Biomarkers of Benzene Exposure and Genotoxicity

苯暴露和遗传毒性的生物标志物

• 批准号: 6780512
• 负责人: MARTYN T SMITH
• 金额: $ 35.81万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6780512
• 关键词: Chinese; DNA damage; benzene; biomarker; chemical carcinogenesis; chemical related neoplasm /cancer; chromosome aberrations; chromosome translocation; clinical research; environmental exposure; environmental toxicology; fluorescent in situ hybridization; gene environment interaction; genetic polymorphism; genetic susceptibility; human genetic material tag; human subject; leukemia; microarray technology; neoplasm /cancer epidemiology; occupational hazard; polymerase chain reaction; proteomics; vitamin B12

DESCRIPTION (provided by applicant): The shape of the dose-response curve for benzene-induced leukemia at exposures below 10 ppm is a key public policy and risk assessment issue involving potentially billions of dollars. During the previous grant period, biological samples were collected from 250 workers exposed to a wide range of benzene concentrations (0.2 to 50 ppm as a time-weighted average, with 88% of the workers being exposed to <10 ppm) and 140 matched controls. These biological samples will be analyzed using a biomarker approach to (a) shed light on the dose-response curve for benzene's hematotoxic and genotoxic effects between 0.2 and 50 ppm in air and its mechanisms of toxicity; and, (b) develop new biomarkers of exposure, early effect and susceptibility for benzene. Leukemia-specific chromosome aberrations will be measured by fluorescence in situ hybridization in the metaphase spreads of lymphocytes of all 390 study subjects and the dose-response relationship evaluated. Further, using a new technique called OctoChrome FISH the effects of benzene on all chromosomes will be investigated to determine if it has selective effects. In a sub-group of 53 subjects hematopoietic progenitor cells circulating in the blood were cultured in colony forming assays, allowing us to evaluate the dose-dependent effects of benzene on these target cells. The level of genetic damage in progenitor cells will also be compared with that found in lymphocytes to determine if the latter are good surrogates. More than 40 genetic polymorphisms and folate and vitamin B status have been determined in all study subjects. This data will be correlated with data on chromosome damage and hematotoxicity to determine the role these effect-modifiers play in susceptibility to benzene. Finally, emerging technologies, such as microarrays and proteomics, offer a significant opportunity to develop new biomarkers and provide key mechanistic information. The use of Affymetrix microarrays is proposed and will reveal changes in gene expression related to benzene exposure. Further, application of a Ciphergen ProteinChip mass spectrometer will allow for differentially expressed proteins and protein modifications related to benzene exposure to be identified and a protein profile for benzene exposure to be established in serum and lymphocytes. The overall goal is to develop new biomarkers of exposure and early effect for benzene and provide new insights into the mechanisms of benzene toxicity.

描述(由申请人提供)：暴露在10ppm以下的苯引起的白血病的剂量-反应曲线的形状是一个关键的公共政策和风险评估问题，可能涉及数十亿美元。在前一次赠款期间，从250名暴露于大范围苯浓度(按时间加权平均为0.2至50ppm，88%的工人暴露于10ppm)的工人和140名匹配的对照组中收集了生物样本。这些生物样本将使用生物标记物方法进行分析，以(A)阐明空气中0.2至50ppm的苯的血液毒性和遗传毒性效应的剂量-反应曲线及其毒性机制；以及(B)开发苯的暴露、早期影响和敏感性的新生物标记物。我们将用荧光原位杂交技术在所有390名研究对象的淋巴细胞中期铺展中测量白血病特异的染色体畸变率，并评估剂量-反应关系。此外，使用一种名为OcChrome FISH的新技术，将研究苯对所有染色体的影响，以确定它是否具有选择性作用。在53名受试者的子组中，血液中循环的造血祖细胞在集落形成试验中进行培养，使我们能够评估苯对这些靶细胞的剂量依赖效应。祖细胞的遗传损伤水平也将与淋巴细胞中发现的水平进行比较，以确定后者是否是良好的替代品。在所有研究对象中，已经确定了40多个基因多态和叶酸和维生素B状态。这些数据将与染色体损伤和血液毒性数据相关联，以确定这些效应修饰物在苯易感性中所起的作用。最后，新兴技术，如微阵列和蛋白质组学，为开发新的生物标记物和提供关键的机制信息提供了重要的机会。建议使用Affymetrix微阵列，并将揭示与苯接触相关的基因表达的变化。此外，Ciphergen蛋白质芯片质谱仪的应用将允许识别与苯接触有关的差异表达蛋白质和蛋白质修饰，并建立血清和淋巴细胞中苯接触的蛋白质图谱。总体目标是开发苯暴露和早期影响的新生物标记物，并为苯毒性的机制提供新的见解。