Pl. Bryant et al., Teratogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice lacking the expression of EGF and/or TGF-alpha, TOXICOL SCI, 62(1), 2001, pp. 103-114
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exposure produces hydronephrosis
and cleft palate in mice. These responses are correlated with disruption o
f expression of epidermal growth factor (EGF) receptor ligands, primarily E
GF and transforming growth factor-alpha (TGF-alpha), 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-alpha, or both EGF a
nd TGF-alpha. Pregnant females were weighed on GD 12 acid dosed by gavage w
ith either corn oil or TCDD at 24 mug/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, in
cidence of cleft palate, and the severity and incidence of hydronephrosis w
ere recorded. TCDD did not affect maternal weight gain, fetal weight, or su
rvival, but maternal and fetal liver weights and liver-to-body weight ratio
s were increased in all genotypes, The WT and TGF-alpha (-/-), but not the
EGF (-/-) and EGF + TGF-alpha (-/-) fetuses, developed cleft palate after e
xposure to 24 mug TCDD/kg. Hydronephrosis was induced by TCDD in all genoty
pes, with the incidence in EGF + TGF-alpha (-/-) fetuses comparable to that
of the WT. The incidence and severity of this defect was substantially inc
reased in EGF (-/-) and TGF-alpha (-/-). In conclusion, this study demonstr
ated that expression of EGF influences the induction of cleft palate by TCD
D. Also, EGF and TGF-cu are not required for the induction of hydronephrosi
s, but when either is absent the response of the fetal urinary tract to TCD
D is enhanced.