DNA ADDUCTS OF DIET CARCINOGENESIS--ANALYSIS BY 32P & MS

污染物/致癌物暴露的分子标记物越来越多 毒物学家和流行病学家在评估人类 健康风险。最近接触和遗传基因的最直接证据 损伤是通过测量细胞中的DNA致癌加合物来实现的。这个 这项计划的长期目标是提高我们对 某些饮食产生的DNA加合物与肿瘤发生的关系。 杂环芳胺(HAA‘s)是一类强致癌物质 烹调过程中的肉和鱼，都是本研究的重点。 流行病学研究表明，摄入含有以下成分的食物 HAa‘s会增加患结直肠癌和胰腺癌的风险。DNA 3种特殊杂环芳胺的加合物2-氨基-1-甲基-2-氨基-1-甲基 6-苯基咪唑并[4，5b]吡啶(PhIP)，2-氨基-3-甲基咪唑[4，5-f] 喹啉(IQ)和2-氨基-3，8-二甲基咪唑并[4，5-f]喹恶啉(MeIQx)， 它们与多种致癌功能有关，包括 小鼠的淋巴瘤、大鼠的结肠癌和非人的肝癌 灵长类动物是检查的目标。改进的检测方法 对它们的DNA加合物进行表征是重要的第一步 为实现这一目标而努力，并在计划中得到强调。 与人类有种间相似性的动物模型将是 用作替代品，以开发评估人类健康的生物标记物 由HAA引起的风险。体外反应也将被检查以提供 更大数量的参考加合物。毛细管分离法 (液相色谱或毛细管区带电泳联用) 电喷雾电离(ESI)/串联质谱仪，它允许 将使用完整DNA加合物的分析和32/P后标记 平行比较法表征肝脏HAA-DNA加合物含量 纸巾。毛细管LC-(或CZE)-MS/MS的高信息含量 分析方法将补充高灵敏度/低灵敏度的方法 32/P后标记的结构信息含量法。MS数据 因此将作为对ITS的32/P方法的评估和验证 其后适用于检验人体样本的情况下 暴露水平明显较低。预计将会有 拟议研究产生的信息将为以下方面提供新的见解 使用生物标记物进行风险评估和按顺序调整饮食 将饮食致癌的风险降至最低。

Molecular markers of contaminant/carcinogen exposure are an increasingly important tool for toxicologists and epidemiologists in assessing human health risk. The most direct evidence of recent exposure and genetic damage is through the measurement of DNA carcinogen adducts in cells. The long-term objective of this program is to improve our understanding of the relationship between certain diet-generated DNA adducts and tumorigenesis. Heterocyclic aromatic amines (HAA's), a class of potent carcinogens formed during the cooking of meat and fish, are the focus of this study. Epidemiological studies suggest that the consumption of foods that contain HAA's increases the risk to colorectal and pancreatic cancer. The DNA adducts of three specific heterocyclic aromatic amines, 2-amino-1-methyl- 6-phenylimidazo[4,5b]pyridine (PhIP), 2-amino-3-methylimidazo[4,5-f] quinoline (IQ) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), which are associated with a variety of carcinogenic functions including lymphomas in mice, colon cancer in rats and liver cancer in non-human primates, are targeted for examination. Improved methods for detection and characterization of their DNA adducts is an important first step toward accomplishing this goal and is emphasized in the program. Animal models, which have interspecies similarities to humans, will be used as surrogates in order to develop biomarkers to assess human health risk due to HAA's. In vitro reactions will also be examined to provide larger quantities of reference adducts. Capillary separation methods (liquid chromatography or capillary zone electrophoresis) coupled to electrospray ionization (ESI)/tandem mass spectrometry, which permits the analysis of intact DNA adducts, and 32/P post-labelling will be used and compared in parallel to characterize the HAA-DNA adduct content of liver tissues. The high information content of the capillary LC-(or CZE)-MS/MS method of analysis will complement that of the high sensitivity/low structural information content method of 32/P post-labelling. The MS data will thus serve as evaluation and validation of the 32/P method for its subsequent application to the examination of human specimens where the exposure levels are significantly lower. It is expected that the information generated from the proposed study will provide new insights on the use of biomarkers for risk assessment and diet modifications in order to minimize risk to dietary cancer.