Toxicogenomic Studies of Human Neural Cells Following Exposure to Organophosphorus Chemical Warfare Nerve Agent VX
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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.
- 1.Balali-Mood M, Balali-Mood K (2005) Nerve agents. In: Brent J (ed) Critical care toxicology. Elsevier Mosby, Philadelphia, pp 1379–1393Google Scholar
- 13.Bajgar J (1993) Noncholinergic effects of organophosphates. Ca. Lek Cesk 132:513–517Google Scholar
- 21.Federation of American Scientists (2012) Types of chemical weapons. Fas Org 2012. http://www.fas.org/cw/cwagents.htm. Accessed 03 Jan 2012
- 34.Neuromics (2012) hN2™ Human Neurons Discovery Kit. Neuromics Website. http://www.neuromics.com/ittrium/visit/A1x66x1y1x85b1x1x9cy1x622bx1x96y1x5c7fx1x82y1x5c85x1x7f. Accessed 16 Nov 2012
- 37.Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc B 57:289–300Google Scholar
- 40.Van Vaerenbergh I, Van Lommel L, Ghislain V, In’t Veld P, Schuit F, Fatemi HM, Devroey P, Bourgain C (2009) In GnRH antagonist/rec-FSH stimulated cycles, advanced endometrial maturation on the day of oocyte retrieval correlates with altered gene expression. Hum Reprod 24:1085–1091PubMedCrossRefGoogle Scholar
- 41.Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G (2000) Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 25:25–29PubMedCrossRefGoogle Scholar
- 43.Luthi-Carter R, Strand A, Peters NL, Solano SM, Hollingsworth ZR, Menon AS, Frey AS, Spektor BS, Penney EB, Schilling G, Ross CA, Borchelt DR, Tapscott SJ, Young AB, Cha JH, Olson JM (2000) Decreased expression of striatal signaling genes in a mouse model of Huntington’s disease. Hum Mol Genet 9:1259–1271PubMedCrossRefGoogle Scholar
- 53.Hodges A, Strand AD, Aragaki AK, Kuhn A, Sengstag T, Hughes G, Elliston LA, Hartog C, Goldstein DR, Thu D, Hollingsworth ZR, Collin F, Synek B, Holmans PA, Young AB, Wexler NS, Delorenzi M, Kooperberg C, Augood SJ, Faull RL, Olson JM, Jones L, Luthi-Carter R (2006) Regional and cellular gene expression changes in human Huntington’s disease brain. Hum Mol Genet 15:965–977PubMedCrossRefGoogle Scholar
- 68.Yamasaki N, Maekawa M, Kobayashi K, Kajii Y, Maeda J, Soma M, Takao K, Tanda K, Ohira K, Toyama K, Kanzaki K, Fukunaga K, Sudo Y, Ichinose H, Ikeda M, Iwata N, Ozaki N, Suzuki H, Higuchi M, Suhara T, Yuasa S, Miyakawa T (2008) Alpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disorders. Mol Brain 1:6PubMedCrossRefGoogle Scholar
- 71.Pickford F, Masliah E, Britschgi M, Lucin K, Narasimhan R, Jaeger PA, Small S, Spencer B, Rockenstein E, Levine B, Wyss-Coray T (2008) The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Invest 118:2190–2199PubMedGoogle Scholar
- 72.Xiong H, Callaghan D, Jones A, Bai J, Rasquinha I, Smith C, Pei K, Walker D, Lue LF, Stanimirovic D, Zhang W (2009) ABCG2 is upregulated in Alzheimer’s brain with cerebral amyloid angiopathy and may act as a gatekeeper at the blood-brain barrier for Abeta(1–40) peptides. J Neurosci 29:5463–5475PubMedCrossRefGoogle Scholar
- 80.Göhlmann H, Talloen W (2009) Gene expression studies using Affymetrix microarrays. CRC Press, Boca RatonGoogle Scholar