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.