Low Level Chemical Toxicity: Relevance to Chemical Agent Defense

摘要

Wright State University conducted a multidisciplinary project to study the influence of low-level exposure to chemical warfare agents which act via inhibition of acetylcholinesterase (AChE). The problem was covered from the level of the cell to the human subject. Project 1 demonstrated that treatment with AChE inhibitors I (sarin or pyridostigmine, PB) in conjunction with stress produced changes in brain gene and protein expression, autonomic function, muscarinic receptor function and behavior. There was evidence that PB entered the brain to exert its physiological actions. An important finding was that a dose of sarin which produced no effect on blood ChE, caused dramatic changes in autonomic neural function and hypothalamic and cerebral cortical genomic and proteomic expression. Data suggest that it is important not to overlook the importance of low level nerve agent exposure in humans. Project 1 also developed a method for sarin exposure which used pretreatment with a carboxylesterase inhibitor. This method produced an enhancement of sarin's central actions. Project 2 tested the effect of DEET, PB and sarin coupled with stress on brainstem function, brain and muscle metabolism in vivo, and brainstem energy metabolism. DEET/PB/stress caused no significant changes, while the sarin/stress combination antagonized the ability of mitochondria to reoxidize NADH. Project 3 focused on investigation of enzymes involved in chemical metabolism, aldehyde dehydrogenase, chi alcohol dehydrogenase, paraoxonase, and aryl esterase. Results suggest that human chemical sensitivity to formaldehyde and organophosphate correlates well with levels of specific enzyme activities in particular blood fractions. Project 4 focused on the study of genetic expression in neuronal cultures. Results showed that PB or sarin had no effect on the patterns of gene expression.