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RETINOIC ACID INDUCTION OF CLEFT PALATE IN EGF AND TGF-ALPHA KNOCKOUT MICE: STAGE SPECIFIC INFLUENCES OF GROWTH FACTOR EXPRESSION
Citation:
Abbott, B D., K E. Leffler, AND A R. Buckalew. RETINOIC ACID INDUCTION OF CLEFT PALATE IN EGF AND TGF-ALPHA KNOCKOUT MICE: STAGE SPECIFIC INFLUENCES OF GROWTH FACTOR EXPRESSION. Presented at Teratology Society Meeting, Philadelphia, PA, June 21-26, 2003.
Description:
ABBOTT, B. D., LEFFLER, K.E. AND BUCKALEW, A.R, Reproductive Toxicology Division, NHEERL, ORD, US EPA, Research Triangle Park, North Carolina. Retinoic acid induction of cleft palate (CP) in EGF and TGF knockout mice: Stage specific influences of growth factor expression.
Epidermal growth factor (EGF) and transforming growth factor-alpha (TGF ) regulate cell proliferation and differentiation in the embryo. EGF and TGF are expressed in the developing palate and changes in levels and patterns of expression are associated with CP induction by retinoic acid (RA) and dioxin. A recent study using EGF knockout (KO) mice showed that in the absence of EGF expression, embryos exposed on gestation day (GD)12 were resistant to TCDD-induced CP. The present study examines the role of EGF and TGF in embryos exposed to RA. Wild type (WT) mice with a mixed C57BL/6J x 129 genetic background served as controls for the EGF KO and C57BL/6J mice were the control for the TGF KO. Pregnant mice (plug day=GD0) were given a single oral dose of all-trans RA (100 mg/kg, 10 ml/kg) or vehicle on either GD10 at noon, GD11 at noon or 4 PM, or GD12 at 8 AM or noon. On GD 18, animals were killed and the fetuses removed and scored for CP. In fetuses treated on GD 12 at 8AM, the incidence of CP in EGF KO (16.7%?10, mean per litter ? SEM) was significantly reduced compared to WT (49%?16). EGF KO embryos treated at other time points were similar to the WT. TGF KO mice treated on GD10 had a significantly higher response (79.8%?8), than the C57BL/6J (40.3%?13), but did not differ at other time points. Xenobiotic-induced CP incidence decreased for all strains as development progressed. Thus, at earlier developmental stages, the absence of TGF appears to increase the susceptibility to RA, whereas at later stages EGF appears to be involved in mediating CP. This stage-specific modification of responsiveness may be related to patterns of EGF and TGF expression during development, as well as to altered regulation after exposure to RA. This abstract does not necessarily reflect EPA policy.