Dioxin treatment of rats results in increased in vitro induction of sister chromatid exchanges by alpha-naphthoflavone: an animal model for human exposure to halogenated aromatics.
Recent reports have shown that alpha-naphthoflavone (alpha-NF) in vivo enhances the sister chromatid exchange (SCE) frequency in lymphocytes from human populations exposed to cigarette smoke or polychlorinated biphenyls and dibenzofurans. In this study, female Sprague-Dawley rats (9-11 weeks old) were administered a single oral dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and killed 6 days after treatment. Blood cultures were established with or without alpha-NF. The baseline and alpha-NF-induced SCE frequencies were assessed in lymphocytes after a 72-hr culture period. No effect on the SCE baseline frequency (cultures without alpha-NF) was detected in rats exposed to 0-30 micrograms TCDD/kg. However, the SCE frequencies from cultures incubated in the presence of alpha-NF were significantly higher in lymphocytes from rats treated with TCDD. Moreover, delta SCE values (SCE alpha-NF minus SCE baseline) were significantly higher in lymphocytes from rats treated with TCDD than in controls. A dose-dependent increase in delta SCE values was observed between 0 and 3 micrograms TCDD/kg, followed by a plateau at higher doses. This induction pattern closely resembled the induction of the liver microsomal aryl hydrocarbon hydroxylase activity by TCDD. In contrast to TCDD, phenobarbital treatment of rats (75 mg/kg/day) had no effect on alpha-NF-induced SCE frequencies in lymphocytes. Liver microsomes from TCDD-treated rats metabolized alpha-NF at a rate much faster than that of control microsomes. These studies indicate that TCDD-exposed rats provide a useful model to investigate the mechanism of enhanced in vitro induction of SCE frequency in lymphocytes from humans exposed to toxic halogenated aromatics or cigarette smoke.
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis; D001571:Benzoflavones / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004147:Dioxins / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D008214:Lymphocytes / Q000648:ultrastructure; D008954:Models, Biological; D010634:Phenobarbital / Q000494:pharmacology; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D012854:Sister Chromatid Exchange / Q000187:drug effects*; D012907:Smoking
D001571:Benzoflavones; D004147:Dioxins; D005419:Flavonoids; D000072317:Polychlorinated Dibenzodioxins; C011512:alpha-naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D010634:Phenobarbital