ToxSci Advance Access published online on October 4, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp226
2,3,7,8-Tetrachlorodibenzo-p-dioxin Inhibits Fibroblast Growth Factor 10-Induced Prostatic Bud Formation in Mouse Urogenital Sinus
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* Department of Comparative Biosciences, School of Veterinary Medicine
Molecular and Environmental Toxicology Center
School of Pharmacy, University of Wisconsin, Madison, WI 53705
Corresponding author: Richard E. Peterson, Ph.D., School of Pharmacy, University of Wisconsin, 777 Highland Avenue, Madison, WI 53705-2222, repeterson{at}pharmacy.wisc.edu, (608) 263-5453, (608) 265-3316 FAX
Received August 7, 2009; revision received September 9, 2009; accepted September 9, 2009
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Abstract |
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2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) dorsalizes the pattern of prostatic buds developing from the urogenital sinus (UGS) of male fetal mice, causing some buds to form in inappropriate positions while blocking formation of others. This teratogenic TCDD action significantly reduces prostate main duct number and causes ventral prostate agenesis in exposed males. The purpose of this study was to determine whether inhibition of fibroblast growth factor 10 (FGF10) signaling is mechanistically linked to mouse prostatic budding impairment by TCDD. In utero TCDD exposure induced aryl hydrocarbon receptor (AHR)-responsive cytochrome P450 1b1 mRNA in ventral UGS regions where Fgf10 and FGF receptor 2 (Fgfr2) mRNA were expressed and where budding was most severely inhibited by TCDD. However, TCDD exposure did not reduce Fgf10 or Fgfr2 mRNA abundance in the UGS or alter their distribution. Addition of FGF10 protein to UGS organ culture media increased the abundance of UGS basal epithelial cells immuno-positive for phosphorylated extracellular signal-regulated kinase (ERK). FGF10 also increased the number of bromodeoxyuridine (BrdU)-labeled UGS epithelial cells and increased the number of prostatic buds formed per UGS. Addition of TCDD to UGS organ culture media did not alter FGF10-induced ERK activation in UGS basal epithelium but prevented FGF10-induced BrdU incorporation and blocked FGF10-induced prostatic bud formation. These results identify basal UGE cells as the key site of FGF10 action during fetal prostate development and suggest that TCDD likely acts downstream of FGFR2 and ERK to restrict UGS epithelial cell proliferation and prevent prostatic bud formation.
Key Words: urogenital sinus; fibroblast growth factor 10; development; mouse; TCDD; prostate.