MOLECULAR BIOMARKERS OF EXPOSURE/ENVIRONMENTAL CARCINOMA

本研究计划的总体目标是系统化的 与分子标记相关的定性和定量数据库的建立 暴露和生物有效剂量(血液中的致癌物加合物 蛋白质和细胞DNA)对选定的生物反应标记物 (特定基因的突变或其他DNA序列变化； 抑制基因活性)与井中肿瘤的诱导 描述了化学致癌的动物模型。研究项目： 实验模型将利用分析程序和方法 将直接适用于细胞和组织的平行研究 人类在环境中接触到相同的化学致癌物和 诱变剂。该计划将集中于人类对四种致癌物质的研究 低水平的暴露基本上是不可避免的，而这一直是 通过以下途径被确定为人类癌症的危险因素 流行病学证据(黄曲霉毒素B1、4-氨基联苯)或可疑风险 基于它们对动物的致癌性的因素(甲基IQx和 氨基甲酸酯)。该计划将由五个互动项目组成 重点有三个方面。项目I，致癌物的分子剂量学 而诱变剂关注的是蛋白质和DNA加合物作为系统性和系统性疾病的标志 生物有效剂量。在第二个重点领域，改建 在基因结构作为早期生物效应的标志方面，有三个相关 项目涉及对体内发生的特定突变的研究 基因序列。项目II将分析突变途径 致癌：大鼠肝脏自发和致癌物诱导的突变。 项目三的目标是评价具体的 特定DNA序列背景下的DNA加合物结构和突变 4-氨基联苯致突变的特异性表征 和其他芳香族N-芳香族化合物。项目IV将重点放在 特异性癌基因和抑癌基因的结构变化 化学致癌的序列。第三个重点领域发生了变化 在肿瘤抑制基因作为早期生物学效应的标志物方面， 由方案V组成，其中肿瘤抑制基因的改变 将对化学致癌的活性进行调查。首字母 方案阶段，这将建立在广泛的信息库的基础上 已由之前的协作组为计划的某些元素创建 这批研究人员的研究努力，将强调世代 尚未在实验中获得的特定关键数据元素 动物模型。同时，将相同的方法应用于 在暴露的人类中的研究已经在进行中，通过现有的 只要有可能，合作将继续并扩大。 剂量相关性和其他特征的综合比较 曝光条件下具有相同参数的实验系统的响应 人体受试者将极大地提高对由此产生的健康危害的评估 这些致癌物质在环境中的暴露。

The overall objective of this research program is the systematic development of qualitative and quantitative data bases relating markers of exposure and biologically effective dose (carcinogen adducts in blood proteins and cellular DNA) to selected markers of biological response (mutations or other DNA sequence changes in specific genes; alterations in suppressor gene activity) and the induction of tumors in well characterized animal models of chemical carcinogenesis. Studies in experimental models will utilize analytical procedures and approaches that will be directly applicable in parallel studies in cells and tissues of humans environmentally exposed to the same chemical carcinogens and mutagens. The program will focus on four carcinogens to which human exposure at low levels is essentially unavoidable, and that have been identified as established risk factors for human cancers through epidemiologic evidence (aflatoxin B1, 4-aminobiphenyl) or suspected risk factors on the basis of their carcinogenicity in animals (methylIQx and urethane). The program will consist of five interactive projects within three areas of emphasis. Project I, Molecular dosimetry of carcinogens and mutagens concerns protein and DNA adducts as markers of systemic and biologically effective doses. In the second area of emphasis, alterations in gene structure as markers of early biological effects, three related projects involve studies of in vivo mutations occurring within specific gene sequences. Project II will analyze Mutational pathways in carcinogenesis: spontaneous and carcinogen-induced mutation in rat liver. Project III has the objective of evaluating relationships between specific DNA adduct structures and mutations within defined DNA sequence contexts through characterization of Specificity of mutagenesis by 4-aminobiphenyl and other aromatic N-aromatic compounds. Project IV will focus on Structural alterations in specific oncogene and tumor suppressor gene sequences in chemical carcinogenesis. the third area of emphasis changes in tumor suppressor gene function as markers of early biological effects, consists of Project V, in which Alterations of tumor suppressor gene activity in chemical carcinogenesis will be investigated. The initial phase of the program, which will build upon an extensive information base already created for certain elements of the program by prior collaborative research efforts of this group of investigators, will emphasize generation of specific critical data elements not yet available in experimental animal models. Concurrently, applications of the same approaches to studies in exposed humans already in progress through existing collaborations will be continued and expanded whenever possible. Comprehensive comparisons of dose relatedness and other characteristics of responses in the experimental systems with the same parameters in exposed human subjects will greatly enhance assessment of health hazards resulting from environmental exposures to these carcinogens.