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Title: Discovery of treatment for nerve agents targeting a new metabolic pathway

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.

Authors:
ORCiD logo [1];  [1];  [2];  [3];  [2];  [1];  [1];  [1];  [1];  [1];  [4];  [4];  [4];  [5];  [1];  [1]; ORCiD logo [1]
+ Show Author Affiliations
  1. Combat Capabilities Development Command (CCDC) Chemical Biological Center, Gunpowder, MD (United States)
  2. Excet, Inc., Springfield, VA (United States)
  3. Combat Capabilities Development Command (CCDC) Chemical Biological Center, Gunpowder, MD (United States); National Academy of Sciences, Washington, DC (United States)
  4. Univ. of Maryland Baltimore County (UMBC), Baltimore, MD (United States)
  5. Kirk U.S. Army Health Clinic, Gunpowder, MD (United States)
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
Defense Threat Reduction Agency (DTRA); USDOE National Nuclear Security Administration (NNSA)
OSTI Identifier:
1673375
Report Number(s):
LA-UR-20-24698
Journal ID: ISSN 0340-5761
Grant/Contract Number:  
89233218CNA000001
Resource Type:
Accepted Manuscript
Journal Name:
Archives of Toxicology
Additional Journal Information:
Journal Volume: 94; Journal Issue: 9; Journal ID: ISSN 0340-5761
Publisher:
Springer
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; proteomics; metabolomics; cardiomyocytes; glycolysis; a-ketoglutarate; VX poisoning

Citation Formats

Glaros, Trevor Griffiths, Dhummakupt, Elizabeth S., Rizzo, Gabrielle M., McBride, Ethan, Carmany, Daniel O., Wright, Linnzi M., Forster, Jeffry S., Renner, Julie A., Moretz, Ruth W., Dorsey, Russell, Marten, Mark R., Huso, Walker, Doan, Alexander, Dorsey, Carrie D., Phillips, Christopher, Benton, Bernard, and Mach, Phillip M. Discovery of treatment for nerve agents targeting a new metabolic pathway. United States: N. p., 2020. Web. doi:10.1007/s00204-020-02820-4.
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Glaros, Trevor Griffiths, Dhummakupt, Elizabeth S., Rizzo, Gabrielle M., McBride, Ethan, Carmany, Daniel O., Wright, Linnzi M., Forster, Jeffry S., Renner, Julie A., Moretz, Ruth W., Dorsey, Russell, Marten, Mark R., Huso, Walker, Doan, Alexander, Dorsey, Carrie D., Phillips, Christopher, Benton, Bernard, & Mach, Phillip M. Discovery of treatment for nerve agents targeting a new metabolic pathway. United States. https://doi.org/10.1007/s00204-020-02820-4
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Glaros, Trevor Griffiths, Dhummakupt, Elizabeth S., Rizzo, Gabrielle M., McBride, Ethan, Carmany, Daniel O., Wright, Linnzi M., Forster, Jeffry S., Renner, Julie A., Moretz, Ruth W., Dorsey, Russell, Marten, Mark R., Huso, Walker, Doan, Alexander, Dorsey, Carrie D., Phillips, Christopher, Benton, Bernard, and Mach, Phillip M. Mon . "Discovery of treatment for nerve agents targeting a new metabolic pathway". United States. https://doi.org/10.1007/s00204-020-02820-4. https://www.osti.gov/servlets/purl/1673375.
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@article{osti_1673375,
title = {Discovery of treatment for nerve agents targeting a new metabolic pathway},
author = {Glaros, Trevor Griffiths and Dhummakupt, Elizabeth S. and Rizzo, Gabrielle M. and McBride, Ethan and Carmany, Daniel O. and Wright, Linnzi M. and Forster, Jeffry S. and Renner, Julie A. and Moretz, Ruth W. and Dorsey, Russell and Marten, Mark R. and Huso, Walker and Doan, Alexander and Dorsey, Carrie D. and Phillips, Christopher and Benton, Bernard and Mach, Phillip M.},
abstractNote = {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.},
doi = {10.1007/s00204-020-02820-4},
journal = {Archives of Toxicology},
number = 9,
volume = 94,
place = {United States},
year = {Mon Jul 27 00:00:00 EDT 2020},
month = {Mon Jul 27 00:00:00 EDT 2020}
}
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Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1007/s00204-020-02820-4
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Figures / Tables:

Fig. 1 Fig. 1: a PCA plot of the 295 proteins that change over the duration of the study for each animal. The proteomes cluster by animal and not by time. b Hierarchical clustering analysis of 295 proteins also shows that the proteins cluster into four main groups based upon their temporalmore » expression over the 14 day time course« less
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