Abstract
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.
Footnotes
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Send reprint requests to: Dr. Peter G. Wells, Faculty of Pharmacy, University of Toronto, 19 Russell Street, Toronto, Ontario, Canada M5S 2S2.
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↵1 A preliminary report was presented at the 35th annual meeting of the Society of Toxicology (Fundam Appl Toxicol30(Suppl. No. 1, Part 2): 198, 1996). This research was supported by a grant from the Medical Research Council of Canada.
- Abbreviations:
- CYP
- cytochrome P450
- DMSO
- dimethyl sulphoxide
- GD
- gestational day
- NNAL
- 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol
- NNK
- 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
- P450
- cytochromes P450
- PAH
- polycyclic aromatic hydrocarbon
- PHS
- prostaglandin H synthase
- ROS
- reactive oxygen species
- SOD
- superoxide dismutase
- UGT
- UDP-glucuronosyltransferase
- PCR
- polymerase chain reaction
- BP
- benzo[a]pyrene
- Received April 16, 1998.
- Accepted July 10, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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