Common pesticide damages brain cell recycling system and increases Parkinson’s risk

A common agricultural pesticide known as chlorpyrifos may play a substantial role in the development of Parkinson’s disease. New research from the University of California, Los Angeles, combines decades of human data with animal models to demonstrate how this specific chemical damages brain cells. The study indicates that the pesticide disrupts the brain’s cellular cleaning system, leading to the accumulation of toxic proteins. These findings were published in the journal Molecular Neurodegeneration.

Parkinson’s disease is a neurodegenerative disorder defined by the progressive death of neurons that produce dopamine. These cells are essential for controlling physical movement. When they die, patients experience tremors, stiffness, and difficulty with balance. While genetic mutations account for a small percentage of cases, the vast majority arise from unknown causes.

Scientists suspect that environmental factors are the primary drivers for most patients. Pesticides as a general class have been linked to the disease for years, yet pinning down which specific agents are responsible has been a challenge for researchers. Identifying individual chemicals is necessary to prove causation and to understand the biological mechanics of the disease.

To address this gap, a team of researchers led by Jeff Bronstein and Kazi Md Mahmudul Hasan at UCLA undertook a multi-layered investigation. They sought to move beyond simple associations and determine if chlorpyrifos is biologically capable of causing Parkinson’s pathology. Chlorpyrifos is an organophosphate insecticide that has been used widely in agriculture since the 1960s.

While its use in residential settings was banned in the United States two decades ago, it remains a tool for commercial agriculture. The researchers aimed to see if historical exposure to this chemical correlates with disease rates and if the chemical actively destroys dopamine neurons in laboratory settings.

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The investigation began with an epidemiological analysis using the Parkinson’s Environment and Genes study. This large-scale project tracks residents in three agricultural counties in California’s Central Valley. The team examined data from 829 patients with Parkinson’s disease and compared them to 824 healthy control subjects from the same communities.

The researchers utilized California’s detailed pesticide use reports, which document agricultural spraying dating back to 1974. By combining this data with land-use maps, they estimated the amount of chlorpyrifos applied near each participant’s home and workplace over a period of more than thirty years.

The analysis produced evidence linking the chemical to the disease. Individuals who lived or worked in areas with high levels of chlorpyrifos application faced a significantly higher probability of developing Parkinson’s. For those with the highest cumulative exposure, the risk increased by more than 2.5 times compared to those with minimal exposure.

The data showed that the timing of the exposure mattered. The association was strongest for exposures that occurred ten to twenty years before the diagnosis. This delay aligns with the understanding that the biological changes associated with Parkinson’s often begin decades before physical symptoms appear.

To verify these statistical observations, the scientists conducted experiments on mice. They designed a system to expose the animals to aerosolized chlorpyrifos. This inhalation method was chosen to mimic how humans typically encounter the pesticide near agricultural fields.

Inhalation allows the chemical to enter the bloodstream and brain without being immediately broken down by the liver, which occurs when chemicals are ingested orally. The mice were exposed to the pesticide vapor for eleven weeks.

Following the exposure period, the mice underwent behavioral testing. The researchers observed that the animals exposed to chlorpyrifos displayed motor deficits. They struggled to maintain their balance on a rotating rod and had difficulty gripping a wire mesh compared to the control group.

These physical symptoms mirrored the motor decline seen in human patients. When the researchers examined the brains of these mice, they found a twenty-six percent loss of dopamine-producing neurons in the substantia nigra. This specific brain region is the epicenter of cell death in Parkinson’s disease.

The examination of the mouse brains revealed other hallmarks of the disorder. The researchers found elevated levels of alpha-synuclein, a protein that misfolds and clumps together in the brains of Parkinson’s patients. Specifically, they found high levels of a phosphorylated version of the protein, which is a chemical marker often associated with pathological clumps.

In addition to these protein aggregates, the brains showed signs of inflammation. Microglia, the immune cells of the brain, had shifted into an activated state. These cells typically change shape when reacting to damage or toxins, and the microglia in the exposed mice displayed the rounded, swollen appearance characteristic of neuroinflammation.

The researchers then turned to zebrafish to uncover the molecular mechanism driving this toxicity. Zebrafish are valuable models for this type of research because they are transparent during their larval stage. This allows scientists to visualize neurons and cellular processes in a living organism. The team exposed the fish to low concentrations of chlorpyrifos and observed the same loss of dopamine neurons seen in the mice.

By manipulating the genetics of the fish, the team identified the root cause of the cell death. They discovered that chlorpyrifos impairs a cellular process called autophagy. Autophagy acts as a waste disposal and recycling system for cells.

It is responsible for clearing out damaged proteins and organelles to keep the cell healthy. In the neurons exposed to chlorpyrifos, this cleaning machinery stalled. As a result, waste products, including the synuclein protein, began to accumulate to toxic levels.

To confirm that this stalled cleaning process was the culprit, the researchers performed a rescue experiment. They treated the fish with a compound called calpeptin, which stimulates autophagy. When the cleaning system was manually reactivated, the dopamine neurons survived, even in the presence of chlorpyrifos.

In a separate experiment, they used genetic tools to remove the fish equivalent of the synuclein protein. Without the protein present to build up and reach toxic levels, the neurons were again spared from death. These findings suggest that the pesticide does not kill the cells directly but rather disables the maintenance systems required to prevent protein toxicity.

There are limitations to the study that warrant consideration. The mouse experiments were conducted solely on male animals. Preliminary tests indicated that male mice were more susceptible to the toxin than females. This aligns with human data, as men are statistically more likely to develop Parkinson’s than women, but it leaves the biological response in females less clearly defined.

Additionally, the zebrafish experiments used developing larvae. Parkinson’s is predominantly a disease of aging, so the developing nervous system of a fish may not perfectly reflect the aging human brain. However, the consistency of the findings across human data, mammalian models, and cellular mechanisms strengthens the conclusion.

The identification of autophagy dysfunction offers a direction for future research. If environmental toxins cause disease by jamming cellular recycling systems, then therapies designed to boost these systems could potentially offer protection. Future studies may investigate whether other pesticides operate through similar mechanisms. The results also emphasize the long-term health implications of agricultural chemical exposure, particularly for those living and working in farming communities.

The study, “The pesticide chlorpyrifos increases the risk of Parkinson’s disease,” was authored by Kazi Md Mahmudul Hasan, Lisa M Barnhill, Kimberly C Paul, Chao Peng, William Zeiger, Beate Ritz, Marisol Arellano, Michael Ajnassian, Shujing Zhang, Aye Theint Theint, Gazmend Elezi, Hilli Weinberger, Julian P Whitelegge, Qing Bai, Sharon Li, Edward A Burton, and Jeff M Bronstein.