Sex differences in soman-induced toxicity and response to medical countermeasures in serum carboxylesterase knockout mice

Abstract

In rodents, exposure to chemical warfare nerve agent soman leads to status epilepticus and extensive neuronal loss. Mice and rats are less sensitive to nerve agent toxicity compared to primates since high levels of plasma carboxylesterase, which acts as a bioscavenger against soman, increase resistance of these rodents to organophosphorus poisoning. One objective of this research project was to determine the LD50s of soman in female plasma carboxylesterase knockout (ES1-/-) mice at the different stages of their estrous cycle and to compare toxicity across estrous and with male mice. Female mice in estrus were less susceptible to the soman lethality compared to female mice in proestrus and to male mice. The second objective was to evaluate dose-response effects of delayed midazolam treatment in soman-exposed ES1-/- mice. Delayed midazolam dose-dependently increased survival and reduced seizure severity but did not prevent epileptogenesis or brain pathology in seizure-sensitive brain regions, independent of sex.