Abstract
Background
Pesticides as a class have been associated with an increased risk of Parkinson’s disease (PD), but it is unclear which specific pesticides contribute to this association and whether it is causal. Since chlorpyrifos (CPF) exposure has been implicated as a risk factor for PD, we investigated its association to incident PD and if this association is biologically plausible using human, rodent, and zebrafish (ZF) studies.
Methods
The association of CPF with PD was performed using the UCLA PEG cohort (829 PD and 824 control subjects), the pesticide use report and geocoding the residence and work locations to estimate exposures. For the mammalian studies, 6 months old male mice were exposed to CPF by inhalation (consistent with human exposures) for …
Abstract
Background
Pesticides as a class have been associated with an increased risk of Parkinson’s disease (PD), but it is unclear which specific pesticides contribute to this association and whether it is causal. Since chlorpyrifos (CPF) exposure has been implicated as a risk factor for PD, we investigated its association to incident PD and if this association is biologically plausible using human, rodent, and zebrafish (ZF) studies.
Methods
The association of CPF with PD was performed using the UCLA PEG cohort (829 PD and 824 control subjects), the pesticide use report and geocoding the residence and work locations to estimate exposures. For the mammalian studies, 6 months old male mice were exposed to CPF by inhalation (consistent with human exposures) for 11 weeks and behavioral and stereological pathological analyses were performed. Transgenic ZF were utilized to determine the mechanism of CPF neurotoxicity.
Results
Long-term residential exposure to CPF was associated with more than a 2.5-fold increased risk of developing PD. Mice exposed to aerosolized CPF developed motor impairment, dopaminergic neuron loss, microglial activation, and an increase in pathological α-synuclein (α-syn). Using ZF, we found that CPF-induced dopaminergic neuron loss was at least partially due to autophagy dysfunction and synuclein accumulation, as knocking down LC3 recapitulated the dopaminergic neuron loss and restoring autophagic flux or eliminating synuclein reduced neuronal vulnerability.
Conclusions
CPF exposure is associated with an increased risk of developing PD and relevant exposures in animal models establish biological plausibility. In addition to establishing a new risk factor for PD, we identified new therapeutic targets for disease modification.
Data availability
No datasets were generated or analysed during the current study.
Abbreviations
α-syn:
α-synuclein
CPF:
Chlorpyrifos (O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphorothioate)
DA:
Dopaminergic
Dpf:
Days post fertilization
γ1-syn:
γ1-synuclein
GFP:
Green fluorescent protein
MO:
Morpholino
PD:
Parkinson’s disease
PEG:
Parkinson’s Environment and Genes
pS129:
Phosphorylated α-syn at serine 129
SNpc:
Substantia nigra pars compacta
TH:
Tyrosine hydroxylase
VTA:
Ventral tegmental area
ZF:
Zebrafish
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Funding
The Levine Foundation, NIH R01 ES031106, and K01AG07204401.
Author information
Authors and Affiliations
Department of Neurology, David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA, 90095, USA
Kazi Md. Mahmudul Hasan, Lisa M. Barnhill, Kimberly C. Paul, Chao Peng, William Zeiger, Marisol Arellano, Michael Ajnassian, Shujing Zhang, Aye Theint Theint, Sharon Li & Jeff M. Bronstein 1.
Department of Epidemiology, University of California-Los Angeles, Los Angeles, CA, 90095, USA
Beate Ritz 1.
Environmental and Molecular Toxicology Interdepartmental Program, University of California Los Angeles, Los Angeles, CA, 90095, USA
Beate Ritz, Marisol Arellano & Jeff M. Bronstein 1.
Pasarow Mass Spectrometry Laboratory, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
Gazmend Elezi, Hilli Weinberger & Julian P. Whitelegge 1.
Department of Neurology and Pittsburgh Institute for Neurodegenerative Disease, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213- 3301, USA
Qing Bai & Edward A. Burton 1.
Geriatric Research, Education, and Clinical Center, Pittsburgh VA Healthcare System, Pittsburgh, PA, 15240, USA
Edward A. Burton
Authors
- 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
- Jeff M. Bronstein
Contributions
K.H. Conceptualization, methodology, data analysis, writing – original draft, writing – review & editing. L.B. Conceptualization, methodology, data analysis, writing – review & editing. K. P. Methodology, data analysis, writing – review & editing. C.P. Methodology, data analysis, writing – review & editing. W.Z. Methodology, data analysis, writing – review & editing. B.R. Conceptualization, methodology, data analysis, writing – review & editing. M.A. Methodology, data analysis, writing – review & editing. M.J. Methodology, data analysis, writing – review & editing. S.Z. Methodology, data analysis, writing – review & editing., A.T. Methodology, data analysis, writing – review & editing. G.E. Methodology, data analysis, writing – review & editing. H.W. Methodology, data analysis, writing – review & editing. J.W. Methodology, data analysis, writing – review & editing. Q.B. Methodology, data analysis, writing – review & editing. S.L. Methodology, data analysis. E.B. Conceptualization, methodology, data analysis, writing – review & editing. J.B. Project administration, conceptualization, methodology, data analysis, writing – original draft, writing – review & editing.
Corresponding author
Correspondence to Jeff M. Bronstein.
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Ethical approval
University of California, Los Angeles (UCLA) Animal Research Committee approved all experiments using animals in accordance with the US National Institutes of Health guidelines. All procedures for the epidemiology study received approval from the institutional review boards of UCLA, and all participants provided informed consent. All authors have approved this manuscript.
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The authors declare no competing interests.
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Cite this article
Hasan, K.M.M., Barnhill, L.M., Paul, K.C. et al. The pesticide chlorpyrifos increases the risk of Parkinson’s disease. Mol Neurodegeneration (2025). https://doi.org/10.1186/s13024-025-00915-z
Received: 14 May 2025
Accepted: 29 November 2025
Published: 11 December 2025
DOI: https://doi.org/10.1186/s13024-025-00915-z