This project addresses carcinogenesis during the perinatal period with regard both to mechanisms underlying susceptibility and to assessment of public health related phenomena. A pharmacogenetic transplacental carcinogenesis experiment has been completed in mice, confirming that both fetal and maternal genotype, with regard to inducibility of metabolism of methylcholanthrene (MC), are critical determinants of susceptibility to tumorigenesis, and showing that pretreatment with a noncarcinogenic inducer can provide some protection of fetuses of inducible phenotype. Also, exposure of the fetuses to a high dose of xenobiotic results in a significant alteration in amount of metabolic products formed by the livers of the mice as adults. Studies of transplacental pharmacokinetics and of induction of the relevant enzymes in individual fetuses are in progress or planned, employing sensitive biochemical assays, monoclonal antibodies as biochemical probes, and DNA-RNA molecular hybridization techniques. Another recently-completed project has involved transplacental exposure of mice to a series of N-nitroso compounds, including N-nitrosodimethylamine, N- nitrosodiethylamine, N-nitrosoethylurea, and N- nitrosocimetidine. This study has yielded interesting information on the comparative actions of these chemicals at different stages of ontogeny. Neurogenic and hepatic tumors from these mice are being analyzed for oncogenes by the Developmental Biology Working Group. An investigation of the transplacental effects of the tobacco-specific nitrosamine 4-(methyl- nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in the mouse is ongoing; although NNK does not appear to be effective in transplacental initiation of lung tumors, some lymphoid neoplasms have appeared. Other studies in progress of potential public health importance include assessment of polychlorinated biphenyls as promoters and enhancers of tumor initiated by a nitrosamine in infant mice and investigation of the effects of the human transplacental carcinogen diethylstilbestrol, in the infant rat, with and without pretreatment with modifiers of metabolism.
