The pyrethroids metabolite 3-phenoxybenzoic acid induces dopaminergic degeneration

Abstract

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, although many different pyrethroids induce roughly the same symptoms of Parkinsonism, the underlying mechanisms remain unknown. To find the shared key features among these mechanisms, we focused on 3-phenoxybenzoic acid (3-PBA), a common and prominent metabolite of most pyrethroids produced via hydrolysis by CEs in mammals. To determine the contribution of 3-PBA to the initiation and progression of PD, we performed in vivo and in vitro experiments, respectively, and found that 3-PBA not only accumulates in murine brain tissues over time but also further induces PD-like pathologies (increased α-syn and phospho-S129, decreased TH) to the same or even greater extent than the precursor pyrethroid. A before-after study of PET-DAT in the same mice revealed that low concentrations of 3-PBA (0.5 mg/kg) could paradoxically cause DAT to increase (22.46% higher than pre-drug test). The intervention of DAT inhibitors and activators respectively alleviated and enhanced the dopaminergic toxicity of 3-PBA, indicating that 3-PBA interacts with DAT. In particular, low concentrations of 3-PBA increase the DAT, which in turn induces 3-PBA to enter the dopaminergic neurons to exert toxic effects. Finally, we described a mechanism underlying this potential role of 3-PBA in the pathological aggregation of α-syn. Specifically, 3-PBA was found to dysregulate C/EBP β levels and further anomalously activate AEP in vivo and in vitro, accompanied by increased accumulation of pathologically cleaved α-syn (N103 fragments) and accelerated α-syn aggregation. All these results suggest that 3-PBA exposure could mimic the pathological and pathogenetic features of PD, showing that this metabolite is a key pathogenic compound in pyrethroid-related pathological effects and a possible dopamine neurotoxin. Additionally, our findings provide a crucial reference for the primary prevention of PD.