TRANSPLACENTAL CARCINOGENESIS OF HETEROCYCLIC AMINES

在准备肉的传统烹饪，高度致癌 产生杂环胺。 这些化合物需要代谢 通过细胞色素P-4501 A家族的酶激活， 它们的致癌作用。 经胎盘暴露于这些杂环 胺可能在肿瘤的发生中起重要作用， 通过这个实验室和其他实验室已经证明了 使其特别容易发生肿瘤的胎儿， 环境致癌物。 这项研究的目的是确定 典型的饮食杂环胺的经胎盘致癌性， 2-氨基-3-甲基咪唑并[4，5-f]喹啉（IQ）。 本研究将评估 靶器官特异性和Cyp 1a 1在转化中的潜在作用 在子宫内暴露于以下物质后，iQ与近似致癌代谢物的关系 致癌物质 诱导肿瘤的发病机制也将是 在分子生物学水平上进行研究。 生物测定将确定 小鼠经胎盘暴露后各种器官中的肿瘤产量 胎儿的智商 IQ增加Cyp 1a 1水平的能力将是 通过生物化学和北方印迹分析评估。 组织生成自 将生物测定包埋在石蜡中并用于确定类型 智商介导的遗传损伤在选定的致癌基因位点， 人类癌症，特别是Ki-ras和p53基因。 通过分析这些 高灵敏度聚合酶链检测突变的致癌基因位点 反应技术，癌基因突变的特定模式可以是 在肿瘤模型中建立。 肿瘤的诱导， 在经胎盘期用智商进行治疗将显示化学物质如何 在母亲的饮食中所含的维生素A可能导致癌症的发生， 在子宫内接触这些饮食致癌物。

During the preparation of meat by conventional cooking, highly carcinogenic heterocyclic amines are generated. These compounds require metabolic activation by the cytochrome P-4501A family of enzymes in order to exert their carcinogenic effects. Transplacental exposure to these heterocyclic amines may play an important role int he initiation of tumors, as studies by this and other laboratories have demonstrated the unique qualities of the fetus that render it particularly susceptible to tumor initiation by environmental carcinogens. The goal of this research will be to determine the transplacental carcinogenicity of a typical dietary heterocyclic amine, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). This study will assess the target organ specificity and the potential role of Cyp1a1 in the conversion of iQ to proximate carcinogenic metabolites following in utero exposure to the carcinogen. The pathogenesis of the induced tumors will also be examined at the molecular biological level. Bioassays will determine the tumor yield in various organs following transplacental exposure of mouse fetuses to IQ. The ability of IQ to increase the levels of Cyp1a1 will be assessed by biochemical and northern blot assays. Tissue generated from the bioassay will be embedded in paraffin and used to determine the types of genetic damage mediated by IQ at selected oncogenic loci implicated in human cancer, in particular the ki-ras and p53 genes. By analysis of these oncogenic loci for mutations by the highly sensitive polymerase chain reaction technique, particular patterns of oncogene mutation can be established in the tumor models. The induction of tumors following treatment during the transplacental period with IQ will show how chemicals contained in the mother's diet can lead to cancer initiation as a result of the in utero exposure to these dietary carcinogens.