Chemical markers of heterocyclic aromatic amines for human biomonitoring

用于人体生物监测的杂环芳香胺化学标记物

• 批准号: 9131528
• 负责人: Robert J. Turesky
• 金额: $ 57.48万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-11 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9131528
• 关键词: 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]pyridine; Acinus organ component; African American; Animals; Atrophic; Benign Prostatic Hypertrophy; Binding; Biological; Biological Markers; Biological Monitoring; Cancer Etiology; Carcinogen Metabolism; Carcinogens; Case-Control Studies; Caucasians; Cells; Cessation of life; Chemicals; Cohort Studies; Consumption; DNA; DNA Adduction; DNA Adducts; DNA Damage; Data; Diagnosis; Diet; Disease; Dose; Drug Metabolic Detoxication; Eating; Enzymes; Epidemiologic Studies; Etiology; Exposure to; Food; Formalin; Frequencies; Genes; Genetic; Genetic Polymorphism; Genotype; Goals; Grant; Hair; Hand; Health; High Fat Diet; Human; Immunohistochemistry; In Vitro; Incidence; Individual; Inflammation; Lead; Life; Life Style; Lipid Peroxidation; Malignant neoplasm of prostate; Measurement; Measures; Meat; Meta-Analysis; Methods; Modeling; Molecular Epidemiology; Monitor; Mutation; Oxidative Stress; Paraffin Embedding; Phase; Polymorphism Analysis; Population; Prevention strategy; Primary Cancer Prevention; Prospective Studies; Prostate; Prostatectomy; Proteins; Questionnaires; Race; Reporting; Risk; Risk Factors; Rodent; Role; Scanning; Second Primary Neoplasms; Serum Albumin; Single Nucleotide Polymorphism; Specimen; Techniques; Testing; Tissues; United States; Urine; Variant; Xenobiotic Metabolism; adduct; base; beef; cancer health disparity; cancer risk; clinical Diagnosis; cohort; cooking; density; epidemiologic data; epidemiology study; feeding; heterocyclic aromatic amines; human tissue; men; prostate carcinogenesis; red meat consumption; toxicant; volunteer

DESCRIPTION (provided by applicant): Prostate cancer is the most frequently diagnosed malignancy and second leading cause of cancer-related death among men in the United States. Identifying risk factors of this disease and developing strategies for prevention are critical. A number of epidemiologic studies have reported an association between frequent consumption of well-done cooked meats, containing the heterocyclic aromatic amine (HAA) 2-amino-1-methyl- 6-phenylimidazo[4,5-b]pyridine (PhIP) and prostate cancer risk. PhIP is a potent rodent prostate carcinogen, and it induces oxidative stress, atrophy of the acini, and inflammation of the prostate. These are critical features that occur in human prostate carcinogenesis. A paradigm has been put forth for a causal role of consumption of well-done cooked meats containing PhIP (and other HAAs) in the etiology of prostate cancer; however, biomarkers of exposure and DNA damage are lacking to validate this model. Our long-term goal is to assess the cancer risk posed by HAAs, by employing chemical markers that may distinguish individuals at different levels of risk. In this grant renewal, our objective is to assess dietary exposure to PhIP and its potential to induce damage to DNA in the prostate in relation to other HAAs, meat genotoxicants, and endogenous electrophiles produced in the cell, by employing mass spectrometric (MS)- based methods to measure genotoxicants and identify their biomarkers of DNA damage in the prostate. We will implement our recently established biomarkers of HAAs and other cooked meat genotoxicants and their DNA adduction products in cohorts of African American and Caucasian men with benign prostate hyper- plasia or prostate cancer who frequently eat well-done cooked meat. In Aim 1) HAA exposure will be assessed by measurement of HAAs accrued in hair; DNA adducts of HAAs, other meat genotoxicants, and endogenous electrophiles, will be determined by different MS scanning methods, in prostate. In Aim 2) Formalin-fixed paraffin embedded prostate tissue, an underutilized biospecimen in biomonitoring DNA damage, will be employed to screen for HAA-DNA adducts in subjects undergoing prostatectomy. Adduct levels will be compared to those values obtained by current but non-specific immunohistochemical techniques. MS methods will also be implemented to measure PhIP-serum albumin adducts as long-lived biomarkers of the biologically effective dose. In Aim 3) we will conduct high density genotyping of genes encoding enzymes involved carcinogen metabolism that may impact DNA damage in the prostate. Prostate HAA-DNA adduct levels will be correlated to HAA levels in hair; the levels of HAA and other DNA adducts in prostate will be correlated to genotypes of phase I and II xenobiotic metabolism enzymes, which impact biological activity. Our findings will provide direct measurement of DNA damage and assess the relative contribution of HAAs, other cooked meat genotoxicants and endogenous electrophiles to the genetic damage of DNA in the prostate.

描述（由申请人提供）：前列腺癌是美国男性最常见的恶性肿瘤和与癌症相关的第二大原因。确定这种疾病的危险因素并制定预防策略至关重要。许多流行病学研究报道了频繁消耗熟练煮熟的肉之间的关联，其中含有杂环芳香胺（HAA）2-氨基-1-甲基-6-苯基胺[4,5-B]吡啶（pHIP）（pHIP）和前列腺癌风险。 PHIP是一种有效的啮齿动物前列腺致癌物，它诱导氧化应激，acini的萎缩和前列腺炎症。这些是人类前列腺癌变中发生的关键特征。在前列腺癌病因中，已经提出了一种范式来消费含有PHIP（和其他HAA）的熟肉的因果关系。但是，缺乏暴露和DNA损伤的生物标志物来验证该模型。 我们的长期目标是通过采用可以区分不同风险水平的个体的化学标记来评估HAA造成的癌症风险。在此赠款续约中，我们的目标是评估饮食中的PHIP暴露及其与其他HAAS，肉类遗传毒性剂和内源性电力相关的前列腺中DNA损害的潜力，该方法是使用质谱法（MS）（MS）的基于质谱的方法来测量遗传毒性和确定其生物标志的DNA损害，并确定DNA损害的生物毒素。 我们将在非裔美国人和良性前列腺癌或前列腺癌的同类中，将最近建立的HAA和其他煮熟的肉类毒素生物标志物及其DNA内收蛋白产物及其DNA内收蛋白产品中的生物标志物进行。在AIM 1）HAA暴露将通过测量头发的HAAS来评估； HAAS的DNA加合物，其他肉类遗传毒性和内源性电力将由前列腺中的不同MS扫描方法确定。在AIM 2）福尔马林固定的石蜡嵌入的前列腺组织，即生物监测DNA损伤中未充分利用的生物体质，用于筛选前列腺切除术受试者中的HAA-DNA加合物。加合物水平将与通过当前但非特异性免疫组织化学技术获得的值进行比较。还将实施MS方法，以测量生物有效剂量的长寿命生物标志物，以测量Phip-Serum白蛋白加合物。在目标3）中，我们将进行编码酶的基因的高密度基因分型，涉及致癌代谢，这可能会影响前列腺中的DNA损伤。前列腺HAA-DNA加合物水平将与头发的HAA水平相关。前列腺中HAA和其他DNA加合物的水平将与影响生物学活性的I期和II期异种生物代谢酶相关。 我们的发现将直接测量DNA损伤，并评估HAA，其他煮熟的肉类遗传毒性和内源性亲电的相对贡献对前列腺中DNA的遗传损害的相对贡献。