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（HAAs）所带来的癌症风险，杂环芳香胺是熟肉和烟草烟雾凝聚物中形成的一类重要基因毒物。最近的致癌物报告，第11版，国家毒理学计划，得出结论，HAAs可以合理预期为人类致癌物。经常食用红肉会增加患结肠癌的风险。根据流行病学研究显示，经常食用熟肉和体内活性较高的活化HAAs酶的人患结肠癌的风险最高，因此HAAs被认为是这种疾病的特定病因。然而，报告的饮食因素和基因多态性数据的关联并不能证实特定化学物质暴露与致癌之间的关系。为了进一步证明这些基因毒物在癌症风险中的作用，需要稳定的、长期存在的暴露和遗传损伤化学标记物。难以无创获取相关组织来评估遗传损伤和癌症发展，以及缺乏明确识别和定量稳定、长期存在的微量HAA生物标志物的分析方法，严重阻碍了人类对HAA的风险评估。毛发、血细胞和血浆是测量HAAs、HAA-DNA和haa -蛋白加合物的丰富物质来源，它们可以作为替代组织中长期存在的生物标志物进行风险评估。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HAAs的个体组织中HAA生物标志物的鉴定、表征和定量：这些分析HAAs生物标志物的MS方法将为确定HAAs在致癌作用中的作用提供优越的方法。这项拟议的研究将通过测量头发、血液蛋白加合物和长寿白细胞中DNA加合物中的HAAs，建立HAAs的非侵入性化学标志物，作为经常吃烤肉的人癌症风险靶点的替代生物标志物。基因毒性HAA代谢物衍生的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修复基因的遗传多态性。拟议的研究对公众健康具有重要影响，并将为制定这类基因毒物的风险评估方法提供重要工具，这些基因毒物被认为会导致人类结直肠癌和其他常见的人类癌症。健康风险有可能在人口水平上得到控制，方法是确定有风险的人，即通过接触或遗传多态性，然后利用疾病预防和早期发现战略对这一群体进行干预。

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.