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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p>

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The pesticide chlorpyrifos increases the risk of Parkinson’s disease

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月11日

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  • 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

摘要

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.