Toxicological Sciences 71, 84-95 (2003)
Copyright © 2003 by the Society of Toxicology
REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY |
EGF and TGF-
Expression Influence the Developmental Toxicity of TCDD: Dose Response and AhR Phenotype in EGF, TGF-, and EGF + TGF- Knockout Mice
* Reproductive Toxicology Division and
Environmental Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711; and
The Procter & Gamble Co., Health Care Research Center, 8700 Mason-Montgomery Road, Mason, Ohio 45040-9642
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), epidermal growth factor (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 7-ethoxyresorufin-O-deethylase (EROD) activity. Animals were dosed by gavage with 0, 0.2, 1, 5, 24, 50, 100, or 150 µg 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 were similar to WT in sensitivity for induction of CP and HN. The responses of EGF + TGF- (–/–) mice were like the WT except at higher doses where sensitivity to CP increased, suggesting that the responses may be mediated by alternative ligands for EGFR that are not functional equivalents of 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.
Key Words: hydronephrosis; cleft palate; EGF; TGF-; EGF receptor; TCDD.
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