MOLECULAR BIOMARKERS OF OCCUPATIONAL BENZENE EXPOSURE

职业苯暴露的分子生物标志物

• 批准号: 6271061
• 负责人: John K. Wiencke
• 金额: $ 21万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6271061
• 关键词: DNA damage; adduct; benzene; biomarker; bladder neoplasm; cancer risk; chemical carcinogenesis; chemical related neoplasm /cancer; cytotoxicity; diet; environmental toxicology; gene deletion mutation; genetic polymorphism; glutathione transferase; human subject; hydrocarbons; methane; neoplasm /cancer genetics; nucleic acid sequence; nutrition related tag; occupational hazard; pediatric neoplasm /cancer; polymerase chain reaction; racial /ethnic difference; statistics /biometry; western blottings

Genetic traits that confer increased susceptibility to DNA and chromosomal damage by reactive epoxide and peroxides could be important individual risk factors in the development of human cancers. In the present study we will focus on polymorphisms within the glutathione S-transferase (GST) family of enzymes as potential markers of susceptibility to carcinogen exposure. The special focus of these studies is to explore in depth the relationship of a newly discovered deletion polymorphism in GSTT1 with biomarkers of exposure, early biologic effect, and cancer occurrence--specifically childhood leukemia, and bladder cancer. Because the prevalence of the GSTT1 deletion is unknown in different populations, it is important to obtain background data on the distribution of the trait in different ethnic and racial groups. We will compare the prevalence of the GSTT1 deletion using a PCR based assay in various ethnic and racial groups including:Caucasian, Chinese, korean, African-American, and mexican, and Mexican Hispanic subjects. Next, studies will be undertaken to examine the role of the GSTT1 polymorphism as a modifier of biomarkers of genotoxicity associated with endogenous and environmental exposures. In vitro studies will be undertaken o test whether individuals deficient in GSTT1 are hypersensitive to chromosomal damage and DNA adducts induced by lipid hydroperoxides, which may be derived from the diet or through exposure to halogenated hydrocarbons. In addition, because of the possible involvement of chlorinated hydrocarbons contaminated drinking water and bladder cancer and leukemia, we will test the effects of GSTT1 deletion on trihalomethanes. Because GSTT1 is associated with background variations in SCE frequencies and is implicated in the detoxification of diet-related fatty acid hydroperoxides, we will examine the potential role of diet on the SCE marker and will correlate the SCE data with the levels of lipid peroxide DNA adducts. To examine the potential modification of cancer risk we will carry out case-control comparisons of the prevalence of the GSTM1 and GSTT1 deletion in childhood leukemia and correlate GSTT1 status with the mutational spectra within the p53 gene in bladder tumors. Mutation data and genotyping data will be merged with the ongoing epidemiologic projects to assess the possible relationships of GDT polymorphisms with dietary and environmental risk factors for childhood leukemia and bladder cancer.

遗传性状赋予增加的DNA和染色体易感性 反应性环氧化物和过氧化物的损伤可能是重要的个体风险 人类癌症发展的因素。 在本研究中，我们将 专注于谷胱甘肽S-转移酶（GST）家族内的多态性， 酶作为致癌物暴露易感性的潜在标志物。 的 这些研究的特别重点是深入探讨 一种新发现的GSTT 1缺失多态性， 暴露，早期生物效应和癌症发生-特别是 儿童白血病和膀胱癌 因为流行的 GSTT 1缺失在不同人群中是未知的， 获得关于该特征在不同种族中的分布的背景数据 和种族群体。 我们将比较GSTT 1缺失的患病率， 在不同种族和人种中使用基于PCR的测定 包括：高加索人、中国人、韩国人、非洲裔美国人和墨西哥人， 西班牙裔墨西哥人。 下一步，将进行研究， GSTT 1多态性作为遗传毒性生物标志物修饰剂的作用 与内源性和环境暴露有关。体外研究 将进行测试是否在GSTT 1缺陷的个人， 对脂质诱导的染色体损伤和DNA加合物过敏 氢过氧化物，可能来自饮食或通过暴露于 卤化烃。 此外，由于可能涉及 氯化碳氢化合物污染的饮用水和膀胱癌 和白血病，我们将测试GSTT 1缺失对 三卤甲烷 由于GSTT 1与背景变化有关， SCE频率，并与饮食相关的解毒有关 脂肪酸氢过氧化物，我们将研究饮食对 SCE标记物，并将SCE数据与脂质水平相关联 过氧化物DNA加合物。 研究癌症风险的潜在改变 我们将对GSTM 1的患病率进行病例对照比较 儿童白血病中GSTT 1和GSTT 1缺失的相关性 膀胱肿瘤中p53基因的突变谱。 突变 数据和基因分型数据将与正在进行的流行病学调查合并， 项目，以评估GDT多态性与 儿童白血病和膀胱癌的饮食和环境危险因素 癌