ToxSci Advance Access originally published online on September 26, 2003
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Toxicological Sciences 76, 427-436 (2003)
Copyright © 2003 by the Society of Toxicology
REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY |
Lack of Expression of EGF and TGF-
in the Fetal Mouse Alters Formation of Prostatic Epithelial Buds and Influences the Response to TCDD
,2,
,
,
* Reproductive Toxicology Division, NHEERL, ORD, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711;
School of Pharmacy,
Molecular and Environmental Toxicology Center, and
Department of Animal Sciences, University of Wisconsin, Madison, WI 53705
In utero, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure causes abnormal ventral, dorsolateral, and anterior prostate development in C57BL/6J mice. Androgens, mesenchymal-epithelial interactions, and growth factor expression all have roles in initiating and regulating development and growth of the prostate. Epidermal growth factor (EGF) and transforming growth factor alpha (TGF-
), both of which bind the EGF receptor (EGFR), are expressed in human and rodent developing prostate. This study examines the influence of null expression of EGF and/or TGF- on prostatic bud development and on the ability of TCDD to inhibit prostatic budding. Growth factor knockout (-/-) and wild-type (WT) mice were exposed either to vehicle or to TCDD (0, 0.2, 1, 5, 10, 50, 100, or 150 µg/kg) on gestation day (GD) 12. The number of anterior, dorsal, and lateral prostatic buds (ADLB) and ventral buds (VB) were counted on GD 17.5. Control WT and EGF (-/-) fetuses had similar numbers of ADLB and VB. In control TGF- (-/-) fetuses, the number of ADLBs was higher relative to the C57BL/6J. Control EGF + TGF- (-/-) had poor bud outgrowth, especially in the ADL region. TCDD induced a dose-related decrease in bud formation in all strains with the formation of VBs being more sensitive than ADLBs. The severity of the response depended on growth factor expression, with the most severe effects on VBs in the EGF (-/-) and on ADLBs in the EGF + TGF- (-/-) fetuses. TGF- (-/-) and C57BL/6J fetuses responded to TCDD similarly. In conclusion, EGF and TGF- expression are important for the formation of ADLBs and VBs, and expression of EGF and TGF- affects the ability of TCDD to inhibit prostatic bud formation in a region-specific manner.
Key Words: prostatic bud; TCDD; urogenital sinus; prostate development.
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