Metabolism and Age-Related Organophosphate Toxicity

描述(申请人提供)：有机磷(OP)杀虫剂，广泛用于农业和居民，显示各种化学物质。OP杀虫剂表现出广泛的急性毒性水平，这在很大程度上取决于化合物特定的解毒效率。幼虫通常比成虫更容易受到有机磷杀虫剂的毒害。幼体未成熟的异物解毒能力较低，导致其脆弱性增强。合乎逻辑的结论是，在成人中容易解毒的化合物在青少年中表现出相对较高的毒性水平，而不容易解毒的化合物；换句话说，所谓的“更安全”的杀虫剂(基于成人的低毒水平)对婴儿和儿童的危险相对大于“不安全”的杀虫剂。这项应用的目的是确定幼年和成年大鼠暴露于一组具有代表性的OP化合物后对毒性效应的相对易感性，并表征解毒在这些易感性中的作用。假设是：在高暴露水平下观察到的OP杀虫剂对成虫毒性的较低脆弱性主要是由于(其成熟的解毒系统更有效；对成虫毒性较小的化合物，即那些传统上被视为“更安全”的化合物，对单个OP化合物的易感性随年龄的差异将更大。该假说源于我们的初步发现，即成人和青少年的急性毒性水平与几种保护性酯酶的水平和效率密切相关。我们计划通过调查以下两个具体目标来验证我们的假设：1.确定12个选定的OP化合物的关键解毒机制的体外效率和发育过程中靶标酶的敏感性；2.确定这12个OP化合物的解毒机制对体内不同年龄OP毒性水平的贡献。该项目将利用我们实验室合成的新型OP化合物，这些化合物显示出独特的0抑制效力和解毒潜力。该项目将研究每个测试化合物的肝脏和血液解毒机制(保护性酯酶：羧酸酯酶、非靶标乙酰胆碱酯酶、丁酰胆碱酯酶、A-酯酶)和靶标酶(脑乙酰胆碱酯酶和外周乙酰胆碱酯酶)的敏感性。实验将在2只幼龄(1天和12天)的大鼠和成年大鼠身上进行。我们预计，解毒效率将是特定于化合物的，这些保护性酯酶对OP的解毒效率的测定将允许预测青少年的毒性水平将与成人的毒性水平有多大差异，以及更容易解毒的化合物将有更显著的年龄相关差异。这些结果将表明脱毒对毒性水平的贡献，并将允许更准确地预测与年龄相关的毒性差异。

DESCRIPTION (provided by applicant): Organophosphorus (OP) insecticides, extensively used agriculturally and residentially, display a variety of chemistries. OP insecticides demonstrate a wide range of acute toxicity levels, which are largely dependent on the compound-specific efficiencies of detoxication. Juveniles are typically more vulnerable than adults to the toxic effects of OP insecticides. The low immature xenobiotic detoxication capacity of juveniles contributes to their enhanced vulnerability. It is logical to conclude that compounds, which are readily detoxified in adults, will display relatively higher toxicity levels in juveniles than compounds, which are not readily detoxified; in other words, the so-called "safer" insecticides (based on low toxicity levels in adults) are of relatively more danger to infants and children than are the "unsafe" insecticides. The objective of this application is to determine the relative degree of vulnerability to toxic effects following exposures to a representative group of OP compounds in juvenile and adult rats, and to characterize the role of detoxication in these vulnerabilities. The hypothesis is: The lower vulnerability of adults to the toxicity of OP insecticides observed at high exposure levels is primarily the result of (he greater effectiveness of their mature detoxication systems; the age-related differences in vulnerability to individual OP compounds will be greater for the compounds which are less toxic to adults, i.e., those traditionally viewed as "safer" This hypothesis was derived from our preliminary findings that acute toxicity levels in both adults and juveniles are strongly related to the levels and the efficiency of several protective esterases. We plan to test our hypothesis by investigating the following two specific aims: 1. Determine for 12 select OP compounds the in vitro efficiency of critical detoxication mechanisms and of target enzyme sensitivity during development; and 2. Determine for these 12 OP compounds the contribution of detoxication mechanisms to the in vivo OP toxicity levels among ages. The project will utilize novel OP compounds synthesized in our laboratories, which demonstrate unique characteristics 0 inhibitory potency plus detoxication potential. The project will investigate the efficiency of hepatic and blood detoxication mechanisms (the protective esterases: carboxylesterases, non-target acetylcholinesterase, butyrylcholinesterase, A-esterase) and target enzyme (brain and peripheral acetylcholinesterase) sensitivity for each test compound. Experiments will be conducted in rats of 2 juvenile ages (1 and 12 days) and adults. We expect that detoxication efficiencies will be compound-specific, that the determination of the efficiencies of these protective esterases to detoxify the OP's will allow a prediction of how greatly the juvenile toxicity levels will differ from those of adults, and that there will be more dramatic age-related differences in compounds which are more readily detoxified. These results will indicate the contribution of detoxication to toxicity level, and will allow more accurate predictions of age-related differences in toxicity.