BIOMARKERS OF EXPOSURE TO PULMONARY TOXICANTS

肺部毒物暴露的生物标志物

• 批准号: 3733705
• 负责人: ALAN R BUCKPITT
• 金额: --
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3733705
• 关键词: adduct; binding proteins; biomarker; chemical substitution; chemical synthesis; cytochrome P450; cytotoxicity; diagnosis design /evaluation; environmental toxicology; enzyme activity; fluorescence microscopy; halocarbon compound; hamsters; high performance liquid chromatography; immunocytochemistry; immunologic assay /test; laboratory mouse; laboratory rat; light microscopy; naphthalenes; naphthoquinones; nucleic acid sequence; respiratory toxin; trichloroethylene

Numerous studies in laboratory animals have demonstrated the importance of respiratory epithelial cells as targets for both inhaled and ingested chemicals. There are, however, significant uncertainties in estimating the risks to humans from exposure to chemicals which are respiratory cytotoxicants in animals. These uncertainties are both species- and dose- related. The overall goals of the work proposed in this application are to develop markers of exposure, effect and susceptibility for chemicals which produce lung toxicity in animals. This work is based on the premise that the development of markers capable of signalling that an exposure has been at a level sufficient to result in cytotoxicity is dependent upon a complete understanding of essential biochemical and metabolic steps involved in toxicity in animals. Accordingly, this work will define the importance of specific protein and nonprotein targets of electrophilic intermediates to cytotoxic injury for three chemicals that produce focal injury to the respiratory epithelium by virtue of cytochrome P450 dependent metabolism. These chemicals are naphthalene, nitronaphthalene and trichloroethylene. The well established difference in sensitivity of various species and the highly focal nature of the injury within the respiratory system will be used as an experimental tool to indicate which protein adducts are important to toxicity. This will then guide the development of biomarkers which are closely related to the mechanism of toxicity. The specific aims of the work are to: (l) validate immunochemical methodology for determination of diastereomeric mercapturic acids of naphthalene as an index of the rate and stereochemistry of formation of naphthalene epoxides, (2) identify critical protein targets for reactive metabolites generated from naphthalene, nitronaphthalene, and trichloroethylene, (3) use the information obtained in (2) to develop markers which can be monitored in nasal lavage, bronchiolar lavage, blood or urine as indices of exposure, effect and susceptibility and (4) refine new systems capable of evaluating samples obtained from hazardous waste sites for the possible presence of pulmonary toxic chemicals. This work is intended to reduce the uncertainty inherent in current assessments of risks associated with human exposure to pulmonary toxic chemicals by developing methodologies that are capable of distinguishing exposures that occur at levels sufficient to cause toxicity from those that are without significant effect. These studies should also provide the tools necessary for determining whether the metabolic and biochemical factors which lead to toxicity in animals are operative in human lungs and whether there are significant interindividual differences in these metabolic and biochemical pathways with human populations.

实验动物的大量研究表明了重要性 吸入和摄入的呼吸上皮细胞的靶标 化学物质。但是，估计有重大的不确定性 暴露于呼吸系统的化学物质的风险 动物中的细胞毒性。这些不确定性既是物种和剂量 - 有关的。本应用程序提出的工作的总体目标是 开发对化学物质的暴露，效果和敏感性的标记 在动物中产生肺毒性。这项工作基于前提 能够发出传播的标记的发展 已经足够导致细胞毒性的水平取决于 完全了解基本的生化和代谢 动物毒性涉及的步骤。因此，这项工作将定义 特定蛋白质和非蛋白质靶标的重要性 亲电中间体会导致三种化学物质的细胞毒性损伤 借助于 细胞色素P450代谢。这些化学物质是萘， 硝基苯二苯和三氯乙烯。良好的差异 在各种物种的敏感性和高度焦点 呼吸系统内的伤害将用作实验工具 指出哪些蛋白质加合物对毒性很重要。这会 然后指导与生物标志物的开发 毒性机制。工作的具体目的是：（l）验证 免疫化学方法学用于确定非对映异构体 萘的胃酸酸作为率的指数和 萘环氧化物的形成立体化学，（2）识别 从 萘，硝酸苯乙烯和三氯乙烯，（3）使用 在（2）中获得的信息开发标记，可以在 鼻腔灌洗，支气管灌洗，血液或尿液作为暴露指数， 效果和敏感性以及（4）完善能够的新系统 评估从危险废物站点获得的样品 肺有毒化学物质的存在。这项工作旨在减少 当前对与相关风险的评估固有的不确定性 通过开发方法，人类接触肺有毒化学物质 能够区分在水平上发生的暴露 足以引起没有意义的人的毒性 影响。这些研究还应提供必要的工具 确定代谢和生化因素是否导致 动物的毒性在人肺中是有效的，是否有 这些代谢和 人类种群的生化途径。