Construction of a toxicity pathway from activation of the TLR4/NF-κB/NLRP3 axis to Parkinson's disease-like non-motor symptoms in mice

Bipyridyl herbicides, like paraquat, are among the most widely used herbicides worldwide. Although the lungs are the main target organ for acute exposure to paraquat, chronic exposure to paraquat is thought to induce neurotoxicity and is one of the environmental risk factors for neurodegenerative diseases. In the last two decades, as paraquat has been banned in some regions, diquat has gradually become its replacement. However, systematic studies of environmental factor-induced neurodegenerative diseases are incomplete, and information on threats and risk assessment is still insufficient. The aim of this study was to investigate the association between bipyridine herbicides and sporadic Parkinson's disease. Among them, we refer to the concept of Adverse Outcome Pathway (AOP), integrate, analyse and propose the toxicity pathway similar to AOP. It provides ideas for us to conduct traditional toxicological studies. As a result, the present study reveals that bipyridine herbicide exposure causes neuronal pyrocytosis in locus coeruleus through activation of the TLR4/NF-κB/NLRP3 axis, resulting in the development of Parkinson's disease-like non-motor symptoms in mice.