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EGF AND TGF ALPHA EXPRESSION INFLUENCE THE DEVELOPMENTAL TOXICITY OF TCDD: DOSE RESPONSE AND AHR PHENOTYPE IN EGF, TGF ALPHA AND EGF+TGF ALPHA KNOCKOUT MICE
Citation:
Abbott, B D., A R. Buckalew, M J. DeVito, D. Ross, P. L. Bryant, AND J E. Schmid. EGF AND TGF ALPHA EXPRESSION INFLUENCE THE DEVELOPMENTAL TOXICITY OF TCDD: DOSE RESPONSE AND AHR PHENOTYPE IN EGF, TGF ALPHA AND EGF+TGF ALPHA KNOCKOUT MICE. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 71(1):84-95, (2003).
Description:
Abstract
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), EGF, and transforming growth factor- (TGF ). In this study, the developmental toxicity of TCDD was examined in EGF, TGF and double EGF+TGF knockout (-/-) and wild type (WT) mice. The influence of background genetics in responsiveness to TCDD was examined using liver EROD activity. Animals were dosed by gavage with 0, 0.2, 1, 5, 24, 50, 100 or 150 g TCDD/kg (5 ml/kg) body weight on gestation day 12. The mixed genetic background of WT, EGF (-/-) and EGF+TGF (-/-) made these mice less responsive to TCDD relative to C57BL/6J and TGF (-/-), which have a C57BL background. These results show that EGF and TGF 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 (-/-) mice express EGF and were similar to WT in sensitivity for induction of CP and HN. The responses of EGF+TGF (-/-) mice were similar to WT except at higher dose where sensitivity to CP increased, suggesting that alternative ligands for EGFR are similar but not identical to EGF or TGF . 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.
Keywords: Hydronephrosis, cleft palate, EGF, TGF , EGF receptor, TCDD