Teratogenic effects of 2,3,7,8-tetrabromodibenzo-p-dioxin and three polybrominated dibenzofurans in C57BL/6N mice.
Brominated flame retardants involved in many industrial uses contain polybrominated dibenzo-p-dioxins (PBDDs) and dibenzofurans (PBDFs) as contaminants. The levels of these contaminants can be dramatically increased by combustion. These chemicals are closely related in structure to the polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs), of which 2,3,7,8-tetrachloridibenzo-p-dioxin (TCDD) is the most toxic isomer. TCDD and related PCDFs are potent mouse teratogens inducing cleft palate and hydronephrosis at doses below those at which overt maternal and embryo/fetal toxicity occurs. This study examines the teratogenic effects of 2,3,7,8-tetrabromodibenzo-p-dioxin (TBDD), 2,3,7,8-tetrabromodibenzofuran (TBDF), 1,2,3,7,8-pentabromodibenzofuran (1PeBDF), and 2,3,4,7,8-pentabromodibenzofuran (4PeBDF) in C57BL/6N mice treated on gestation day (gd) 10 and examined on gd 18. Pregnant dams were treated with 0-4000 micrograms of each congener per kilogram body weight in 10 ml corn oil/kg. Dose selection was based on the relative toxicity of the chlorinated isomers. Maternal toxicity and developmental toxicity were assessed, and the hard palate and kidney, the target organs for the teratogenic effects of TCDD and related compounds, were examined for structural abnormalities. While the maternal liver weight increased at all dose levels examined for all four compounds, there was no evidence of any maternal toxicity. Embryo/fetal mortality was increased only at greater than or equal to 500 microgram TBDF/kg, while fetal weight increased in a dose-related manner following exposure to TBDD and TBDF. All compounds produced hydronephrosis (HN) at doses below that at which cleft palate (CP) occurred. The incidence of HN was significantly increased above background levels at the following doses (micrograms/kg): TBDD, 3; TBDF, 25; 1PeBDF, 500; 4PeBDF, 400. The LOELs (micrograms/kg) for CP were: TBDD, 48; TBDF, 200; 1PeBDF, 4000; 4PeBDF, 2400. The cleft palate incidence for all four brominated compounds and TCDD could be fit to a common slope, compatible with the concept that these chemicals all exert their teratogenic effects through a common mechanism. The potency of these chemicals, relative to TCDD as 1 for the induction of cleft palate, is TBDD, 0.24; TBDF, 0.10; 1PeBDF, 0.004; and 4PeBDF, 0.005. Previous studies from our laboratory had determined that the chlorinated dibenzofuran isomers had relative potencies of 0.05 (TCDF), 0.03 (1PeCDF), and 0.09 (4PeCDF). Thus, bromination decreases the teratogenic activity of TBDD relative to TCDD and of both 1- and 4PeBDF relative to the chlorinated isomers. However, substitution of bromines for chlorines increases the potency of TBDF relative to TCDF.(ABSTRACT TRUNCATED AT 400 WORDS)
Birnbaum
L S
LS
National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Morrissey
R E
RE
Harris
M W
MW
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000704:Analysis of Variance; D000818:Animals; D001572:Benzofurans / Q000633:toxicity*; D002972:Cleft Palate / Q000139:chemically induced*; D004147:Dioxins / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005260:Female; D005411:Flame Retardants; D006869:Hydronephrosis / Q000139:chemically induced*; D051379:Mice; D008810:Mice, Inbred C57BL; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D011247:Pregnancy
D001572:Benzofurans; D004147:Dioxins; D005411:Flame Retardants; D000072317:Polychlorinated Dibenzodioxins; C066841:2,3,7,8-tetrabromodibenzo-4-dioxin