Chemical markers of heterocyclic aromatic amines for human biomonitoring

描述（由申请人提供）：本申请的广泛、长期目标是评估杂环芳香胺（哈斯）（熟肉和烟草烟雾冷凝物中形成的一类重要遗传毒性物质）造成的癌症风险。最近的致癌物报告，第十一版，国家毒理学计划，得出的结论是，哈斯可以合理地预期是人类致癌物。经常食用红肉会增加患结肠癌的风险。哈斯被认为是这种疾病的特异性病原体，基于流行病学研究，已经显示个体发展结肠癌的最高风险被赋予那些经常食用煮熟的肉类和生物活化哈斯的酶活性升高的受试者。然而，膳食因素和遗传多态性数据的相关性报道不能证实特定化学品暴露与致癌之间的关系。为了加强这些遗传毒物在癌症风险中的作用的证据，需要暴露和遗传损伤的稳定、长寿命的化学标记。非侵入性地获得相关组织以评估遗传损伤和癌症发展的困难，以及明确鉴定和定量痕量水平的稳定、长寿命HAA生物标志物的分析方法的缺乏，严重阻碍了人类对哈斯的风险评估。毛发、血细胞和血浆是测量哈斯、HAA-DNA和HAA-蛋白质加合物的丰富材料来源，其可作为替代组织中的长寿命生物标志物用于风险评估。我们假设，质谱（MS）仪器灵敏度的最新进展将允许通过饮食暴露于哈斯的个体组织中HAA生物标志物的鉴定、表征和定量：这些分析哈斯生物标志物的MS方法将为确定哈斯在致癌作用中的作用提供上级的方法。这项拟议中的研究将通过测量头发中的哈斯、血液蛋白加合物和长寿白色血细胞中的DNA加合物，建立哈斯的非侵入性化学标记物，作为经常吃烤肉的人类癌症风险靶点的替代生物标记物。来自遗传毒性HAA代谢物的DNA和蛋白质加合物生物标志物可用于确定暴露、生物有效剂量、遗传损伤，并鉴定调节HAA遗传毒性的酶代谢基因或DNA修复基因中的遗传多态性。拟议的研究对公共卫生具有重要影响，并将为开发这类遗传毒物的风险评估方法提供重要工具，这些遗传毒物被认为有助于人类结直肠癌和其他常见的人类癌症。通过识别风险人群，即通过暴露或遗传多态性，然后使用疾病预防和早期检测策略对这一群体进行干预，可以在人群水平上控制健康风险。

DESCRIPTION (provided by applicant): The broad, long-term objective of this application is to assess the cancer risk posed by heterocyclic aromatic amines (HAAs), an important class of genotoxicants formed in cooked meats and tobacco smoke condensate. The recent Report on Carcinogens, Eleventh Edition, National Toxicology Program, concluded that HAAs may be reasonably anticipated to be human carcinogens. The frequent consumption of red meats leads to an increased risk for colon cancer. HAAs have been implicated as specific etiological agents in this disease, based upon epidemiological studies that have shown the highest risk for individuals to develop colon cancer is conferred in those subjects who frequently consume meats cooked well-done and who harbor elevated activities in enzymes that bioactivate HAAs. However, the reported associations of dietary factors and genetic polymorphism data can not confirm the relationships between specific chemical exposures and carcinogenesis. Stable, long-lived chemical markers of exposure and genetic damage are required to strengthen the evidence for a role of these genotoxicants in cancer risk. The difficulty of obtaining relevant tissues non-invasively to assess genetic damage and cancer development, as well as the paucity of analytical methods that unambiguously identify and quantitate stable, long-lived HAA biomarkers at trace levels, has severely impeded human risk assessment of HAAs. Hair, blood cells, and plasma are rich sources of material to measure HAAs, HAA-DNA and HAA-protein adducts, which may serve as long-lived biomarkers in surrogate tissues for risk assessment. We hypothesize that recent advances in the sensitivity of mass spectrometry (MS) instrumentation will permit the identification, characterization and quantification of HAA biomarkers in tissues of individuals exposed to HAAs through the diet: these analytical MS methods on biomarkers of HAAs will provide superior approaches for establishing a role of HAAs in carcinogenesis. This proposed research will establish noninvasive chemical markers of HAAs, by measuring HAAs in hair, blood protein adducts, and DNA adducts in long-lived white blood cells, as surrogate biomarkers for target sites of cancer risk in humans who frequently eat grilled meats. The DNA and protein adduct biomarkers derived from the genotoxic HAA metabolites can be used to determine exposure, the biologically effective dose, genetic damage, and to identify genetic polymorphisms in enzyme metabolism genes or DNA repair genes that modulate HAA genotoxicity. The proposed research has important impact on public health and will provide an essential tool for developing risk assessment methods for this class of genotoxicants, which are believed to contribute to human colorectal and other common human cancers. The health risk can potentially be controlled at a population level by identifying those at risk, i.e. through exposures, or genetic polymorphisms, and then intervening in this group using disease prevention and early detection strategies.