The Pyrethroids Metabolite 3-Phenoxybenzoic Acid Induces Dopaminergic Degeneration
Exposure to pyrethroids, a significant class of the most widely used agricultural chemicals, has been associated with an increased risk of Parkinson’s disease (PD). However, the underlying mechanisms of pyrethroid-induced Parkinsonism remain unknown. In this study, we focused on 3-phenoxybenzoic acid (3-PBA), a common and prominent metabolite of most pyrethroids produced via hydrolysis by carboxylesterases (CEs) in mammals. We performed liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis and observed the accumulation of 3-PBA in mouse brain tissues over time following exposure to pyrethroids. By quantifying the binding of 11C-2β-carbomethoxy-3β-(4-fluorophenyl) tropane (11C-CFT) to the dopamine transporter (DAT) using positron emission tomography (PET), we observed that different concentrations of 3-PBA induced different variations in DAT levels in vivo, and confirmed that DAT might be a gateway for 3-PBA in dopaminergic cells. By elucidating the relationship between 3-PBA and neurodegeneration in a 3-PBA-treated mouse model, we revealed that the lysosomal protease asparagine endopeptidase (AEP) could cleave human α-synuclein (α-syn), thereby inducing its aggregation, escalating its neurotoxicity, and leading to dopaminergic neuronal loss, decreased tyrosine hydroxylase (TH) levels, and motor impairments. Overall, these findings support that 3-PBA exposure could mimic the pathological and pathogenetic features of PD, showing that this metabolite is a key pathopoiesis compound in pyrethroid-related etiopathological effects and a possible dopamine neurotoxin. Although this metabolite is easily accumulated, it is an often ignored environmental risk factor for PD.
| Medienart: |
E-Book |
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| Erscheinungsjahr: |
[2022] |
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| Erschienen: |
S.l.: SSRN ; 2022 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wan, Fang [VerfasserIn] |
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| Links: |
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| Umfang: |
1 Online-Ressource (38 p) |
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| doi: |
10.2139/ssrn.4032237 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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1810364736 |
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| 520 | |a Exposure to pyrethroids, a significant class of the most widely used agricultural chemicals, has been associated with an increased risk of Parkinson’s disease (PD). However, the underlying mechanisms of pyrethroid-induced Parkinsonism remain unknown. In this study, we focused on 3-phenoxybenzoic acid (3-PBA), a common and prominent metabolite of most pyrethroids produced via hydrolysis by carboxylesterases (CEs) in mammals. We performed liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis and observed the accumulation of 3-PBA in mouse brain tissues over time following exposure to pyrethroids. By quantifying the binding of 11C-2β-carbomethoxy-3β-(4-fluorophenyl) tropane (11C-CFT) to the dopamine transporter (DAT) using positron emission tomography (PET), we observed that different concentrations of 3-PBA induced different variations in DAT levels in vivo, and confirmed that DAT might be a gateway for 3-PBA in dopaminergic cells. By elucidating the relationship between 3-PBA and neurodegeneration in a 3-PBA-treated mouse model, we revealed that the lysosomal protease asparagine endopeptidase (AEP) could cleave human α-synuclein (α-syn), thereby inducing its aggregation, escalating its neurotoxicity, and leading to dopaminergic neuronal loss, decreased tyrosine hydroxylase (TH) levels, and motor impairments. Overall, these findings support that 3-PBA exposure could mimic the pathological and pathogenetic features of PD, showing that this metabolite is a key pathopoiesis compound in pyrethroid-related etiopathological effects and a possible dopamine neurotoxin. Although this metabolite is easily accumulated, it is an often ignored environmental risk factor for PD | ||
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