New biomonitoring methodologies to measure DNA adducts in human tissues

测量人体组织中 DNA 加合物的新生物监测方法

• 批准号: 8021222
• 负责人: Robert J. Turesky
• 金额: $ 31.26万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8021222
• 关键词: Affect; Animals; Archives; Aristolochia; Aristolochic Acids; Balkan Nephropathy; Balkans; Biological; Biological Assay; Biological Markers; Biological Monitoring; Botanicals; Bread; C3H/He Mouse; Cancer Patient; Carboxylic Acids; Carcinogens; Chemical Models; Chinese Herbs; Chromatography; Chronic Kidney Failure; Clinical; Country; Croatia; DNA; DNA Adduction; DNA Adducts; DNA Repair Enzymes; Data; Diagnosis; Disease; Epidemiologic Studies; Etiology; Exposure to; Flour; Formalin; Freezing; Funding; Genes; Genetic Predisposition to Disease; Goals; Herb; Human; Incidence; Individual; Infusion procedures; Ingestion; Internet; Ions; Kidney; Kidney Diseases; Kidney Failure; Laboratories; Lesion; Link; Malignant Neoplasms; Mass Fragmentography; Mass Spectrum Analysis; Measurement; Measures; Methodology; Methods; Modeling; Molecular; Molecular Toxicology; Mus; Mutation; Nephrotoxic; PO-1; Patients; Population Study; Public Health; Radioactivity; Renal Tissue; Renal carcinoma; Research; Retrieval; Risk; Role; Rural; Safety; Sampling; Screening procedure; Seeds; Source; Specimen; Staging; Structure; Study Subject; Syndrome; TP53 gene; Techniques; Time; Tissue Sample; Tissues; Toxic effect; Toxicogenomics; Translational Research; United States; United States Food and Drug Administration; United States National Institutes of Health; Xenobiotic Metabolism; adduct; base; cancer risk; carcinogenicity; case control; chemical carcinogen; cost effective; design; exposed human population; global health; human tissue; kidney cortex; liquid chromatography mass spectrometry; mass spectrometer; nano-electrospray; nephrotoxicity; novel; phenanthrene; population based; programs; research study; rural area; tissue fixing; toxicant

DESCRIPTION (provided by applicant): The objective of this proposal is to develop new biomonitoring methodologies designed to measure DNA adducts in tissues of humans exposed to chemical carcinogens. Our chemical model for this project is structurally related nitro-phenanthrene carboxylic acids, a class of human carcinogens and nephrotoxicants that include aristolochic acids (AA). These compounds are universally present in herbs of the genus Aristolochia, used for medicinal purposes throughout the world for 2000 years. The nephrotoxicity and carcinogenicity of herbs containing AA are very well documented. Epidemiologic studies reveal AA to be the causal agent for the clinical syndromes known as Chinese herb and Balkan endemic nephropathies. In the latter, exposure to AA involves ingestion of bread prepared from flour contaminated with seeds of Aristolochia clematitis. Due to their toxicities, importation of traditional Chinese herbs containing AA are banned in some, but not all countries. Despite the Food and Drug Administration's warnings concerning the safety of botanical remedies containing AA, these herbs are still widely distributed in the United States via the Internet, and the incidence of chronic renal failure and urothelial cancer worldwide attributed to exposure to AA remains very high. Recently, we provided unequivocal evidence for the presence of AA-DNA adducts in the renal cortex of patients affected by BEN, using a novel, multi-stage ion trap mass spectrometry (MSn) method. Quantitative MS methods are essential for measuring DNA adduct biomarkers of this devastating and uniformally fatal disease. The biomonitoring methods will be used in translational research studies conducted in Balkan countries where the residents have dietary exposure to AA. A critical technological advance in DNA adduct screening methodologies will be achieved by extending the analysis of AA-DNA adducts from freshly frozen tissue samples to archived, formalin-fixed renal tissues, an untapped but rich source of material for toxico- logical research. Finally, a novel screening method will be established, employing an automated chip-based infusion nano-electrospray tandem MS method. This technique will provide a rapid throughput and cost- effective method to screen for DNA adducts in population-based studies. Traditional herbal remedies containing carcinogenic AA are used worldwide and are a global health problem. Recent epidemiological studies have linked herbs containing AA with renal failure and cancer. Rapid and quantitative analytical MS data to screen for AA-DNA adducts are needed to assess the exposure and the causal role of AA in nephropathy and upper urothelial cancer risk. The AA-DNA adducts also serve as critical biomarkers in studies of genetic susceptibility to Balkan endemic nephropathy and its associated upper urothelial cancer. The novel biomonitoring techniques established in this application can be appllied to examine the role of other chemical carcinogens in the etiology of human cancer. PUBLIC HEALTH RELEVANCE: Novel mass spectrometry biomonitoring methods will be established to measure DNA adducts of aristolochic acids (AA), potent nephrotoxicants and carcinogens found in herbs of the genus Aristolochia, which have been used for medicinal purposes world-wide. These novel screening techniques will be employed to measure AA-DNA adducts in human populations exposed to AA and diagnosed with upper urothelial cancer.

描述(申请人提供)：这项建议的目标是开发新的生物监测方法，旨在测量暴露于化学致癌物的人类组织中的DNA加合物。我们这个项目的化学模型是结构上相关的硝基菲羧酸，这是一类人类致癌物质和肾毒性物质，包括马兜铃酸(AA)。这些化合物普遍存在于马兜铃属草本植物中，世界各地的药用植物已有2000年的历史。含有AA的草药对肾脏的毒性和致癌性是有很好的文献记载的。流行病学研究表明，AA是被称为中草药和巴尔干地方性肾病的临床症状的病原体。在后者中，接触AA包括摄取由受马兜铃属植物种子污染的面粉制成的面包。由于其毒性，含有AA的传统中草药在一些国家被禁止进口，但并不是所有国家。尽管美国食品和药物管理局就含有AA的植物药物的安全性发出警告，但这些草药仍通过互联网在美国广泛分发，全球因接触AA而导致的慢性肾功能衰竭和尿路上皮癌的发病率仍然很高。最近，我们使用一种新的多阶段离子陷阱质谱仪(MSN)方法，为BEN患者的肾皮质中存在AA-DNA加合物提供了明确的证据。定量MS方法对于测量这种毁灭性和非正式致命疾病的DNA加合物生物标记物是必不可少的。生物监测方法将用于在居民饮食中接触AA的巴尔干国家进行的转化性研究。通过将AA-DNA加合物的分析从新鲜冰冻组织样本扩展到存档的福尔马林固定的肾组织，将实现DNA加合物筛选方法的关键技术进步，这是毒理学研究的一个尚未开发但丰富的材料来源。最后，将建立一种新的筛选方法，采用基于自动芯片的输液纳米电喷雾串联质谱法。这项技术将为在人群研究中筛选DNA加合物提供一种快速、经济的方法。含有致癌AA的传统草药在世界各地使用，是一个全球性的健康问题。最近的流行病学研究将含有AA的草药与肾功能衰竭和癌症联系在一起。需要快速和定量的MS数据来筛选AA-DNA加合物，以评估AA在肾病和上尿路上皮癌风险中的暴露和原因作用。AA-DNA加合物也是巴尔干地方性肾病及其相关上尿路上皮癌遗传易感性研究中的关键生物标记物。在这一应用中建立的新的生物监测技术可以应用于研究其他化学致癌物在人类癌症病因学中的作用。 与公共健康相关：将建立新的质谱仪生物监测方法来测量马兜铃酸(AA)的DNA加合物，马兜铃酸是一种在世界各地被用于医疗目的的马兜铃属草本植物中发现的有效的肾脏毒物和致癌物。这些新的筛查技术将被用于测量暴露于AA并被诊断为上尿路上皮癌的人群中的AA-DNA加合物。