Long-term residential exposure to the agricultural pesticide chlorpyrifos was associated with more than 2.5 times the risk of Parkinson’s disease in a study by UCLA Health researchers. Experiments in mice and zebrafish also suggested how the chemical may damage the brain: by disrupting autophagy, the cellular process that removes damaged proteins and other waste, potentially leading to the loss of neurons involved in movement.
Why chlorpyrifos is being investigated
Parkinson’s disease affects approximately 1 million Americans. The progressive neurological condition damages brain cells involved in movement and can cause tremors, muscle stiffness, slowed movements and difficulty coordinating actions.
A defining feature of Parkinson’s disease is the loss of neurons that produce dopamine. This chemical messenger enables communication between nerve cells and helps the brain coordinate smooth, controlled movements. As dopamine levels fall, the brain becomes less able to regulate movement.
Genetic factors can influence who develops Parkinson’s disease, but researchers are increasingly studying environmental exposures that may also contribute to the condition. Pesticides are of particular interest because some chemicals used to kill insects and other agricultural pests can interfere with biological processes in the nervous system.
Chlorpyrifos has been widely used in agriculture for decades. Its residential use was banned in the United States in 2001, and agricultural uses faced additional restrictions in 2021. The pesticide is still used on many crops in the United States and remains widely used in other countries.
Understanding its possible long-term effects is important because exposure may occur years before Parkinson’s symptoms appear. Identifying specific chemicals associated with the disease could help researchers develop prevention strategies and determine whether people with previous exposure might benefit from additional neurological monitoring.
Parkinson’s risk more than doubled among people with long-term exposure
To investigate the potential link, UCLA researchers examined information from 829 people diagnosed with Parkinson’s disease and 824 people without the disease. All participants were enrolled in the university’s long-term Parkinson’s Disease Environment and Genetics Study, which examines how environmental exposures and genetic factors influence Parkinson’s risk.
The researchers combined California’s detailed pesticide-application records with participants’ residential and work-address histories. This enabled them to estimate how much chlorpyrifos each person may have encountered over time based on where they lived or worked.
People with long-term residential exposure to chlorpyrifos had more than 2.5 times the risk of Parkinson’s disease compared with people without such exposure.
The population analysis could not prove that chlorpyrifos directly caused Parkinson’s disease. The researchers therefore conducted additional experiments to determine whether the pesticide could produce brain changes resembling those seen in people with the condition.
Chlorpyrifos produced Parkinson’s-related changes in mice
The research team exposed mice to chlorpyrifos in aerosol form for 11 weeks. The inhalation method was intended to resemble a common way people encounter pesticides in the environment.
The exposed mice developed movement difficulties and lost neurons involved in dopamine production. The loss of these nerve cells is a central feature of Parkinson’s disease.
The researchers also found inflammation and abnormal accumulation of a protein called alpha-synuclein in the animals’ brains.
Under normal conditions, α-synuclein is found inside neurons and is involved in neuronal function. However, it can accumulate in abnormal clumps and is closely associated with Parkinson’s disease. These deposits are a major focus of research into why certain brain cells deteriorate over time.
Together, the findings indicate that chlorpyrifos exposure can reproduce several key features of Parkinson’s disease in laboratory animals, strengthening the biological evidence for the association observed in people.
Disrupted cellular waste removal may damage neurons
The researchers then used zebrafish to examine more closely how chlorpyrifos harms neurons. These fish are frequently used in neuroscience research because they allow scientists to study biological processes involved in the development and survival of nerve cells.
The experiments pointed to disruption of autophagy, a natural cell-maintenance process that removes damaged proteins and other unwanted substances.
Autophagy functions much like a cellular recycling system. Cells use it to break down worn or defective components and prevent potentially harmful substances from accumulating. The process is especially important for neurons, many of which must continue functioning throughout life.
When chlorpyrifos interfered with this system, damaged substances accumulated within neurons and contributed to their deterioration.
The researchers also found that restoring the cells’ purification process or removing the synuclein protein protected neurons from damage in their experiments.
This result suggests that the harmful effects of pesticides may partly depend on biological pathways that could be targeted by future treatments.
Potential implications for prevention and treatment
The findings raise the possibility of developing treatments that strengthen the brain’s cellular waste-removal mechanisms and protect vulnerable neurons. Such treatments could eventually prove useful for people exposed to chlorpyrifos or other pesticides that interfere with similar processes.
However, the protective effects have so far been demonstrated only in laboratory models. Further research is needed to determine whether enhancing autophagy can prevent or reduce pesticide-related brain damage in humans.
Scientists also want to determine whether other commonly used pesticides disrupt the same cellular mechanisms. Although chlorpyrifos use has declined in the United States, many people were exposed before restrictions were introduced, and related pesticides remain widely used.
The findings may also help identify people with a history of substantial pesticide exposure who could benefit from closer neurological monitoring. As researchers work to develop treatments that slow or prevent Parkinson’s disease progression, early recognition of possible changes in brain function may become increasingly important.
Dr. Jeff Bronstein, a professor of neurology at UCLA Health and the study’s lead author, emphasized the importance of identifying specific chemicals rather than treating all pesticides as a single category.
“This study demonstrated that chlorpyrifos is not just a common type of pesticide, but a specific environmental risk factor for Parkinson’s disease,” said Dr. Jeff Bronstein.
“By demonstrating the biological mechanism in an animal model, we have demonstrated that this association is likely to be causal. The finding that autophagy dysfunction causes neurotoxicity also leads us to potential therapeutic strategies to protect vulnerable brain cells.”
Source: www.sciencedaily.com