Common pesticide chlorpyrifos linked to more than double the risk of Parkinson’s disease, UCLA study finds
A study published in Molecular Neurodegeneration has found that exposure to the common agricultural pesticide chlorpyrifos is associated with a significantly elevated risk of developing Parkinson’s disease, with the strongest effects seen in people who worked directly with the chemical over many years. The research, led by UCLA’s Parkinson’s Environment and Genes (PEG) study, also provides a detailed molecular mechanism: the pesticide disrupts autophagy — the cell’s waste-recycling system — leading to the accumulation of toxic alpha-synuclein and the selective death of dopamine-producing neurons in the substantia nigra.
The human evidence
The PEG study analyzed 829 Parkinson’s disease cases and 824 population-based controls recruited from three agricultural counties in central California — Kern, Fresno, and Tulare — across two enrollment waves spanning 2000 to 2015. Diagnoses were confirmed by movement disorder specialists.
Using California’s Pesticide Use Report (PUR) database — a comprehensive record of agricultural pesticide applications dating back to 1974 — the researchers linked participants’ lifetime residential and workplace addresses to chlorpyrifos application data within a 500-meter buffer. The analysis adjusted for age, sex, race, smoking, and co-exposures to other pesticides including paraquat, glyphosate, and diazinon.
The results were stark. People with the longest duration of workplace chlorpyrifos exposure showed a 2.74-fold increased risk (OR 2.74, 95% CI 1.55–4.89, p = 5.94 × 10⁻⁴) compared to unexposed controls. Any workplace application ever was associated with a 1.39-fold increase (95% CI 1.12–1.73, p = 0.003), and residential exposure in the 20-to-10-year window before diagnosis carried a 1.47-fold increase (95% CI 1.19–1.82, p = 3.97 × 10⁻⁴). Combined residential and workplace exposure at any time produced a 1.82-fold increase (95% CI 1.26–2.63).
The senior and corresponding author, Dr Jeff M. Bronstein, director of the Levine Family Center for Movement Disorders at UCLA Neurology, said the data show a clear dose-response relationship: longer exposure meant higher risk.
The mechanism
To establish causality, the team conducted parallel experiments in mice and zebrafish. Adult male C57BL/6 mice were exposed to aerosolized chlorpyrifos for 11 weeks, five days per week, at concentrations (0.65–2.9 mg/m³ per day) relevant to human environmental exposure. The mice developed significant motor deficits on rotarod and wire-hang tests.
Post-mortem analysis revealed a 26% reduction in tyrosine hydroxylase-positive (TH+) neurons in the substantia nigra pars compacta — the same brain region that degenerates in Parkinson’s disease. The ventral tegmental area, which is relatively spared in Parkinson’s, was unaffected.
The molecular cascade, traced in both mice and zebrafish, begins with chlorpyrifos reducing autophagic flux — the process by which cells degrade and recycle damaged proteins and organelles. Key autophagy proteins were depleted: LC3-II, a marker of autophagosome formation, and Lamp2a, the receptor for chaperone-mediated autophagy. Meanwhile p62/SQSTM1, a substrate that accumulates when autophagy is blocked, trended upward. As waste built up, insoluble alpha-synuclein phosphorylated at serine 129 — the pathological form of the protein that aggregates in Parkinson’s — increased 1.66-fold in the midbrain.
In zebrafish, the team showed that knocking out γ1-synuclein (the fish functional homolog of human alpha-synuclein) completely protected dopamine neurons from chlorpyrifos toxicity, and that calpeptin, an autophagy-inducing drug, rescued the neurons — confirming that autophagy disruption is the causal link, not merely a correlation.
First author Kazi Md. Mahmudul Hasan noted that microglia (brain immune cells) became activated but were not required for the neurotoxicity; depleting them with a PU.1 morpholino did not protect dopamine neurons, meaning the damage originates inside the neurons themselves.
Why this matters
Chlorpyrifos is one of the most widely used organophosphate insecticides in global agriculture, applied to crops including corn, soybeans, fruit trees, and nuts. It was banned for residential use in the United States in 2001 but remains approved for agricultural applications. The European Union banned it outright in 2020. In California — where the study was conducted — it remains in use, particularly in the Central Valley’s intensive farming regions.
Parkinson’s disease is the world’s fastest-growing neurodegenerative disorder, with prevalence projected to surpass 12 million globally by 2040. While genetic factors play a role, the majority of cases are believed to involve environmental triggers interacting with genetic susceptibility. The PEG study — co-directed by Dr Beate Ritz at UCLA Epidemiology — has been instrumental in building the case for environmental risk factors, particularly pesticides, since its inception in the early 2000s.
The study was funded by the National Institutes of Health and the National Institute of Environmental Health Sciences.
Sources:
1. Hasan, K.M.M., Barnhill, L.M., Paul, K.C. et al. “Chlorpyrifos exposure increases Parkinson’s disease risk through autophagy disruption and alpha-synuclein accumulation.” Molecular Neurodegeneration 21, Article 3 (2026). DOI: 10.1186/s13024-025-00915-z
2. UCLA Health. Press release, January 7, 2026.
3. California Pesticide Use Report (PUR) database, California Department of Pesticide Regulation.