In our nonhuman primate model for human cancer risk, the patas monkey, we have completed or continued studies related to both direct and transplacental exposure to both environmental xenobiotics and iatrogenic chemicals. Levels of the promutagenic DNA adduct, O6-methylguanine, after oral administration of N-nitrosodimethylamine, were even higher in gastric mucosa than in liver, confirming nitrosamines as contributors to human gastric cancer. The repair enzyme, alkylguanine alkyltransferase, varied over a 30-fold range in the tissues, being highest in liver and stomach, and lowest in brain. After treatment of pregnant monkeys, the adduct was highest in placenta and fetal liver, and ethanol reduced these levels, while increasing adducts in all other fetal tissues. These results confirm the nitrosamines as potential human transplacental carcinogens, and alcohol consumption as a modulating factor. In ongoing studies of metabolism of the tobacco-specific nitrosamine, 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK), monkey liver and lung microsomes were found to have similarities to those from humans, with regard to involvement of cytochrome P450 isoforms 1A2 and 2A6 in liver, and contribution of non-P450 metabolism in lung. Thus the monkey may be used to aid in the development of chemopreventive approaches. Two therapeutic drugs have been studied in the transplacental context, cisplatin, an anti-cancer agent, and 3'-azido- 3'-deoxythymidine (AZT), an anti-AIDS drug being administered to HIV-positive pregnant women and their newborn infants. Cisplatin caused both genomic and mitochondrial DNA adducts in fetal tissues. In combination with other findings (see Project ZO1 BC 05352) these results confirm high susceptibility of primate fetal tissues to metal-containing chemicals. Early results with AZT indicates fetal genotoxicity of this compound, which, in the context of our new demonstration of transplacental carcinogenicity by AZT, indicate the possibility of risk associated with treatment of human fetuses and newborns with this drug.
