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<p>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. 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. 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. This study firstly demonstrated that dimethyl phosphate (DMP) does not independently induce a complete glaucomatous phenotype but significantly aggravates optic nerve damage under elevated IOP conditions. By simultaneously regulating multi-pathways and activating inflammatory and fibrotic pathways, DMP amplified oxidative stress and promoted retinal ganglion cell apoptosis. These findings supported the concept that environmental toxicants may act as disease modifiers in glaucoma progression.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月20日

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  • Bingjie Cui,
  • Yumei Tao,
  • Siyu Gui,
  • Xinchen Wang,
  • Xiaochuan Sun,
  • Song Wang

摘要

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. 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. 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. This study firstly demonstrated that dimethyl phosphate (DMP) does not independently induce a complete glaucomatous phenotype but significantly aggravates optic nerve damage under elevated IOP conditions. By simultaneously regulating multi-pathways and activating inflammatory and fibrotic pathways, DMP amplified oxidative stress and promoted retinal ganglion cell apoptosis. These findings supported the concept that environmental toxicants may act as disease modifiers in glaucoma progression.