ADDUCT FORMATION IN THE TOXICITY OF DITHIOCARBAMATES

描述：(改编自《调查者摘要》)人类接触 二硫代氨基甲酸酯源于它们在农业、工业和工业中的许多用途 医药。尽管二硫代氨基甲酸酯的降解途径相当 众所周知，目前关于分子的知识很少 观察到的生物效应的靶点和机制 二硫代氨基甲酸酯。它的主要分解产物之一 二硫代氨基甲酸酯，CS2，是一种已知的神经毒物。主要目标 这个项目的目的是勾勒出 生物体系中的二硫代氨基甲酸酯及其分解产物 并确定这些交互作用作为 毒性和这些相互作用作为暴露和感染的生物标志物的效用 效果。这项调查以以下工作假设为指导： 1)二烷基二硫代氨基甲酸酯和二(硫代氨基甲酰基)二硫化物 通过释放二硫化碳产生的神经毒性，产生 蛋白质的衍生化和交联化；以及2)共价 含二硫代氨基甲酸酯的二硫化碳修饰蛋白质 形成和共价交联可作为暴露的生物标志物 对二硫代氨基甲酸酯、二(硫代氨基甲酰基)二硫化物和CS2的影响。 这些假说将通过确定形态上的 神经系统的变化和产生的共价修饰 神经内的外周标志蛋白和可能的靶蛋白 二(硫代氨基甲酰基)二硫化物体系； 剂量反应、检测灵敏度和蓄积率 消除CS2在血红蛋白和二硫代氨基甲酸酯上的交联 急性、亚急性和慢性接触对血液蛋白质形成的影响 二硫代氨基甲酸盐和CS2的环境相关水平。划定 分子机制和有效生物标记物的开发将 促进基于机械的风险评估和 这些广泛使用的化合物的构效关系的制定 化合物。

DESCRIPTION: (Adapted from the Investigator's Abstract) Human exposure to dithiocarbamates derives from their many uses in agriculture, industry and medicine. Although the degradative pathways of dithiocarbamates are fairly well understood, there is presently little knowledge regarding the molecular targets and mechanisms underlying the observed biological effects of dithiocarbamates. One of the major decomposition products of dithiocarbamates, CS2, is a known neurotoxicant. The principal objectives of this project are to delineate the potential interactions of dithiocarbamates and their decomposition products within biological systems and to determine both the relevance of these interactions as mechanisms of toxicity and the utility of these interactions as biomarkers of exposure and effect. This investigation is guided by the following working hypotheses: 1) dialkyldithiocarbamates and bis(thiocarbamoyl) disulfides exert neurotoxicity through liberation of carbon disulfide, producing derivatization and cross-linking of proteins; and 2) that covalent modification of proteins by carbon disulfide including dithiocarbamate formation and covalent cross-linking can be used as biomarkers of exposure and effect for dithiocarbamates, bis(thiocarbamoyl) disulfides and CS2. These hypotheses will be tested through determining the morphological changes in the nervous system and the covalent modifications produced on peripheral marker proteins and putative target proteins within the nervous system by bis(thiocabamoyl) disulfides; and through determination of the dose response, sensitivity for detection and the rate of accumulation and elimination of CS2-mediated cross-linking on hemoglobin and dithiocarbamate formation on blood proteins following acute, subacute and chronic exposures to environmentally relevant levels of dithiocarbamates and CS2. Delineation of the molecular mechanisms and the development of valid biomarkers will facilitate the performance of mechanistically based risk assessments and the formulation of structure activity relationships for these widely used compounds.