Teratogenic effects of retinoic acid are modulated in mice lacking expression of epidermal growth factor and transforming growth factor-α

BACKGROUND: Epidermal growth factor (EGF) and transforming growth factor-alpha (TGFu) regulate cell proliferation and differentiation in the embryo. The induction of cleft palate (CP) by all traps-retinoic acid (RA) was associated with altered expression of TGF alpha, EGF receptor, and binding of EGF. This study uses knockout (KO) mice to examine the roles of EGF and TGFa in teratogenic responses of embryos exposed to RA. METHODS: Pregnant wild-type (WT) mice of mixed genetic background, EGF KO, C57BL/6J, and TGFa 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. RESULTS: After exposure to RA on GD 12, the incidence of CP in EGF KO was significantly reduced relative to WT. In TGFu 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 TGFa with region-specific amelioration or exacerbation of the effects of RA. In TGFu 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 TGFa and EGF KO mice had increased incidences of dilation of the renal pelvis and this was reduced by RA. CONCLUSIONS: RA exposure produced skeletal and visceral defects in all genotypes; however, EGF or TGFu KO influenced the incidence and severity of defects. This study supports a role for EGF and TGFa in the response to RA. Birth Defects Research (Part A) 73:204-217, 2005. Published 2005 Wiley-Liss, Inc.(dagger).