PROTEIN AND DNA ADDUCTS FOLLOWING LOW DOSE EXPOSURE BY ACCELERATOR MS

加速器 MS 低剂量照射后的蛋白质和 DNA 加合物

• 批准号: 5211139
• 负责人: KENNETH W TURTLETAUB
• 金额: --
• 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/5211139
• 关键词: DNA binding protein; adduct; arsenic; benzene; binding proteins; chemical carcinogen; dosage; environmental toxicology; gel electrophoresis; high performance liquid chromatography; industrial waste; laboratory mouse; macromolecule; mass spectrometry; method development; phenols; radiotracer; toluene; toxicant interaction; toxin metabolism; trichloroethylene

The scope of this proposal is to study the extent of benzene and trichloroethylene (TCE) macromolecular adduct formation, metabolism,a and interaction with other solvents at concentrations equivalent to human exposure levels outside the workplace. Benzene and TCE are important toxicants in the workplace and are ubiquitous in the environment. Most importantly, they are carcinogenic and are often found in combination with other potential carcinogens at wastesites and the behavior of chemicals in mixtures may differ substantially from pure compounds. Our goal for this project is to understand the relationship between chemical dose, the dose reaching the target issues and the resultant levels of macromolecular adducts that are formed at doses equivalent to those encountered around superfund waste sits. A second goal is to determine feasibility of measuring benzene and TCE metabolism in humans. Specifically, we will: 1. develop and validate methodology for ultra-low level measurement of TCE and benzene metabolism in rodents by accelerator mass spectrometry (AMS) in combination with HPLC and electrophoresis:" 2. identify the specific protein targets for benzene and TCE adduct formation in animal lymphocytes, hepatocytes, and plasma; 3. evaluate how xylene and toluene influence 14C-benzene metabolism in a murine model at low doses by AMS. The influence of these solvents on formation of DNA and protein adducts by AMS in target and non-target tissues will also be investigated: 4. compare how benzene and phenol, when administered in vivo, at low doses are metabolized. The extent of DNA and protein binding by these two compounds will be evaluated as well; and 5. determine how arsenic exposure influences 14C-benzene metabolism and macromolecular binding at exposure concentrations relevant for human environmental exposure. The results of this research project will be important for calculating the risk posed to humans by these compounds in the environment and will help pinpoint protein or DNA adducts that can be used for exposure assessments. This work will also lead to development of protocols for determining how benzene is metabolized at low dose and physiologically-based pharmacokinetic models relevant to determining the risk these compounds pose to the American public.

这项建议的范围是研究苯和 三氯乙烯(TCE)大分子加合物的形成、代谢、a和 在相当于人体的浓度下与其他溶剂的相互作用 工作场所以外的暴露水平。苯和三氯乙烯很重要 工作场所和环境中无处不在的有毒物质。多数 重要的是，它们是致癌的，经常被发现与 废物中的其他潜在致癌物质和化学物质在 混合物可能与纯化合物有很大不同。我们的目标是 项目是了解化学剂量和剂量之间的关系 达到目标问题和由此产生的大分子水平 形成的加合物的剂量与周围遇到的相同 超级基金浪费坐在那里。第二个目标是确定 测定苯和三氯乙烯在人体内的代谢。具体来说，我们会： 1.开发和验证三氯乙烯超低水平测量方法 和苯代谢在啮齿动物体内的加速器质谱仪(AMS) 与高效液相色谱和电泳法相结合： 2.确定苯和三氯乙烯加合物的特定蛋白质靶点。 在动物淋巴细胞、肝细胞和血浆中形成； 3.评估二甲苯和甲苯对14C-苯代谢的影响。 小剂量AMS建立小鼠模型。这些溶剂对黄曲霉毒素的影响 AMS在靶和非靶体内形成DNA和蛋白质加合物 还将对组织进行调查： 4.比较苯和苯酚在体内低剂量给药时的情况 被新陈代谢。这两者结合DNA和蛋白质的程度 还将对化合物进行评估；以及 5.确定砷暴露如何影响14C-苯代谢和 与人体相关的暴露浓度下的大分子结合 暴露在环境中。 这一研究项目的结果将对计算 环境中这些化合物对人类构成的风险，并将有助于 精确定位可用于暴露评估的蛋白质或DNA加合物。 这项工作还将导致开发协议，以确定如何 苯的代谢是低剂量的，以生理为基础。 与确定这些化合物的风险相关的药代动力学模型 向美国公众摆姿势。