U.S. Army Medical Research Institute of Chemical Defense, 8350 Ricketts Point Rd, Aberdeen Proving Ground, MD 21010, United States.
U.S. Army Medical Research Institute of Chemical Defense, 8350 Ricketts Point Rd, Aberdeen Proving Ground, MD 21010, United States.
Toxicology. 2018 Dec 1;410:10-15. doi: 10.1016/j.tox.2018.08.016. Epub 2018 Aug 30.
Genetics likely play a role in various responses to nerve agent (NA) exposure, as genetic background plays an important role in behavioral, neurological, and physiological responses. This study uses different mouse strains to identify if mouse strain differences in sarin exposure exist. In Experiment 1, basal levels of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and carboxylesterase (CE) were measured in different strains of naïve mice to account for potential pharmacokinetic determinants of individual differences. In Experiment 2, median lethal dose (MLD) levels were estimated in 8 inbred mouse strains following subcutaneous (s.c.) administration of sarin. Few strain or sex differences in esterase activity levels were observed, with the exception of erythrocyte AChE activity in the C57BL/6J strain. Both sex and strain differences in toxicity were observed, with the most resistant strains being the BALB/cByJ and FVB/NJ strains and the most sensitive strain being the DBA/2J strain. These findings can be expanded to explore pathways involved in NA response, which may provide an avenue to develop therapeutics for preventing and treating the damaging effects of NA exposure.
遗传学可能在对神经毒剂（NA）暴露的各种反应中起作用，因为遗传背景在行为、神经和生理反应中起着重要作用。本研究使用不同的小鼠品系来确定沙林暴露是否存在小鼠品系差异。在实验 1 中，测量了不同品系未接触过沙林的小鼠的基础乙酰胆碱酯酶（AChE）、丁酰胆碱酯酶（BChE）和羧酸酯酶（CE）水平，以解释个体差异的潜在药代动力学决定因素。在实验 2 中，估计了 8 种近交系小鼠经皮下（s.c.）给予沙林后的半数致死剂量（MLD）水平。观察到酯酶活性水平的品系或性别差异很少，除了 C57BL/6J 品系的红细胞 AChE 活性外。毒性存在性别和品系差异，最具抗性的品系是 BALB/cByJ 和 FVB/NJ 品系，最敏感的品系是 DBA/2J 品系。这些发现可以扩展到探索参与 NA 反应的途径，这可能为预防和治疗 NA 暴露的破坏性影响提供治疗方法。
