Organophosphate pesticide exerts toxic effect on the optic nerve of glaucoma rats by promoting oxidative stress and inflammation

Background Glaucoma, a leading cause of irreversible blindness, involves progressive retinal ganglion cell (RGC) loss. Beyond intraocular pressure (IOP), environmental risk factors like pesticide exposure are increasingly implicated. Dimethyl phosphate (DMP), a key metabolite of organophosphorus pesticides, accumulates in the body and exhibits systemic toxicity. However, its direct role and mechanism in glaucoma pathogenesis remain entirely unexplored. Methods We investigated the impact of DMP on glaucoma progression using a rat glaucoma model. Animals were subjected to DMP exposure at varying concentrations. We assessed IOP, optic nerve thickness, and expression of neurotrophic factors (NGF, BDNF). Molecular mechanisms were elucidated via Western blotting for key signaling pathways and apoptosis/inflammation markers, complemented by ELISA for oxidative stress. Functional validation was performed using specific pathway agonists and inhibitors. Results DMP exposure exacerbated core glaucomatous pathology in a concentration-dependent manner, significantly elevating IOP, reducing optic nerve thickness, and downregulating NGF/BDNF. Mechanistically, DMP concurrently inhibited the pro-survival PI3K/Akt pathway while activating the pro-inflammatory JAK/STAT and NF-κB pathways, and the fibrotic Wnt/β-catenin pathway. This multi-pathway disruption synergistically amplified retinal oxidative stress and triggered RGC apoptosis. Rescue experiments confirmed that the modulation of these specific pathways directly influenced the observed oxidative injury and cellular damage. Conclusion This study provides the first evidence that dimethyl phosphate (DMP), a common organophosphorus metabolite, promotes glaucoma progression by regulating a multi-pathway signaling network that ultimately converges on oxidative stress and apoptosis. This work redefines DMP as a novel environmental risk factor for glaucoma, reveals its complex mechanism of action, and offers new perspectives for optic nerve protection strategies and environmental risk assessment.