Quantitative Proteomic Changes after Organophosphorous Nerve Agent Exposure in the Rat Hippocampus

The widespread use of organophosphorous (OP) compounds and recent misuse of nerve agents on civilians requires an urgent need to decode their complex biological response to develop effective drugs. Proteomic profiling of biological target tissues helps in identification of molecular toxicity mechanisms. Quantitative proteomics profiling of the rat hippocampus was studied in this study. Liquid chromatography mass spectrometry (LC-MS) analysis of tandem mass tag (TMT)-labeled lysates identified 6356 proteins. A total of 69, 61, and 77 proteins were upregulated, and 66, 35, and 70 proteins were downregulated at 30 min, 1 day, and 7 days after soman exposure. This is the first report on the soman-induced proteomic changes to the best of our knowledge. Bioinformatics analysis revealed soman-induced broad-range proteomic changes in key pathways related to glutamate, acetylcholine, GABA, 5-hydroxytryptamine, and adrenergic receptors, G-protein signaling, chemokine and cytokine-mediated inflammation, cytoskeleton, neurodegeneration (Parkinson's and Alzheimer's), Wnt signaling, synaptic vesicle trafficking, MAP kinases, proteosome degradation, metabolism, and cell death. Selected protein changes were verified by immunoblotting, and neuropathological findings indicated significant brain damage. Results demonstrate that persistent proteomic changes in the brain can cause multiple neurological effects through cholinergic and non-cholinergic pathways, and these mechanistic insights are useful in the development of novel drugs.