Year: 2020
Type: article
Abstract: The inhibition of acetylcholinesterase is regarded as the primary toxic mechanism of action for chemical warfare agents. Recently, there have been numerous reports suggesting that metabolic processes could significantly contribute to toxicity. As such, we applied a multi-omics pipeline to generate a detailed cascade of molecular events temporally occurring in guinea pigs exposed to VX. Proteomic and metabolomic profiling resulted in the identification of several enzymes and metabolic precursors involved in glycolysis and the TCA cycle. All lines of experimental evidence indicated that there was a blockade of the TCA cycle at isocitrate dehydrogenase 2, which converts isocitrate to α-ketoglutarate. Using a primary beating cardiomyocyte cell model, we were able to determine that the supplementation of α-ketoglutarate subsequently rescued cells from the acute effects of VX poisoning. This study highlights the broad impacts that VX has and how understanding these mechanisms could result in new therapeutics such as α-ketoglutarate.
Source: Archives of Toxicology
Authors: Trevor Glaros, Elizabeth S. Dhummakupt, Gabrielle M. Rizzo, Ethan McBride, Daniel O. Carmany, Linnzi K. M. Wright, Jeffry S. Forster, Julie A. Renner, Ruth W. Moretz, Russell Dorsey, Mark R. Marten, Walker Huso, Alexander Doan, Carrie D. Dorsey, Christopher Phillips, Bernard Benton, Phillip M. Mach
Institutions: Los Alamos National Laboratory, United States Army Combat Capabilities Development Command, U.S. Army Combat Capabilities Development Command Chemical Biological Center, Excet (United States), National Academy of Sciences, National Academies of Sciences, Engineering, and Medicine, United States Army, University of Maryland, Baltimore County
Language: English
Subfield: Toxicology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,480
Funder: Defense Threat Reduction Agency
Award: G8849124428
OpenAlex ID: W3045052002