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
基本信息
- 批准号:8738198
- 负责人:
- 金额:$ 33.97万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-02-01 至 2015-01-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAnimalsArchivesAristolochiaAristolochic AcidsBalkan NephropathyBalkansBiologicalBiological AssayBiological MarkersBiological MonitoringBotanicalsBreadC3H/He MouseCancer PatientCarboxylic AcidsCarcinogensChemical ModelsChinese HerbsChromatographyChronic Kidney FailureClinicalCountryCroatiaDNADNA AdductionDNA AdductsDNA Repair EnzymesDataDiagnosisDietDiseaseEpidemiologic StudiesEtiologyExposure toFlourFormalinFreezingFundingGenesGenetic Predisposition to DiseaseGoalsHerbHumanIncidenceIndividualInfusion proceduresIngestionInternetIonsKidneyKidney DiseasesKidney FailureLaboratoriesLesionLinkMalignant NeoplasmsMass FragmentographyMass Spectrum AnalysisMeasurementMeasuresMethodologyMethodsModelingMolecularMolecular ToxicologyMusMutationNephrotoxicPO-1PatientsPopulation StudyPublic HealthRadioactivityRenal TissueRenal carcinomaResearchRetrievalRiskRoleRuralSafetySamplingSeedsSourceSpecimenStagingStructureStudy SubjectSyndromeTP53 geneTechniquesTimeTissue SampleTissuesToxic effectToxicogenomicsTranslational ResearchUnited StatesUnited States Food and Drug AdministrationUnited States National Institutes of HealthXenobiotic Metabolismadductbasecancer riskcarcinogenicitycase controlchemical carcinogencost effectivedesignexposed human populationglobal healthhuman tissuekidney cortexliquid chromatography mass spectrometrymass spectrometernano-electrospraynephrotoxicitynovelphenanthrenepopulation basedprogramsresearch studyrural areascreeningtissue fixingtoxicant
项目摘要
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.
描述(由申请人提供):本提案的目的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相关的硝基菲羧酸,一类人类致癌物和肾毒性物质,包括马兜铃酸(AA)。这些化合物普遍存在于马兜铃属的草药中,在世界各地用于药用已有2000年的历史。含有AA的草药的肾毒性和致癌性已被充分证明。流行病学研究显示AA是中医和巴尔干地区肾病的病因。在后一种情况下,暴露于AA涉及食用由受马兜铃种子污染的面粉制成的面包。由于其毒性,一些国家禁止进口含有AA的传统中草药,但并非所有国家都禁止进口。尽管美国食品和药物管理局对含有AA的植物疗法的安全性提出了警告,但这些草药仍然通过互联网在美国广泛传播,并且由于暴露于AA而导致的慢性肾衰竭和尿路上皮癌的发病率在世界范围内仍然很高。最近,我们使用一种新的多级离子阱质谱(MSn)方法,为BEN患者肾皮质中存在AA-DNA加合物提供了明确的证据。定量质谱方法是必不可少的DNA加合物生物标志物的测量这种毁灭性的和统一致命的疾病。生物监测方法将用于在巴尔干国家进行的转化研究,这些国家的居民通过饮食接触到AA。DNA加合物筛选方法的关键技术进步将通过扩展对新鲜冷冻组织样本的ha -DNA加合物的分析来实现,福尔马林固定肾组织,这是一个尚未开发但丰富的毒理研究材料来源。最后,将建立一种新的筛选方法,采用基于芯片的自动输注纳米电喷雾串联质谱法。该技术将为基于人群的DNA加合物筛选提供一种快速通量和成本效益的方法。含有致癌物AA的传统草药在世界范围内使用,是一个全球性的健康问题。最近的流行病学研究将含有AA的草药与肾衰竭和癌症联系起来。需要快速定量分析质谱数据来筛选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因果作用。AA-DNA加合物也可作为巴尔干地区地方性肾病及其相关上尿路上皮癌遗传易感性研究的关键生物标志物。在本应用中建立的新型生物监测技术可用于检查其他化学致癌物在人类癌症病因学中的作用。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Robert J. Turesky其他文献
Synthesis of multiply-labeled [15N3,13C1]-8-oxo-substituted purine bases and their corresponding 2'-deoxynucleosides.
多重标记的[15N3,13C1]-8-氧代取代的嘌呤碱基及其相应的2-脱氧核苷的合成。
- DOI:
- 发表时间:
1994 - 期刊:
- 影响因子:4.1
- 作者:
Richard H. Stadler;Andreas A. Staempfli;Laurent B. Fay;Robert J. Turesky;D. Welti - 通讯作者:
D. Welti
本邦におけるアリストロキア酸に起因する上部尿路癌の実態
日本马兜铃酸所致上尿路癌现状
- DOI:
- 发表时间:
2019 - 期刊:
- 影响因子:0
- 作者:
猪口淳一、Kathleen G. Dickman;Arthur P. Grollman;Robert J. Turesky;Jiri. Zavadil;森谷正明,潮田真己、立神勝則、内藤誠二、江藤正俊 - 通讯作者:
森谷正明,潮田真己、立神勝則、内藤誠二、江藤正俊
Mammalian cell mutagenicity and metabolism of heterocyclic aromatic amines.
哺乳动物细胞致突变性和杂环芳香胺的代谢。
- DOI:
- 发表时间:
1991 - 期刊:
- 影响因子:0
- 作者:
H. Aeschbacher;Robert J. Turesky - 通讯作者:
Robert J. Turesky
The inhibitory effects of coffee on radical-mediated oxidation and mutagenicity.
咖啡对自由基介导的氧化和致突变性的抑制作用。
- DOI:
10.1016/0027-5107(94)90153-8 - 发表时间:
1994 - 期刊:
- 影响因子:0
- 作者:
Richard H. Stadler;Robert J. Turesky;Olivier Müller;J. Markovic;Phaik - 通讯作者:
Phaik
Metabolism of the food-borne mutagen/carcinogen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline in the rat: assessment of biliary metabolites for genotoxicity.
食源性诱变剂/致癌物 2-氨基-3,8-二甲基咪唑[4,5-f]喹喔啉在大鼠体内的代谢:评估胆汁代谢物的遗传毒性。
- DOI:
- 发表时间:
1988 - 期刊:
- 影响因子:4.3
- 作者:
Robert J. Turesky;H. Aeschbacher;A. Malnoöe;H. Würzner - 通讯作者:
H. Würzner
Robert J. Turesky的其他文献
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{{ truncateString('Robert J. Turesky', 18)}}的其他基金
DNA adductome of human bladder from the tobacco exposome
来自烟草暴露组的人类膀胱 DNA 加合物
- 批准号:
10543523 - 财政年份:2019
- 资助金额:
$ 33.97万 - 项目类别:
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 - 财政年份:2019
- 资助金额:
$ 33.97万 - 项目类别:
DNA adductome of human bladder from the tobacco exposome
来自烟草暴露组的人类膀胱 DNA 加合物
- 批准号:
10318141 - 财政年份:2019
- 资助金额:
$ 33.97万 - 项目类别:
Carcinogen DNA adduct biomarkers in formalin fixed tissues
福尔马林固定组织中的致癌物 DNA 加合物生物标志物
- 批准号:
8737541 - 财政年份:2014
- 资助金额:
$ 33.97万 - 项目类别:
Carcinogen DNA adduct biomarkers in formalin fixed tissues
福尔马林固定组织中的致癌物 DNA 加合物生物标志物
- 批准号:
9117955 - 财政年份:2014
- 资助金额:
$ 33.97万 - 项目类别:
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:
9538187 - 财政年份:2011
- 资助金额:
$ 33.97万 - 项目类别:
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 - 财政年份:2011
- 资助金额:
$ 33.97万 - 项目类别:
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:
9754142 - 财政年份:2011
- 资助金额:
$ 33.97万 - 项目类别:
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