Toxicological Sciences 62, 103-114 (2001)
Copyright © 2001 by the Society of Toxicology
REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY |
Teratogenicity of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) in Mice Lacking the Expression of EGF and/or TGF-
,2
* Environmental Sciences and Engineering Department, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599;
Biostatistics and Research Support Staff, National Health and Environmental Effects Research Laboratory, Research Triangle Park, North Carolina 27711; and
Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exposure produces hydronephrosis and cleft palate in mice. These responses are correlated with disruption of expression of epidermal growth factor (EGF) receptor ligands, primarily EGF and transforming growth factor-alpha (TGF-
), and altered epithelial cell proliferation and differentiation. This research examined the role of these growth factors in TCDD-induced teratogenicity by using wild type (WT) and knockout (–/–) mice that do not express EGF, TGF-, or both EGF and TGF-. Pregnant females were weighed on GD 12 and dosed by gavage with either corn oil or TCDD at 24 µg/kg, 5 ml/kg. On GD 17.5, the maternal parameters evaluated included body weight, body weight gain, liver weight (absolute and adjusted for body weight). The number of implantations, live and dead fetuses, early or late resorptions, the proportion of males, fetal body weight, fetal absolute and relative liver weight, placenta weight, incidence of cleft palate, and the severity and incidence of hydronephrosis were recorded. TCDD did not affect maternal weight gain, fetal weight, or survival, but maternal and fetal liver weights and liver-to-body weight ratios were increased in all genotypes. The WT and TGF- (–/–), but not the EGF (–/–) and EGF + TGF- (–/–) fetuses, developed cleft palate after exposure to 24 µg TCDD/kg. Hydronephrosis was induced by TCDD in all genotypes, with the incidence in EGF + TGF- (–/–) fetuses comparable to that of the WT. The incidence and severity of this defect was substantially increased in EGF (–/–) and TGF- (–/–). In conclusion, this study demonstrated that expression of EGF influences the induction of cleft palate by TCDD. Also, EGF and TGF- are not required for the induction of hydronephrosis, but when either is absent the response of the fetal urinary tract to TCDD is enhanced.
Key Words: TCDD; hydronephrosis; cleft palate; EGF; TGF-; EGF receptor..
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