Limited PCB antagonism of TCDD-induced malformations in mice.
C57BL/6N mice used to model induction of cleft palate and kidney malformations in offspring following maternal treatment with TCDD, were dosed on gestation day (gd) 9 with 2,2',4,4',5,5'-hexachlorobiphenyl (HCB) (62.5, 125, 250, 500, 1000 mg/kg) and/or gd 10 with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (15 or 18 micrograms/kg) to investigate the potential protective effects of HCB against TCDD-induced teratogenicity. Maternal body weight gain was increased by combinations of 15 micrograms TCDD/kg and 125-500 mg HCB/kg and decreased at doses of 15 micrograms TCDD/kg + 1000 HCB mg/kg. At the doses used in this study, there was no effect of either compound on number of live or dead offspring. Fetal body weight was slightly decreased in all groups dosed with greater than or equal to 250 mg HCB/kg. HCB did not induce cleft palate at a dose of 1000 mg/kg, but did induce increases in hydronephrosis and hydroureter at 500 and 1000 mg/kg. Combinations of HCB and TCDD decreased the incidence of cleft palate induced by TCDD alone, but only at doses of 15 micrograms TCDD/kg combined with 125-500 mg HCB/kg. The antagonism of hydronephrosis (incidence and severity) appeared over a narrower dose range (15 micrograms TCDD/kg + 500 mg HCB/kg). HCB induced increases (3-fold) in ethoxyresorufin-O-deethylase (EROD) activity at doses of 500 and 1000 mg/kg, suggesting that the limited antagonism of TCDD teratogenicity by HCB could be under the control of the Ah-receptor.
Morrissey
R E
RE
Systemic Toxicology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27711.
Harris
M W
MW
Diliberto
J J
JJ
Birnbaum
L S
LS
D000014:Abnormalities, Drug-Induced / Q000517:prevention & control*; D000818:Animals; D002972:Cleft Palate / Q000139:chemically induced / Q000517:prevention & control*; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D005260:Female; D006869:Hydronephrosis / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010088:Oxidoreductases / Q000032:analysis; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D000072317:Polychlorinated Dibenzodioxins / Q000037:antagonists & inhibitors*; D011247:Pregnancy
D000072317:Polychlorinated Dibenzodioxins; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; C014024:2,4,5,2',4',5'-hexachlorobiphenyl