TRANSPLACENTAL CARCINOGENESIS OF HETEROCYCLIC AMINES

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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.