Abstract / Summary
Abstract Glyphosate is a widely used organophosphorus herbicide that causes frequent high-dose occupational exposure in frontline workers. Epidemiological studies have suggested a potential association between glyphosate exposure and elevated Parkinson’s disease (PD) risk; however, it remains unclear whether glyphosate directly induces PD-specific pathogenesis, and the molecular alterations reported in relevant studies are generally attributed to non-specific neuroinflammation and neurotoxic stress rather than PD-exclusive pathways. To address this gap, this study combined network toxicology, computational docking, and in vivo animal experiments to systematically clarify the molecular mechanism of glyphosate-induced neurotoxicity and its potential to trigger PD-relevant neurophenotypes. ProTox-3.0 analysis confirmed neurotoxicity as the core toxicological endpoint. We screened 73 glyphosate-responsive neurotoxicity-related targets, and PPI network analysis revealed the critical involvement of neuronal apoptosis, inflammatory secretion, and cellular stress pathways, which represent common downstream responses of neural toxic injury. Molecular docking verified that glyphosate stably binds to FOS, MAPK3, and IL6 with high affinity (binding energy < − 20.0 kcal/mol), indicating robust interactions with core neuroinflammatory and neuronal stress mediators. In vivo results demonstrated that glyphosate exposure induced significant motor dysfunction, substantia nigra dopaminergic neuron loss, and elevated c-Fos expression in mice. Mechanistically, glyphosate upregulates c-Fos to trigger dopaminergic neuronal stress and abnormal activation, aggravates neuronal apoptosis, and causes progressive dopaminergic neuron ablation. Notably, although these molecular changes belong to generalized neurotoxic and inflammatory responses, the preferential damage of substantia nigra dopaminergic neurons results in typical parkinsonian-like neuropathological alterations, which serve as critical prodromal pathological basis for increased PD susceptibility. This study clarifies the c-Fos-mediated mechanism of glyphosate neurotoxicity and reveals a potential pathological link between glyphosate exposure and PD-related neurophenotype formation, providing novel targets for glyphosate neural risk assessment.