transforming-growth-factor-alpha and Abnormalities--Drug-Induced

Epidermal growth factor (EGF) and transforming growth factor-alpha (TGFalpha) regulate cell proliferation and differentiation in the embryo. The induction of cleft palate (CP) by all trans-retinoic acid (RA) was associated with altered expression of TGFalpha, EGF receptor, and binding of EGF. This study uses knockout (KO) mice to examine the roles of EGF and TGFalpha in teratogenic responses of embryos exposed to RA.. Pregnant wild-type (WT) mice of mixed genetic background, EGF KO, C57BL/6J, and TGFalpha KO mice were given a single oral dose of RA (100 mg/kg, 10 ml/kg) or corn oil on GD 10 at 12 PM, GD 11 at 12 PM or 4 PM, or GD 12 at 8 AM or 12 PM (plug day = GD 0). GD 18 fetuses were examined for external, visceral, and skeletal effects.. After exposure to RA on GD 12, the incidence of CP in EGF KO was significantly reduced relative to WT. In TGFalpha KO fetuses, RA exposure on GD 10 increased the incidence of CP versus C57BL/6J. The incidence of skeletal defects in the limbs, vertebrae, sternebrae, and ribs were also affected by lack of expression of EGF or TGFalpha with region-specific amelioration or exacerbation of the effects of RA. In TGFalpha KO fetuses, incidences of forelimb long bone and digit defects increased relative to C57BL/6J. In EGF KO fetuses, relative to WT, the incidence of hindlimb oligodactyly was increased. In EGF KO, but not WT, RA produced short, bent radius, humerus, and ulna. Both TGFalpha and EGF KO mice had increased incidences of dilation of the renal pelvis and this was reduced by RA.. RA exposure produced skeletal and visceral defects in all genotypes; however, EGF or TGFalpha KO influenced the incidence and severity of defects. This study supports a role for EGF and TGFalpha in the response to RA.

Topics: Abnormalities, Drug-Induced; Animals; Bone and Bones; Cleft Palate; Epidermal Growth Factor; Female; Fetus; Kidney Pelvis; Mice; Mice, Knockout; Phenotype; Pregnancy; Prenatal Injuries; Transforming Growth Factor alpha; Tretinoin

The environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) produces cleft palate (CP) and hydronephrosis (HN) in mice. The etiology of these defects involves hyperproliferation of epithelial cells of the secondary palatal shelf and ureter, respectively. These effects correlate with altered expression of the epidermal growth factor receptor (EGFR), epidermal growth factor (EGF), and transforming growth factor-alpha (TGF-alpha). In this study, the developmental toxicity of TCDD was examined in EGF, TGF-alpha, and double EGF + TGF-alpha knockout (-/-) and wild type (WT) mice. The influence of background genetics in responsiveness to TCDD was examined using liver 7-ethoxyresorufin-O-deethylase (EROD) activity. Animals were dosed by gavage with 0, 0.2, 1, 5, 24, 50, 100, or 150 micro g TCDD/kg (5 ml/kg) body weight on gestation day 12. The mixed genetic background of WT, EGF (-/-), and EGF + TGF-alpha (-/-) made these mice less responsive to TCDD relative to C57BL/6J and TGF-alpha (-/-), which have a C57BL background. These results show that EGF and TGF-alpha are not required for response to TCDD; however, the specific ligand available to bind EGFR affects the responsiveness to TCDD. EGF (-/-) mice are less responsive for CP, but more sensitive to HN. TGF-alpha (-/-) mice were similar to WT in sensitivity for induction of CP and HN. The responses of EGF + TGF-alpha (-/-) mice were like the WT except at higher doses where sensitivity to CP increased, suggesting that the responses may be mediated by alternative ligands for EGFR that are not functional equivalents of EGF or TGF-alpha. In conclusion, the EGFR pathway is mechanistically important in responses of the embryo to TCDD. Specific ligands confer sensitivity or resistance that are target tissue-dependent.

Topics: Abnormalities, Drug-Induced; Administration, Oral; Animals; Cleft Palate; Cytochrome P-450 CYP1A1; Dose-Response Relationship, Drug; Environmental Pollutants; Epidermal Growth Factor; Female; Genetic Predisposition to Disease; Hydronephrosis; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microsomes, Liver; Polychlorinated Dibenzodioxins; Pregnancy; Teratogens; Transforming Growth Factor alpha

In utero, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure causes abnormal ventral, dorsolateral, and anterior prostate development in C57BL/6J mice. Androgens, mesenchymal-epithelial interactions, and growth factor expression all have roles in initiating and regulating development and growth of the prostate. Epidermal growth factor (EGF) and transforming growth factor alpha (TGF-alpha), both of which bind the EGF receptor (EGFR), are expressed in human and rodent developing prostate. This study examines the influence of null expression of EGF and/or TGF-alpha on prostatic bud development and on the ability of TCDD to inhibit prostatic budding. Growth factor knockout (-/-) and wild-type (WT) mice were exposed either to vehicle or to TCDD (0, 0.2, 1, 5, 10, 50, 100, or 150 microg/kg) on gestation day (GD) 12. The number of anterior, dorsal, and lateral prostatic buds (ADLB) and ventral buds (VB) were counted on GD 17.5. Control WT and EGF (-/-) fetuses had similar numbers of ADLB and VB. In control TGF-alpha (-/-) fetuses, the number of ADLBs was higher relative to the C57BL/6J. Control EGF + TGF-alpha (-/-) had poor bud outgrowth, especially in the ADL region. TCDD induced a dose-related decrease in bud formation in all strains with the formation of VBs being more sensitive than ADLBs. The severity of the response depended on growth factor expression, with the most severe effects on VBs in the EGF (-/-) and on ADLBs in the EGF + TGF-alpha (-/-) fetuses. TGF-alpha (-/-) and C57BL/6J fetuses responded to TCDD similarly. In conclusion, EGF and TGF-alpha expression are important for the formation of ADLBs and VBs, and expression of EGF and TGF-alpha affects the ability of TCDD to inhibit prostatic bud formation in a region-specific manner.

Topics: Abnormalities, Drug-Induced; Administration, Oral; Animals; Dose-Response Relationship, Drug; Epidermal Growth Factor; Epithelium; Female; Gene Expression Regulation, Developmental; Genetic Predisposition to Disease; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Electron, Scanning; Polychlorinated Dibenzodioxins; Pregnancy; Prostate; Teratogens; Transforming Growth Factor alpha

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-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 and TGF-alpha. Pregnant females were weighed on GD 12 and dosed by gavage with either corn oil or TCDD at 24 microg/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-alpha (-/-), but not the EGF (-/-) and EGF + TGF-alpha (-/-) fetuses, developed cleft palate after exposure to 24 microg TCDD/kg. Hydronephrosis was induced by TCDD in all genotypes, with the incidence in EGF + TGF-alpha (-/-) fetuses comparable to that of the WT. The incidence and severity of this defect was substantially increased in EGF (-/-) and TGF-alpha (-/-). In conclusion, this study demonstrated that expression of EGF influences the induction of cleft palate by TCDD. Also, EGF and TGF-alpha are not required for the induction of hydronephrosis, but when either is absent the response of the fetal urinary tract to TCDD is enhanced.

Topics: Abnormalities, Drug-Induced; Administration, Oral; Animals; Body Weight; Cleft Palate; Environmental Pollutants; Epidermal Growth Factor; Female; Hydronephrosis; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Organ Size; Polychlorinated Dibenzodioxins; Pregnancy; Reproduction; Teratogens; Toxicity Tests; Transforming Growth Factor alpha