Investigation of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone for in vivo and iIn vitro murine embryopathy and embryonic ras mutations.
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 microM NNK had decreases in yolk sac diameter, crown-rump length and somite development (P <.05), and 100 microM NNK decreased anterior neuropore closure and crown-rump length (P <.05). Embryos exposed to 100 microM 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.
Winn
L M
LM
Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
Kim
P M
PM
Wells
P G
PG
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004622:Embryo, Mammalian / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000473:pathology; D011905:Genes, ras; D051379:Mice; D009154:Mutation; D009602:Nitrosamines / Q000378:metabolism / Q000633:toxicity*; D009924:Organ Culture Techniques; D010634:Phenobarbital; D010947:Plants, Toxic; D011247:Pregnancy; D014026:Nicotiana / Q000633:toxicity*
D002273:Carcinogens; D009602:Nitrosamines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D010634:Phenobarbital