DNA adductome of human bladder from the tobacco exposome

来自烟草暴露组的人类膀胱 DNA 加合组

• 批准号: 9904674
• 负责人: Robert J. Turesky
• 金额: $ 45.45万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9904674
• 关键词: 4-biphenylamine; Air; Aromatic Amines; Aromatic Polycyclic Hydrocarbons; Bacteria; Benzo(a)pyrene; Biological Markers; Biopsy; Bladder; Butanones; Cancer Patient; Carcinogen Metabolism; Carcinogens; Cell Culture Techniques; Cell Line; Cells; Centers for Disease Control and Prevention (U.S.); Chemical Exposure; Chemical Structure; Chemicals; Chemoprevention; Cigarette; Clinical; Coculture Techniques; Colorectal Cancer; DNA; DNA Adduction; DNA Adducts; DNA Damage; DNA Repair Enzymes; Data; Diet; Dyes; Environment; Environmental Exposure; Environmental Pollutants; Enzymes; Epithelial; Epithelial Cells; Epithelium; Etiology; Exposure to; Future; Goals; Hepatocyte; Human; Incubated; Indoles; Industry; Investigation; Isotope Labeling; Laboratories; Life Style; Link; Liver; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of urinary bladder; Mass Spectrum Analysis; Measurement; Measures; Meat; Metabolism; Methods; Microsomes; Mission; Modeling; Mutation; Nitrosamines; Nitroso Compounds; Occupational Exposure; Organ; Oxidative Stress; Pathogenesis; Patients; Phase; Phenotype; Prevention strategy; Public Health; Reporting; Research; Risk; Risk Factors; Rodent; Role; Rubber; Screening procedure; Site; Smoker; Source; Structure; System; Textiles; Tobacco; Tobacco Use Cessation; Tobacco smoke; Tobacco smoking behavior; Tobacco-Associated Carcinogen; Toluidines; Toxic Environmental Substances; Toxic effect; United States; United States National Institutes of Health; Urine; Urothelium; adduct; base; bladder surgery; bronchial epithelium; cancer risk; cancer surgery; carcinogenicity; cigarette smoke; cooking; epidemiology study; exposed human population; genotoxicity; heterocyclic aromatic amines; liver metabolism; non-smoker; non-smoking; novel; pollutant; tobacco carcinogenesis; tobacco toxicant; tool; toxicant; urinary

Summary More than 70 chemicals in tobacco smoke are carcinogens. Tobacco smoking is a risk factor for bladder cancer; however, despite many years of study, the principal chemicals in tobacco smoke and environment that damage DNA of the bladder are unknown. Aromatic amines (AAs) and heterocyclic aromatic amines (HAAs) arise in tobacco smoke and are responsible for much of the mutagenicity in urine of smokers. Some AAs (and possibly HAAs) are bladder carcinogens, and also induce liver, bladder, and colorectal cancer in rodents, and likely contribute to these cancers in humans. 4-Aminobiphenyl (4-ABP) is a human bladder carcinogen; however, several alkylanilines and structurally related HAAs occur in tobacco smoke at levels up to 100-fold greater than 4-ABP. Some epidemiological studies have linked N-nitroso compounds and polycyclic aromatic hydrocarbons as risk factors for bladder cancer. Robust measurements of DNA adducts are important to understand the chemicals in tobacco smoke, the environment, and diet that damage the bladder and may contribute to bladder cancer. Apart from 4-ABP, the chemicals in tobacco smoke that damage bladder DNA are unknown. The objective of this application is to apply robust screening tools to identify DNA adducts derived from exogenous and endogenous sources that damage bladder DNA. We will employ our newly developed mass spectrometry (MS) adductomic tools to identify the major chemicals in tobacco smoke condensate that form DNA adducts in the bladder of smokers. In Aim 1, we will conduct studies with cigarette smoke extract (CSE) and human bladder cells incubated alone or in co-culture with hepatocytes to assess the role of liver metabolism in DNA damage of the bladder. The panel of DNA adducts formed in bladder cells with CSE will serve as a guide to facilitate the characterization of the DNA adductome of the urothelium of smokers and nonsmokers undergoing bladder cancer surgery in Aim 2. Some procarcinogens in CSE can reach the bladder and undergo bioactivation by P450s expressed in the bladder, particularly aromatic amines and HAAs. Therefore, in Aim 3, we will examine the urinary exposome of AAs and HAAs in smokers participating in a tobacco cessation study by novel mass- tagging methods to measure the totality of these potential bladder carcinogens in urine, and assess the capacity of bladder enzymes to bioactivate these compounds. Our research is relevant to NIH's mission on public health. Our studies will provide a greater understanding about genotoxicants in tobacco smoke the environment that damage bladder DNA and contribute to bladder cancer. By merging chemical exposures and DNA adducts with mutational data, clues about the identities of environmental, dietary and endogenous genotoxicants can be established to identify subjects at risk for bladder cancer. Once identified, pragmatic measures can be taken to reduce human exposure to chemicals, by changes in life- style or mitigation of environmental exposures, which are probably the most efficient means of chemoprevention.

概括 烟草烟雾中有70多种化学物质是致癌物。吸烟是膀胱癌的危险因素。 然而，尽管研究了多年，但烟草烟雾和环境中的主要化学物质会损害 膀胱的DNA未知。芳香胺（AAS）和杂环芳香胺（HAA）出现在 烟草吸烟，并负责吸烟者尿液中的大部分诱变。一些AA（可能还有 Haas）是膀胱致癌物，也诱导啮齿动物中的肝脏，膀胱和大肠癌，并且可能 在人类中为这些癌症做出贡献。 4-氨基苯基（4-ABP）是人类膀胱致癌；然而， 烟草烟中发生了几种烷基苯胺和与结构相关的HAA，其水平高达100倍，大于100倍 4-abp。一些流行病学研究已将N-亚硝基化合物和多环芳烃联系起来 作为膀胱癌的危险因素。 DNA加合物的强大测量对于了解 烟草中的化学物质，环境和饮食损害膀胱，可能导致膀胱癌。 除了4-ABP外，烟草烟雾中的化学物质损害了膀胱DNA是未知的。目的 此应用是应用强大的筛选工具来识别从外源和 损害膀胱DNA的内源性来源。我们将采用新开发的质谱法（MS） 鉴定烟草烟雾中的主要化学物质的辅助工具，形成了DNA加合物 吸烟者的膀胱。在AIM 1中，我们将使用香烟烟雾提取物（CSE）和人膀胱进行研究 单独或与肝细胞共培养的细胞，以评估肝脏代谢在DNA损伤中的作用 膀胱。用CSE在膀胱细胞中形成的DNA加合物面板将作为促进 吸烟者和非吸烟者的尿路上皮的DNA成合体的表征 AIM 2中的癌症手术。CSE中的某些procarcinogens可以到达膀胱并通过生物活化 P450在膀胱中表达，尤其是芳香胺和HAA。因此，在AIM 3中，我们将检查 在吸烟者中，AAS和HAA的尿液驱动器参与了新的质量戒烟研究 标记方法来测量尿液中这些潜在的膀胱致癌物的总数，并评估能力 膀胱酶以生物活化为生。 我们的研究与NIH的公共卫生任务有关。我们的研究将对 烟草中的遗传毒性吸烟会损害膀胱DNA并导致膀胱癌的环境。 通过将化学暴露和DNA加合物与突变数据合并，有关 可以建立环境，饮食和内源性遗传毒性，以识别患有膀胱癌风险的受试者。 一旦确定，就可以采取务实的措施来减少人类对化学物质的接触，并通过生活的变化 - 风格或缓解环境暴露，这可能是最有效的化学预防手段。