Evaluating mice lacking serum carboxylesterase as a behavioral model for nerve agent intoxication.

Area of Science:

• Toxicology
• Pharmacology
• Genetics

Background:

• Rodents are common models for nerve agent research due to carboxylesterase activity.
• Human blood lacks significant carboxylesterase, making rodent models less accurate for therapeutic development.
• Serum carboxylesterase (Es1) is a natural bioscavenger that detoxifies nerve agents.

Purpose of the Study:

• To evaluate the utility of a serum carboxylesterase knockout (Es1 KO) mouse as a more human-like model for nerve agent research.
• To compare gene expression, soman (GD) median lethal dose (MLD), and behavior between Es1 KO and wild type (WT) mice.

Main Methods:

• Gene expression analysis across over 34,000 genes.
• Determination of median lethal dose (MLD) for soman (GD) in Es1 KO and WT mice.
• Behavioral testing including open field, zero maze, Barnes maze, and sucrose preference tests.

Main Results:

• No significant gene expression differences were found between Es1 KO and WT mice.
• Es1 KO mice exhibited a significantly lower MLD for soman (GD) compared to WT mice, indicating higher susceptibility.
• Behavioral and neuropathological assessments showed largely similar responses between Es1 KO and WT mice following GD exposure, despite differing toxicities.

Conclusions:

• Es1 KO mice demonstrate enhanced susceptibility to soman (GD) toxicity.
• Es1 KO mice maintain typical physiological and behavioral responses to nerve agents, unlike WT mice.
• The Es1 KO mouse represents a more accurate and human-relevant model for studying nerve agent toxicity and developing therapeutics.