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.

总结 烟草烟雾中的70多种化学物质是致癌物质。吸烟是膀胱癌的危险因素; 然而，尽管经过多年的研究，烟草烟雾和环境中的主要化学物质， 膀胱的DNA未知。芳族胺（AA）和杂环芳族胺（哈斯）产生于 烟草烟雾，并负责吸烟者尿液中的大部分致突变性。一些AA（可能 哈斯）是膀胱致癌物，并且还在啮齿动物中诱导肝癌、膀胱癌和结肠直肠癌，并且可能 导致了人类的这些癌症4-氨基联苯（4-ABP）是一种人类膀胱癌致癌物;然而， 几种烷基苯胺和结构上相关的哈斯在烟草烟雾中的含量高达100倍， 4-ABP。一些流行病学研究将N-亚硝基化合物和多环芳烃联系起来 膀胱癌的危险因素。DNA加合物的稳健测量对于理解 烟草烟雾、环境和饮食中的化学物质损害膀胱，可能导致膀胱癌。 除了4-ABP，烟草烟雾中损害膀胱DNA的化学物质尚不清楚。的目标 本申请是应用强有力的筛选工具来鉴定来源于外源和外源DNA的DNA加合物， 内源性来源，损害膀胱DNA。我们将采用我们新开发的质谱（MS） 内收工具，以确定烟草烟雾冷凝物中形成DNA加合物的主要化学物质， 吸烟者的膀胱在目标1中，我们将用香烟烟雾提取物（CSE）和人膀胱进行研究。 细胞单独孵育或与肝细胞共培养，以评估肝代谢在肝细胞DNA损伤中的作用。 膀胱在膀胱细胞中与CSE形成的一组DNA加合物将作为指导，以促进CSE的表达。 吸烟者和非吸烟者膀胱移行细胞癌DNA内收体的特征 目标2中的癌症手术。CSE中的一些原致癌物可以到达膀胱并通过膀胱内的肿瘤细胞进行生物活化。 膀胱中表达的P450，特别是芳香胺和哈斯。因此，在目标3中，我们将研究 通过新的质量- 标记方法来测量尿液中这些潜在膀胱致癌物的总量，并评估其能力。 来激活这些化合物。 我们的研究与NIH在公共卫生方面的使命有关。我们的研究将提供一个更好的理解， 烟草中的遗传毒素会破坏环境，破坏膀胱DNA，导致膀胱癌。 通过将化学暴露和DNA加合物与突变数据相结合， 可以确定环境、饮食和内源性遗传毒物以鉴定处于膀胱癌风险中的受试者。 一旦确定，就可以采取务实的措施，通过改变生活方式，减少人类接触化学品的机会- 环境暴露的方式或减轻，这可能是最有效的化学预防手段。