor
of neurology at UCLA, said the study demonstrated their approach could broadly
screen for pesticides implicated in Parkinson’s and better understand the
strength of these associations.
“We were able to implicate individual agents more than
any other study has before, and it was done in a completely agnostic manner,”
Paul said. “When you bring together this type of agnostic screening with a
field-to-bench paradigm, you can pinpoint pesticides that look like they’re
quite important in the disease.”
The researchers are next planning to study epigenetic and
metabolomic features related to exposure using integrative omics to help
describe which biologic pathways are disrupted among Parkinson’s patients who
experienced pesticide exposure. More detailed mechanistic studies of the
specific neuronal processes impacted by pesticides such as trifluralin and
copper are also underway at the Harvard/Brigham and Women’s labs.
The lab work is focused on distinct effects on dopamine
neurons and cortical neurons, which are important for the 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 influence the function of these
critical cells.
Reference: “A pesticide and iPSC dopaminergic neuron
screen identifies and classifies Parkinson-relevant pesticides” 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, Nature Communications.
DOI: 10.1038/s41467-023-38215-z