BIOMARKERS OF BENZENE EXPOSURE AND GENOTOXICITY

苯暴露和基因毒性的生物标志物

• 批准号: 6045502
• 负责人: MARTYN T SMITH
• 金额: $ 42.59万
• 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 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6045502
• 关键词: Chinese; DNA damage; benzene; biomarker; chemical carcinogenesis; chromosome aberrations; chromosome translocation; clinical research; environmental exposure; environmental toxicology; fluorescent in situ hybridization; genetic polymorphism; genetic susceptibility; human subject; leukemia; neoplasm /cancer epidemiology; occupational hazard; polymerase chain reaction; vitamin B12

Benzene is an important industrial chemical (greater than 2 billion pounds produced annually in U.S.) And component of gasoline. It is also an established human leukemogen. The shape of the dose-response curve for benzene-induced leukemia at exposures below 10 ppm is highly controversial and a key public policy and risk assessment issue involving potentially billions of dollars. Conventional epidemiology and toxicology studies are unlikely to resolve this controversy. Work performed to date on this grant has led to the development of a mechanistically- relevant biomarker that should be sufficiently sensitive to shed light on the dose-response curve in the low dose region. This biomarker is the simultaneous detection of leukemia-specific aberrations in chromosomes 5, 7, 8 and 21 by fluorescence in situ hybridization in metaphase cells. We propose to examine this and other biomarkers in the blood of 300 workers exposed to a wide range of benzene concentrations (0.5 to greater than 10 ppm) and 150 unexposed matched controls. The first year will be devoted to the collection of these biological samples with detailed exposure information and sophisticated sample processing such that many new endpoints can be examined. Prior work on this grant has also shown that specific chromosomal translocations related to leukemogenesis can be detected by the reverse transcriptase-polymerase chain reaction (RT-PCR) in benzene- exposed workers. Recent advances in kinetic real-time PCR now make it possible to quantitate accurately the level of various chromosome translocations. We propose to use quantitative real- time PCR to measure levels of the translocations t(8;21), t(9;22), t(11q23) and t(14;18) in the peripheral blood lymphocytes and granulocytes of workers exposed to benzene and unexposed controls. Our studies to date also suggest that individuals differ in their susceptibility to benzene toxicity in relation to their folate status and genetic make-up. We therefore propose to further examine the role folate, vitamin B12, and various genetic polymorphisms play in individual susceptibility to benzene-induced chromosome damage. These studies will contribute to our understanding of the mechanism of benzene-induced leukemia, the risk benzene poses at low doses, and factors associated with susceptibility to this compound.

苯是一种重要的工业化学品(美国年产量超过20亿磅)以及汽油的成分。它也是一种公认的人类白血病原。在低于10ppm的暴露下，苯致白血病的剂量-反应曲线的形状是极具争议的，也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。传统的流行病学和毒理学研究不太可能解决这一争议。到目前为止，在这笔赠款上所做的工作已经导致了一种与机械相关的生物标记物的开发，该标记物应该足够灵敏，以揭示低剂量区域的剂量-反应曲线。这一生物标志物是通过中期细胞中的荧光原位杂交同时检测5、7、8和21号染色体上的白血病特异性异常。我们建议对300名接触大范围苯浓度(0.5到大于10ppm)的工人和150名未接触的对照工人的血液中的这一生物标志物和其他生物标志物进行检测。第一年将专门收集这些生物样本，提供详细的暴露信息和复杂的样本处理，以便可以检查许多新的终点。这项赠款之前的工作也表明，可以通过逆转录聚合酶链式反应(RT-PCR)在苯接触工人中检测到与白血病发生相关的特定染色体易位。动态实时聚合酶链式反应的最新进展使精确定量各种染色体易位水平成为可能。我们建议用实时定量聚合酶链式反应检测苯接触者和非苯接触者外周血淋巴细胞和粒细胞中t(8；21)、t(9；22)、t(11q23)和t(14；18)易位的水平。到目前为止，我们的研究还表明，个体对苯中毒的易感性与其叶酸状况和遗传构成有关。因此，我们建议进一步研究叶酸、维生素B12和各种基因多态在个体对苯引起的染色体损伤易感性中所起的作用。这些研究将有助于我们理解苯诱发白血病的机制，低剂量苯带来的风险，以及与这种化合物的易感性相关的因素。