Fenpropathrin Induces GLT-1 Ubiquitination and Increases IL-6 Secretion through the Mdm2-p53 Pathway

Abstract

Human exposure to fenpropathrin, a widely used pesticide, is linked to Parkinson’s-like symptoms in the body. However, a specific pathogenic mechanism is still unclear. This study found that fenpropathrin increased the expression of murine double minute 2 (Mdm2) and reduced the expression of p53. Fenpropathrin stimulated the expression of neural precursor cell expressed, developmentally down-regulated 4-like (Nedd4L) and promoted the secretion of the inflammatory cytokine interleukin-6 (IL-6) through the Mdm2-p53 pathway. Nedd4L, a ubiquitin ligase, mediated the ubiquitination degradation of glutamate transporter 1 (GLT-1), resulting in glutamate accumulation and excitotoxicity aggravation. Our findings elucidate part of the pathogenic mechanism of fenpropathrin toxicity and provide scientific evidence to help develop guidance for pesticide control and environmental protection.

Exploring the link between pyrethroids exposure and dopaminergic degeneration through morphometric, immunofluorescence, and in-silico approaches: the therapeutic role of chitosan-encapsulated curcumin nanoparticles

“…These findings underscore the consideration of FNE as a possible neurotoxin for DA and an environmental risk factor for PD. Additionally, glutamate was significantly elevated in the brains of rats exposed to FNE, as stated in many other studies ( Xiong et al, 2016 ; Wu et al, 2023 ). This could be attributed to several mechanisms, among them the ability of FNE to cause glutamate buildup and exacerbation of excitotoxicity of a ubiquitin ligase that facilitates the ubiquitination and degradation of glutamate transporter 1, which causes the accumulation of glutamate in the synapse ( Cao et al, 2011 ).…”