MOLECULAR BIOMARKERS OF EXPOSURE/ENVIRONMENTAL CARCINOMA

本研究计划的总体目标是系统地 建立与生物标志物有关的定性和定量数据库， 接触和生物有效剂量（血液中的致癌物加合物 蛋白质和细胞DNA）对所选择的生物学应答标记物 （特定基因的突变或其他DNA序列变化; 抑制基因活性）和诱导肿瘤的作用 化学致癌作用的动物模型。 研究 实验模型将利用分析程序和方法， 将直接适用于以下细胞和组织的平行研究： 人类在环境中暴露于相同的化学致癌物质， 诱变剂 该计划将重点关注四种致癌物质， 低水平的暴露基本上是不可避免的， 确定为人类癌症的既定风险因素， 流行病学证据（黄曲霉毒素B1，4-氨基联苯）或疑似风险 根据其在动物中的致癌性（甲基IQx和 氨基甲酸乙酯）。 该计划将包括五个互动项目， 三个重点领域。 项目I，致癌物的分子剂量学 诱变剂涉及蛋白质和DNA加合物作为系统性和 生物有效剂量。 在第二个重点领域， 在基因结构作为早期生物学效应的标记中，三个相关的 项目涉及研究体内发生的突变， 基因序列 项目II将分析突变途径， 致癌作用：大鼠肝脏中的自发和致癌物诱导突变。 项目三的目标是评估具体的 DNA加合物结构和定义的DNA序列背景内的突变 通过对4-氨基联苯致突变特异性的表征 和其它芳族N-芳族化合物。 项目四将侧重于 特定癌基因和抑癌基因的结构改变 化学致癌作用中的序列 第三个重点领域的变化 在肿瘤抑制基因作为早期生物学效应标志物的功能中， 包括项目V，其中肿瘤抑制基因的改变 将研究化学致癌作用。 初始 该计划的第一阶段，将建立在广泛的信息基础上 已经为该计划的某些元素创建， 这组研究人员的研究工作，将强调一代 在实验中尚未提供的特定关键数据元素 动物模型 同时，将同样的方法应用于 通过现有的方法， 将继续开展合作，并尽可能扩大合作。 剂量相关性和其他特征的综合比较 在相同参数的实验系统中， 人类受试者将大大提高对健康危害的评估， 这些致癌物质的环境暴露。

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.