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: 8217315
• 负责人: Robert J. Turesky
• 金额: $ 31.71万
• 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/8217315
• 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; Diet; 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; public health relevance; research study; rural area; tissue fixing; toxicant; 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; Diet; 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; public health relevance; 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（由申请人提供）：该提案的目的是开发旨在测量暴露于化学致癌物的人类组织中DNA加合物的新生物监测方法。我们针对该项目的化学模型是与结构相关的硝基苯烷羧酸，一类人类致癌物和肾毒性剂，其中包括aristolochicain（AA）。这些化合物普遍存在于阿里斯洛希亚（Aristolochia）属的草药中，用于2000年的全球药物目的。含有AA的草药的肾毒性和致癌性有充分的文献记载。流行病学研究表明，AA是临床综合征的因果剂，称为中草药和巴尔干地方性肾病。在后者中，暴露于AA涉及摄入从面粉中摄入的面包，这些面粉被阿里斯托洛希亚血丝炎种子污染。由于它们的毒性，在某些国家（但不是所有国家）禁止进口含有AA的传统中国草药。尽管食品药品监督管理局关于含有AA的植物疗法的安全性的警告，但这些草药仍通过互联网广泛分布在美国，慢性肾衰竭和全球尿路上皮癌的发生率归因于暴露于AA的情况下仍然很高。 最近，我们使用一种新型的多阶段离子陷阱质谱法（MSN）方法提供了在受BEN影响的患者的肾脏皮层中存在AA-DNA加合物的明确证据。定量MS方法对于测量这种毁灭性和统一致命疾病的DNA加合物生物标志物至关重要。生物监测方法将用于在巴尔干国家进行的转化研究中，在巴尔干国家进行了饮食中的AA。通过将AA-DNA加合物从新鲜冷冻的组织样品扩展到存档的，福尔马林固定的肾脏组织，将实现DNA加合筛选方法中的重要技术进步，这是一种未开发但丰富的毒性材料来源。最后，将建立一种新型的筛选方法，该方法采用基于自动的基于芯片的输注纳米 - 电喷雾串联MS方法。该技术将为基于人群的研究中的DNA加合物提供快速的吞吐量和具有成本效益的方法。 含有致癌AA的传统草药疗法在全球范围内使用，是全球健康问题。最近的流行病学研究将含有AA的草药与肾衰竭和癌症联系起来。需要快速和定量的分析MS数据以筛选AA-DNA加合物来评估AA在肾病和上尿皮上癌的风险中的暴露和因果作用。 AA-DNA加合物在对巴尔干地方性肾病及其相关的上尿皮细胞癌的遗传易感性研究中也是关键生物标志物。可以使用在本应用中建立的新型生物监测技术来检查其他化学致癌物在人类癌症病因中的作用。 公共卫生相关性：将建立新型的质谱生物监测方法，以测量阿里斯托胆道酸（AA）的DNA加合物，在阿里斯托洛基亚属的草药中发现的有效的肾毒性和致癌物，这些毒素已用于全球范围内。这些新型的筛查技术将用于测量暴露于AA并被诊断出患有上尿皮癌的人群中的AA-DNA加合物。