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TERATOGENIC EFFECTS OF RETINOIC ACID ARE MODULATED IN MICE LACKING EXPRESSION OF EPIDERMAL GROWTH FACTOR AND TRANSFORMING GROWTH FACTOR-ALPHA
Citation:
ABBOTT, B. D., D. S. BEST, AND M. G. NAROTSKY. TERATOGENIC EFFECTS OF RETINOIC ACID ARE MODULATED IN MICE LACKING EXPRESSION OF EPIDERMAL GROWTH FACTOR AND TRANSFORMING GROWTH FACTOR-ALPHA. BIRTH DEFECTS RESEARCH PART A: CLINICAL AND MOLECULAR TERATOLOGY. Wiley Liss, New York, NY, (73):204-217, (2005).
Description:
Background: EGF and TGF 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 TGF, EGF receptor and binding of EGF. The present study uses knockout (KO) mice to examine the roles of EGF and TGF in teratogenic responses of embryos exposed to RA. Methods: Pregnant wild type (WT) mice of mixed genetic background, EGF KO, C57BL/6J, and TGF KO mice were given a single oral dose of RA (100 mg/kg, 10 ml/kg) or corn oil on gestation day (GD)10 at 12PM, GD11 at 12PM or 4 PM, or GD12 at 8 AM or 12PM (plug day=GD0). GD18 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 TGF KO fetuses, RA exposure on GD 10 increased the incidence of CP vs C57BL/6J. The incidence of skeletal defects in the limbs, vertebrae, sternebrae, and ribs were also affected by lack of expression of EGF or TGF with region-specific amelioration or exacerbation of the effects of RA. In TGF KO fetuses, incidences of fore limb long bone and digit defects increased relative to C57BL/6J. In EGF KO fetuses, relative to WT, the incidence of hind limb oligodactyly was increased. In EGF KO but not WT, RA produced short, bent radius, humerus, and ulna. Both TGF 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 TGF KO influenced the incidence and severity of defects. This study supports a role for EGF and TGF in the response to RA.