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Production of ES1 plasma carboxylesterase knockout mice for toxicity studies
Ellen G Duysen1, Frank Koentgen, Gareth R Williams
1Eppley Institute, University of Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA.
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.
Insights
Mice lacking plasma carboxylesterase (ES1-/- mice) are more susceptible to nerve agents like soman. This ES1 knockout mouse model is crucial for studying organophosphorus compound toxicity and developing effective countermeasures.
Area of Science:
- Toxicology
- Genetics
- Pharmacology
Background:
- Human susceptibility to soman is significantly higher than mouse susceptibility.
- This difference is linked to the presence of plasma carboxylesterase in mice, which is absent in humans.
Purpose of the Study:
- To create a mouse model lacking functional plasma carboxylesterase.
- To investigate the protective role of plasma carboxylesterase against organophosphorus compounds.
Main Methods:
- Homologous recombination was used to inactivate the carboxylesterase ES1 gene.
- Exon 5 deletion and frameshift mutation were introduced in the ES1 gene.
- ES1-/- mice were challenged with a soman analog and compared to wild-type littermates.
Main Results:
- ES1-/- mice exhibited no plasma carboxylesterase activity but retained tissue activity.
- A soman analog at 3 mg/kg was lethal to ES1-/- mice but only intoxicating to wild-type mice.
- Plasma carboxylesterase demonstrated a protective effect against a highly toxic organophosphorus compound.
Conclusions:
- The ES1-/- mouse is a valuable model for studying highly toxic nerve agents.
- This model can be used to evaluate the efficacy of nerve agent countermeasures.
- Plasma carboxylesterase plays a critical role in mitigating organophosphorus compound toxicity.
