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EVIDENCE FOR EGFR PATHWAY MEDIATION OF CLEFT PALATE INDUCTION BY TCDD
Abbott, B D., A R. Buckalew, AND K E. Leffler. EVIDENCE FOR EGFR PATHWAY MEDIATION OF CLEFT PALATE INDUCTION BY TCDD. Presented at Society of Toxicology, Salt Lake City, UT, March 09 - 13, 2003.
EVIDENCE FOR EGFR PATHWAY MEDIATION OF CLEFT PALATE INDUCTION BY TCDD. B D Abbott, A R Buckalew, and K E Leffler. RTD, NHEERL, ORD,US EPA, RTP, NC, USA.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is teratogenic in C57BL/6J mice, producing cleft palate (CP) after exposure in utero. Epidermal growth factor receptor (EGFR), EGF and TGF-alpha (TGF) expression in the palate is disrupted by TCDD exposure affecting proliferation and differentiation. The key role of EGF in mediating the teratogenicity was confirmed using EGF knockout (KO) mice. The EGF KO embryos were less responsive for the induction of cleft palate than the wild type mice (WT=C57BL/6J x 129). However, exposure of TGF KO mice (having C57BL/6J background) produced incidences of CP that were similar that observed in C57BL/6J wild type mice. In this study, the pivotal role of EGF in the response to TCDD was confirmed using palatal organ culture. Embryonic mouse palates from C57BL/6J, TGF KO, WT and EGF KO mice were placed in organ culture on gestation day (GD) 12 and cultured with or without TCDD (1x10-8 M) in presence or absence of growth factor supplements (2 ng/ml EGF or TGF). After 5 days in culture, the effects of the treatments on palatal fusion were evaluated. The palates from all of the genotypes fused in the serum-free, defined control medium. Similar to the in vivo response, EGF KO palates exposed to TCDD fused and the rate of fusion did not differ from the control cultures. EGF KO palates exposed to TCDD in presence of EGF (2ng/ml) failed to fuse (p<0.05 vs control medium or TCDD without EGF). The responses of TGF KO palates differed as only TGF supplementation significantly reduced fusion rates in the presence of TCDD. Our lab and others have reported a requirement for serum for many cell types to respond to TCDD in culture. The present study demonstrates that addition of EGF or TGF alone can be sufficient to mediate responses to TCDD. The palatal culture model also confirms that providing EGF to the palates of EGF KO mice restores the responsiveness to TCDD. These studies support the hypothesis that the mechanism for induction of CP by TCDD is mediated via the EGFR pathway. Disclaimer: This abstract does not necessarily reflect EPA policy.