ADDUCT FORMATION IN THE TOXICITY OF DITHIOCARBAMATES

描述：（改编自研究者摘要）人体暴露于 二硫代氨基甲酸酯衍生自它们在农业、工业和医药中的许多用途。 药 虽然二硫代氨基甲酸酯的降解途径相当复杂， 很好地理解，目前关于分子的知识很少。 所观察到的生物效应的目标和机制 二硫代氨基甲酸盐。 其中一个主要的分解产物 二硫代氨基甲酸盐CS2是一种已知的神经毒剂。 主要目标 这个项目的目的是描述潜在的相互作用， 二硫代氨基甲酸酯及其在生物系统中的分解产物 并确定这些相互作用的相关性， 毒性和这些相互作用作为暴露的生物标志物的效用， 效果 本调查以下列工作假设为指导： 1)二烷基二硫代氨基甲酸酯和双（硫代氨基甲酰基）二硫化物 通过释放二硫化碳产生神经毒性， 蛋白质的衍生和交联;和2）共价 用二硫化碳包括二硫代氨基甲酸酯修饰蛋白质 形成和共价交联可用作暴露的生物标志物 以及对二硫代氨基甲酸酯、双（硫代氨基甲酰基）二硫化物和CS2的影响。 这些假设将通过确定形态学 神经系统的变化和产生的共价修饰 外周标记蛋白和神经内推定的靶蛋白 系统的双（硫代氨基甲酰）二硫化物;并通过测定 剂量反应、检测灵敏度和蓄积率， 消除CS2介导的血红蛋白和二硫代氨基甲酸酯的交联 急性、亚急性和慢性接触后对血液蛋白的影响 二硫代氨基甲酸盐和CS2的环境相关水平。 划定 的分子机制和有效的生物标志物的发展将 促进进行基于机制的风险评估， 这些广泛使用的结构活性关系的制定 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.