Comparing the susceptibility of genetically modified mice to intoxication by organophosphorus nerve agents

Abstract

To examine the contributions of butyrylcholinesterase (BuChE) and paraoxonase 1 (PON1) to the gestalt resistance of mice to organophosphorus (OP) nerve agents, we determined the LD50s of GB, GD, and VX in mice deficient in BuChE, PON1, or both; likewise, mice expressing either human PON1 or the mutant G117H human BuChE were tested. The results indicate that the absence of BuChE, PON1, or both does not enhance susceptibility to GB or GD, and has only a modest effect on susceptibility to VX (statistically significant only for female mice). The transgenic expression of human PON1 or G117H BuChE did not enhance resistance to OP intoxication. LD50s varied by as much as 50% between mice of different backgrounds, independent of the presence of knockout or transgene alleles. Female mice of all backgrounds were more resistant to OP intoxication than corresponding males. The results suggest that in mice, neither BuChE nor PON1 plays a substantial role in resistance to OP intoxication. Further, for these enzymes to provide protection if administered as exogenous bioscavengers, they must be present at concentrations higher than normally found in mice.This work was supported by funding from DTRA.