Characterization of Serum Carboxylesterase Knockout Mice as a Model for Organophosphorous Nerve Agent Research

Abstract

Mice are low on the phylogenetic scale and consume fewer resources than other animal models, but one drawback in chemical defense research is their increased resistance to G-type organophosphorus nerve agents (OPs) relative to non-human primates and presumably humans. The protein serum carboxylesterase (sCaE) expressed by the Es-1gene is found in mice and rats, but not in primates; this protein confers increased protection against G-type OPs such as sarin (GB) and soman (GD), but not V-type OPs such as VX. Using standard mating schemes coupled with appropriate genetic and phenotypic monitoring, we are breeding mice lacking the gene Es-1 (sCaE knockout [KO] mice) and wild-type (WT) counterparts, on the C57BL/6 background. sCaE plays no known physiological role in mice, and KO and WT mice are expected to exhibit similar physiological profiles; to confirm this, we compared the overall health, blood chemistry profiles, and CBCs from mice of each background. Additionally, we performed Affymetrix gene chip analyses on multiple organs from KO and WT mice to examine gene expression levels. These data suggest that with the exception of a lack of sCaE activity in their blood, KO mice exhibit similar physiological profiles to WT mice. We have determined LD50 values of VX, GB, and GD in both KO and WT mice using the Dixon and Massey method. LD50 values of GB and GD in the KO mice are 10-20% of those in WT mice, while LD50 values for VX do not differ substantially between KO and WT mice. Bioscavenger enzymes such as BuChE can be administered to the KO mice, and provide protection against 2 X LD50 GB and GD. Together, these data support the hypothesis that sCaE KO mice are a more relevant small animal model for predicting human responses to these OPs than guinea pigs, rats, or WT mice.