Toxicogenomic Studies of Human Neural Cells Following Exposure to Organophosphorus Chemical Warfare Nerve Agent VX
Organophosphorus (OP) compounds represent an important group of chemical warfare nerve agents that remains a significant and constant military and civilian threat. OP compounds are considered acting primarily via cholinergic pathways by binding irreversibly to acetylcholinesterase, an important regulator of the neurotransmitter acetylcholine. Many studies over the past years have suggested that other mechanisms of OP toxicity exist, which need to be unraveled by a comprehensive and systematic approach such as genome-wide gene expression analysis. Here we performed a microarray study in which cultured human neural cells were exposed to 0.1 or 10 μM of VX for 1 h. Global gene expression changes were analyzed 6, 24, and 72 h post exposure. Functional annotation and pathway analysis of the differentially expressed genes has revealed many genes, networks and canonical pathways that are related to nervous system development and function, or to neurodegenerative diseases such as Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease. In particular, the neuregulin pathway impacted by VX exposure has important implications in many nervous system diseases including schizophrenia. These results provide useful information valuable in developing suitable antidotes for more effective prevention and treatment of, as well as in developing biomarkers for, VX-induced chronic neurotoxicity.
KeywordsOrganophosphorus compound Chemical warfare agent Nerve agent VX Neural cells Neurotoxicity Microarray
We thank Dr. Maryanne T. Vahey and her staff of the WRAIR Vaccine Genomics Laboratory (Rockville, MD), Mr. Martin E. Nau and Dr. Zhining Wang, for their kind help in performing the microarray experiments and providing the raw data. We also thank Ms. Betty J. Benton and Dr. Brian M Keyser at USAMRICD for their help with VX exposure, and Mr. Jack Amnuaysirikul at WRAIR for his help with RNA sample preparation. This work was supported by the Defense Threat Reduction Agency (DTRA) Project No. CBS.MEDCHEM.01.10.WR.005. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting true views of the US Army or the Department of Defense.
Conflict of interest
The authors declare that they have no conflict of interest.
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