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Possible role of enhanced microtubule phosphorylation in dichlorvos induced delayed neurotoxicity in rat
S Choudhary1, K Joshi, K D Gill
1Department of Biochemistry, Postgraduate Institute of Medical Education and Research, - 160012, Chandigarh, India.
Abstract:
The effect of a single subcutaneous dose of 200 mg/kg body weight dichlorvos on neuronal microtubule phosphorylation has been studied in rat following the development of organophosphate induced delayed neurotoxicity (OPIDN). Microtubule associated Ca2+/calmodulin dependent as well as cAMP dependent protein kinases were assayed. Dichlorvos administration led to a consistent increase in the activity of both the kinases at all post exposure intervals (7th, 15th and 21st day) as compared to that of controls. After in vitro phosphorylation using [gamma-32P]ATP, various proteins were resolved on one-dimensional 8% SDS-PAGE, stained with Coomassie Blue and autoradiographed. The amount of 32P incorporated was quantified by microdensitometry. Dichlorvos enhanced the phosphorylation of 55- and 280-kDa proteins. These two proteins were identified as tubulin and microtubule associated protein-2 (MAP-2) by immunoblotting. This study showed that dichlorvos induced hyperphosphorylation of tubulin and MAP-2 which in turn destabilizes microtubule assembly, and may ultimately result in axonal degeneration leading to dichlorvos induced delayed neurotoxicity.
Insights
Dichlorvos exposure in rats increased neuronal microtubule phosphorylation, specifically of tubulin and MAP-2 proteins. This hyperphosphorylation may lead to microtubule destabilization and axonal degeneration, causing organophosphate-induced delayed neurotoxicity (OPIDN).
Area of Science:
- Neuroscience
- Toxicology
- Molecular Biology
Background:
- Organophosphate-induced delayed neurotoxicity (OPIDN) is a severe neurological condition.
- The precise molecular mechanisms underlying OPIDN, particularly concerning neuronal microtubules, require further elucidation.
Purpose of the Study:
- To investigate the impact of dichlorvos, an organophosphate, on neuronal microtubule phosphorylation in rats.
- To identify specific proteins affected by dichlorvos-induced phosphorylation changes.
Main Methods:
- Rats were administered a single subcutaneous dose of dichlorvos (200 mg/kg).
- Neuronal microtubule-associated protein kinases (Ca2+/calmodulin-dependent and cAMP-dependent) activity was assayed.
- In vitro phosphorylation, SDS-PAGE, immunoblotting, and microdensitometry were used to quantify protein phosphorylation.
Main Results:
- Dichlorvos administration significantly increased the activity of both tested kinases at 7, 15, and 21 days post-exposure.
- Enhanced phosphorylation of 55-kDa (tubulin) and 280-kDa (MAP-2) proteins was observed.
- Dichlorvos exposure led to hyperphosphorylation of tubulin and MAP-2.
Conclusions:
- Dichlorvos induces hyperphosphorylation of tubulin and MAP-2, destabilizing microtubule assembly.
- This destabilization is a potential mechanism leading to axonal degeneration and OPIDN.
- The findings provide molecular insights into dichlorvos-induced neurotoxicity.