Chemical markers of heterocyclic aromatic amines for human biomonitoring

描述(由申请人提供)：这项申请的广泛、长期目标是评估杂环芳胺(HAAs)构成的癌症风险，HAAs是熟肉和烟草烟雾冷凝物中形成的一种重要的遗传毒物。关于致癌物的最新报告，第11版，国家毒理学计划，得出结论，HAAs可以合理地被预期为人类致癌物。经常食用红肉会增加患结肠癌的风险。根据流行病学研究，HAAs被认为是这种疾病的特定病原体，这些研究表明，经常食用熟肉的受试者患结肠癌的风险最高，并且HAAs的生物活性酶活性升高。然而，已报道的饮食因素和遗传多态数据之间的关联并不能证实特定的化学暴露与癌症发生之间的关系。为了加强这些基因毒物在癌症风险中的作用的证据，需要稳定、长期存在的暴露和遗传损伤的化学标记。非侵入性地获取相关组织以评估遗传损害和癌症发展的困难，以及缺乏在痕量水平上明确识别和定量稳定、长寿的HAA生物标记物的分析方法，严重阻碍了人类对HAA的风险评估。头发、血细胞和血浆是检测HAAs、HAA-DNA和HAA-蛋白质加合物的丰富材料来源，这些加合物可能作为替代组织中的长期生物标志物进行风险评估。我们推测，最近在质谱学(MS)仪器灵敏度方面的进展将使通过饮食接触HAA的个体组织中的HAA生物标记物得以识别、表征和定量：这些关于HAAs生物标记物的MS分析方法将为确定HAAs在癌症发生中的作用提供更好的方法。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的DNA加合物来建立HAAS的非侵入性化学标记，作为经常吃烤肉的人类癌症风险目标位置的替代生物标记。来源于HAA遗传毒性代谢物的DNA和蛋白质加合物生物标志物可用于确定HAA的暴露、生物有效剂量、遗传损伤，以及识别调节HAA遗传毒性的酶代谢基因或DNA修复基因的遗传多态。这项拟议的研究对公众健康具有重要影响，并将为开发这类基因毒物的风险评估方法提供必要的工具，这种毒物被认为是人类结直肠癌和其他常见人类癌症的诱因。通过确定风险人群，即通过暴露或基因多态，然后利用疾病预防和早期检测战略对这一群体进行干预，可以潜在地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.