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TERATOGENICITY OF 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD) IN MICE LACKING THE EXPRESSION OF EGF AND/OR TGFALPHA
Citation:
Bryant, P. L., J E. Schmid, S E. Fenton, A R. Buckalew, AND B D. Abbott. TERATOGENICITY OF 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD) IN MICE LACKING THE EXPRESSION OF EGF AND/OR TGFALPHA. TOXICOLOGICAL SCIENCES 62(1):103-114, (2001).
Description:
Abstract
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 knockout mice which do not express EGF, TGF" or the double null for both EGF and TGF", and wild type (WT) mice of the same genetic background. Pregnant females of each genotype were weighed on GD 12 and dosed by gavage with either corn oil or TCDD at 24 :g/kg, 5ml/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" null fetuses, developed cleft palate in response to TCDD. Hydronephrosis was induced by TCDD in all genotypes, with the incidence in EGF+TGF" null fetuses comparable to that of the WT. The incidence and severity of this defect was substantially increased in EGF and TGF" nulls. In conclusion, this study demonstrated that EGF is a mediator of TCDD-induced cleft palate and that EGF and TGF" are not required for the induction of hydronephrosis, but when either EGF or TGF" is absent the response of the fetal urinary tract to TCDD is enhanced.