title: Production of ES1 plasma carboxylesterase knockout mice for toxicity studies.
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.
authors.affiliation: Eppley Institute, University of Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA.
authors.forename: Ellen G
authors.initials: EG
authors.lastname: Duysen
authors.forename: Frank
authors.initials: F
authors.lastname: Koentgen
authors.forename: Gareth R
authors.initials: GR
authors.lastname: Williams
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Timperley
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Schopfer
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Cerasoli
authors.forename: Oksana
authors.initials: O
authors.lastname: Lockridge
mesh_terms: D000483:Alleles; D000818:Animals; D001947:Breeding; D043182:Carboxylesterase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D002619:Chemical Warfare Agents / Q000009:adverse effects; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D005818:Genetic Engineering / Q000379:methods*; D005838:Genotype; D059765:Homologous Recombination; D006720:Homozygote; D006801:Humans; D007279:Injections, Subcutaneous; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000097:blood / Q000235:genetics*; D010641:Phenotype; D012999:Soman / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives
chemical_list: D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D012999:Soman; D043182:Carboxylesterase; C469486:Ces1c protein, mouse