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.
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-alpha (TGF-alpha). In this study, the developmental toxicity of TCDD was examined in EGF, TGF-alpha, and double EGF + TGF-alpha 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 micro g TCDD/kg (5 ml/kg) body weight on gestation day 12. The mixed genetic background of WT, EGF (-/-), and EGF + TGF-alpha (-/-) made these mice less responsive to TCDD relative to C57BL/6J and TGF-alpha (-/-), which have a C57BL background. These results show that EGF and TGF-alpha 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-alpha (-/-) mice were similar to WT in sensitivity for induction of CP and HN. The responses of EGF + TGF-alpha (-/-) 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-alpha. 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.
Abbott
Barbara D
BD
Reproductive 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, USA. abbott.barbara@epa.gov
Buckalew
Angela R
AR
DeVito
Michael J
MJ
Ross
David
D
Bryant
P Lamont
PL
Schmid
Judith E
JE
D000014:Abnormalities, Drug-Induced / Q000235:genetics*; D000284:Administration, Oral; D000818:Animals; D002972:Cleft Palate / Q000139:chemically induced / Q000196:embryology / Q000235:genetics; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000633:toxicity*; D004815:Epidermal Growth Factor / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006869:Hydronephrosis / Q000139:chemically induced / Q000196:embryology / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000633:toxicity*; D011247:Pregnancy; D013723:Teratogens / Q000633:toxicity*; D016211:Transforming Growth Factor alpha / Q000235:genetics*
D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D013723:Teratogens; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; D019363:Cytochrome P-450 CYP1A1