Citation

Chaubey K, Alam SI, Nagar DP, Waghmare CK, Pant SC, Singh L, Srivastava N, Bhattacharya BK. Toxicol. Sci. 2017; 160(1): 136-149.

Affiliation

Defence Research & Development Establishment (DRDE), Jhansi Road, Gwalior (MP), 474002, India.

Copyright

(Copyright © 2017, Oxford University Press)

DOI

10.1093/toxsci/kfx162

PMID

28973502

Abstract

Sarin is an organophosphorus chemical warfare agent which irreversibly inhibits acetylcholinesterase. Acute toxicity after sarin exposure is due to hyper activation of the nicotinic and muscarinic receptor. Survivors of sarin exposure often develop long term neuropathology referred as organophosphorus ester induced chronic neurotoxicity. However, the exact mechanism of chronic neuro-toxicity is yet unknown. We studied proteomic changes in rat brain regions after 0.5 LD50 dose of sarin and investigated some milestone changes associated with long term CNS injury. We used 2DE-MS approach to identify early proteomic changes and traced expression of selected proteins for longer time points. This study shows changes in chaperone function, ER stress and defect in cytoskeleton functions at earlier stages. Predictive interaction analysis demonstrated putative role of Parkinson's disease related proteins after sarin exposure. Our results clearly indicated neurodegenerative changes which started after 2.5 h and showed prominence after three months, post exposure. The study also unmasks changes in proteins related to movement and cognitive function. The markers for astrocytosis (GFAP) and neurodegenerative changes (alpha synuclein and amyloid precursor protein) exhibited altered expression in brain. This is the first proteomic study among survivors of sarin exposure in animal model. Some of the early changes, including those involved in neurodegeneration, movement and cognitive function, defects in chaperone function and cytoskeleton, were shown to persist for a longer period. The study provides a preliminary framework for further validation of major mechanisms of sarin toxicity is suggested here and opens new avenues for elucidation of therapeutic intervention.

© The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Language: en

Keywords

Alpha synuclein; Brain proteome; GFAP; Neurodegeneration; Sarin