Production of ES1 plasma carboxylesterase knockout mice for toxicity studies

Ellen G. Duysen, Frank Koentgen, Gareth R. Williams, Christopher M. Timperley, Lawrence M Schopfer, Douglas M. Cerasoli, Oksana Lockridge

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

The LD 50 for soman is 10-20-fold higher for a mouse than a human. The difference in susceptibility is attributed to the presence of carboxylesterase in mouse but not in human plasma. Our goal was to make a mouse lacking plasma carboxylesterase. We used homologous recombination to inactivate the carboxylesterase ES1 gene on mouse chromosome 8 by deleting exon 5 and by introducing a frame shift for amino acids translated from exons 6 to 13. ES1-/- mice have no detectable carboxylesterase activity in plasma but have normal carboxylesterase activity in tissues. Homozygous ES1-/- mice and wild-type littermates were tested for response to a nerve agent model compound (soman coumarin) at 3 mg/kg sc. This dose intoxicated both genotypes but was lethal only to ES1-/- mice. This demonstrated that plasma carboxylesterase protects against a relatively high toxicity organophosphorus compound. The ES1-/- mouse should be an appropriate model for testing highly toxic nerve agents and for evaluating protection strategies against the toxicity of nerve agents.

Original languageEnglish (US)
Pages (from-to)1891-1898
Number of pages8
JournalChemical Research in Toxicology
Volume24
Issue number11
DOIs
StatePublished - Nov 21 2011

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Carboxylesterase
Knockout Mice
Toxicity
Plasmas
Soman
Exons
Organophosphorus Compounds
Plasma (human)
Poisons
Chromosomes
Chromosomes, Human, Pair 8
Homologous Recombination
Genes
Tissue
Amino Acids
Genotype
Testing
Nerve Agents

ASJC Scopus subject areas

  • Toxicology

Cite this

Production of ES1 plasma carboxylesterase knockout mice for toxicity studies. / Duysen, Ellen G.; Koentgen, Frank; Williams, Gareth R.; Timperley, Christopher M.; Schopfer, Lawrence M; Cerasoli, Douglas M.; Lockridge, Oksana.

In: Chemical Research in Toxicology, Vol. 24, No. 11, 21.11.2011, p. 1891-1898.

Research output: Contribution to journalArticle

Duysen EG, Koentgen F, Williams GR, Timperley CM, Schopfer LM, Cerasoli DM et al. Production of ES1 plasma carboxylesterase knockout mice for toxicity studies. Chemical Research in Toxicology. 2011 Nov 21;24(11):1891-1898. https://doi.org/10.1021/tx200237a
Duysen, Ellen G. ; Koentgen, Frank ; Williams, Gareth R. ; Timperley, Christopher M. ; Schopfer, Lawrence M ; Cerasoli, Douglas M. ; Lockridge, Oksana. / Production of ES1 plasma carboxylesterase knockout mice for toxicity studies. In: Chemical Research in Toxicology. 2011 ; Vol. 24, No. 11. pp. 1891-1898.
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