Characterization of Genetically Modified Mice as Improved Animal Models for Organophosphorus Nerve Agent Research

Miceand other small rodent animal models are known to have greater resistance tointoxication by the organophosphorus (OP) nerve agents sarin, soman, andcyclosarin than do humans and non‐human primates. This resistance has beendirectly attributed to the presence of carboxylesterase in the blood plasma of these animals. Carboxylesterase acts asan endogenous bioscavenger and is not found in the blood plasma of humans andnon‐human primates. To create an improved small animal model of nerve agentintoxication, the gene encoding serum carboxylesterase ( Es1 ) in C57BL/6 mice was deleted to generate a transgenic strain of mice (Es1 KO) that no longer expresses this protein. In contrast with previousgenetic modification efforts to remove other endogenous bioscavenger enzymes frommice, the median lethal dose for several OP nerve agents in Es1 KO mice was significantly lower than that in wild type control mice. Physiological and behavioral characterizations of these mice have been conducted in an effort to determine their suitability as a small animal model for OP nerve agentintoxication. Removal of serum carboxylesterasere presents one piece of a gestalt in vivo model not only for predicting human OP nerve agent susceptibility but also for testing medical countermeasures for that intoxication. One of the primary molecular targets of many current and novel OP countermeasures isacetylcholinesterase (AChE), the enzyme which hydrolyzes the neurotransmitter acetylcholineto terminate nerve signaling. When the active site of this enzyme is covalently inhibited by OP nerve agents, the resulting cholinergic crisis can quickly result in death. Several countermeasures have been developed which act directly upon inhibited AChE to remove the OP nerve agent and restore enzyme activity. While AChE is found in all species, significant biochemical differences resulting from species‐specific amino acid variations have been observed in a variety of in vitro experiments. Efforts to quantify these differences using in vitro models have been undertaken in this study. Support or Funding Information *This research was supported in part by an appointment to the Postgraduate Research Participation Program at the U.S. Army Medical Research Institute of Chemical Defense administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U. S. Army Medical Research and Materiel Command. The experimental protocol was approved by the Animal Care and Use Committee at the United States Army Medical Research Institute of Chemical Defense and all procedures were conducted in accordance with the principles stated in the Guide for the Care and Use of Laboratory Animals (National Research Council, 2011), and the Animal Welfare Act of 1966 (P.L. 89‐544), as amended. This research was supported by the Defense Threat Reduction Agency – Joint Science and Technology Office, Medical S&T Division. The views expressed in this abstract are those of the author(s) and do not reflect the official policy of the Department of Army, Department of Defense, or the U.S. Government. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .