Vol. 287, Issue 3, 1128-1135, December 1998

Investigation of the Tobacco-Specific Carcinogen 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone for In Vivo and In Vitro Murine Embryopathy and Embryonic ras Mutations¹

Louise M. Winn, Perry M. Kim and Peter G. Wells

Faculty of Pharmacy (L.M.W., P.M.K., P.G.W.) and Department of Pharmacology (P.G.W.), University of Toronto, Toronto, Ontario, Canada

The teratological potential of the carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is unknown. In vivo, NNK (100 mg/kg i.p.) was administered to pregnant CD-1 mice during organogenesis, with or without pretreatment with the P450 inducer phenobarbital (60 mg/kg i.p.). With NNK alone, 3 of 374 fetuses had open eye and one had a cleft palate, which were not observed in 160 controls. With phenobarbital plus NNK, two fetuses had a cleft palate, two had exencephaly and one had a kinky tail, although phenobarbital controls showed no anomalies (P < .05). NNK-initiated fetal postpartum lethality was enhanced by phenobarbital pretreatment. There were no fetal skeletal anomalies or alterations in resorptions or fetal body weight in any group. In embryo culture, gestational day 9.5 embryos exposed to 10 µM NNK had decreases in yolk sac diameter, crown-rump length and somite development (P < .05), and 100 µM NNK decreased anterior neuropore closure and crown-rump length (P < .05). Embryos exposed to 100 µM NNK were assessed for K-ras codon 12 mutations and none were detected. This is the first evidence for NNK teratogenicity and embryotoxicity, the molecular mechanism of which appears to differ from that for its carcinogenicity.