This project consists of whole-animal, biochemical, and-molecular approaches to determination of the factors that determine and modulate susceptibility to carcinogenesis during the perinatal period. Significant progress has been made with a murine model for the pharmacogenetics of transplacental carcinogenesis by a polycyclic aromatic hydrocarbon (PAH), 3-methylcholanthrene (MC). Genetics allowing induction of metabolism of this chemical predisposed mouse fetuses to susceptibility to tumor initiation in lung and liver, whereas inducibility in the mother allowed protection of the fetuses. Pretreatment with a noncarcinogenic enzyme inducer s-naphthoflavone (BNF) enhanced fetal protection if the mother was inducible, but enhanced tumorigenesis in fetal organs if she was not. Transplacental induction of cytochrome P- 450-dependent PAH activating enzyme activity and of gene expression for this P-450 were followed for MC and BNF. Dramatic induction occurred and MC and BNF were noted to have different time- and organ-specific induction patterns. Monoclonal antibody and PAH- inducible P-450s and cDNA probes for the genes specifying these enzymes were used to delineate these phenomena. Transplacental induction of the phase II detoxicating activity, uridine diphosphoglucuronic acid transferase, was found to be inducible by BNF but not MC. Transplacental MC but not BNF had a permanent imprinting effect on MC metabolism by the livers of the adult offspring, and this effect was dependent on genetically-controlled induction of metabolism by either the fetus or the mother. Gene methylation differences are being explored as a possible mechanism for this effect. In other perinatal experiments in progress or recently completed N-nitrosodimethylamine has been found to be a transplacental carcinogen in the mouse, causing liver tumors and, interestingly, sarcomas. Liver tumors initiated by N- nitrosoethylurea in this study have been analyzed for activated oncogenes and found to contain H-ras in some cases. The tobacco- specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) has been administered to several strains of mice transplacentally and neonatally with limited effect.
