Human Sensitivity to Genotoxic Effects of Butadiene

描述(申请人提供)：丁二烯(BD)是一种用于制造合成橡胶的气体化合物，是一种来自汽车尾气和烟草烟雾的环境污染物。它是一种强有力的啮齿动物致癌物质，也可能是人类致癌物质。在目前的职业性接触水平下，很难确定与工作场所BD接触有关的癌症风险。该项目的广泛目标是通过使用接触BD的生物标记物、暴露影响的标记物和接触BD的工人的易感性标记物来表征人类对BD的敏感性。在之前的项目期间，我们发现BD暴露与尿中丁二烯相关代谢物浓度的增加以及AN患者淋巴细胞HPRT突变的剂量相关增加有关。缺失和移码突变的比例增加。此外，暴露于BD的个体中突变频率增加，其多态组合导致微粒体环氧化物水解酶(MeH)活性降低。本建议的目的是1)描述微体环氧化物水解酶多态对职业接触BD个体HPRT基因突变频率和不同类型突变谱的影响，2)在体外表征mEH多态在丁二烯二环氧化物诱导的遗传损伤中的功能意义，以及3)表征mEH蛋白不同等位形式的稳定性如何影响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的遗传毒性效应的敏感性，并更好地理解生物转化基因中的变异在改变人类对有毒化学物质的敏感性中的作用。

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