Human Sensitivity to Genotoxic Effects of Butadiene

描述（由申请人提供）：丁二醇（BD）是一种用于合成橡胶生产的气态化合物，是一种来自汽车尾气和烟草烟雾的环境污染物。它是一种强效啮齿动物致癌物，也可能是人类致癌物。在目前的职业暴露水平下，很难确定与工作场所BD暴露相关的癌症风险。该项目的广泛目标是通过使用暴露的生物标志物、暴露影响的标志物和暴露于BD的工人对暴露的敏感性的标志物来表征人类对BD的敏感性。在上一个项目期间，我们发现BD暴露与尿液中丁二烯相关代谢物浓度增加以及淋巴细胞中hprt突变的剂量相关增加相关。缺失和移码突变的比例增加。此外，突变的频率增加BD暴露的个人与多态性的组合，导致微粒体环氧化物水解酶（mEH）的活性低。本提案的目的是1）描述微粒体环氧化物水解酶多态性对职业暴露于BD的个体中HPRT基因中突变频率和不同类型突变谱的影响，2）体外表征mEH多态性在丁二烯二环氧化物诱导的遗传损伤中的功能意义，和3）表征mEH蛋白的不同等位基因形式的稳定性如何有助于mEH活性的细胞水平。通过这些目标，我们期望更好地了解mEH的遗传变异如何影响人类对BD遗传毒性效应的敏感性，并更好地了解生物转化基因变异在改变人类对有毒化学品敏感性中的作用

DESCRIPTION (provided by applicant): Butadiene (BD) is a gaseous compound used in the manufacture of synthetic rubber and is an environmental contaminant derived from auto exhaust and tobacco smoke. It is a potent rodent carcinogen and probable human carcinogen. At current levels of occupational exposure it will be very difficult to determine the cancer risks related to workplace BD exposure. The broad objective of this project has been to characterize human sensitivity to BD by using biological markers of exposure, markers of the effects of exposure, and markers of susceptibility to exposure in BD-exposed workers. In the previous project period we found that BD exposure is associated with an increase in the concentration of a butadiene-related metabolite in urine, and a dose-related increase in hprt mutation in lymphocytes with an. increased proportion of deletion and frameshift mutations. Also, the frequency of mutations was increased in BD-exposed individuals with a combination of polymorphisms resulting in low activity of microsomal epoxide hydrolase (mEH). The aims of the current proposal are to 1) delineate the influence of microsomal epoxide hydrolase polymorphisms on mutant frequency and on the spectrum of different types of mutations in the HPRT gene in individuals occupationally exposed to BD, 2) characterize, in vitro, the functional significance of mEH polymorphisms in butadiene diepoxide- induced genetic damage, and 3) characterize how the stability of the different allelic forms of mEH proteins contributes to the cellular level of mEH activity. Through these aims we expect to better understand how genetic variation in mEH influences human sensitivity to the genotoxic effects of BD, and better understand the role of variants in biotransformation genes in modifying human susceptibility to toxic chemicals