2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) impairs mouse ventral prostate development by blocking formation of epithelial buds giving rise to prostate ducts in the ventral urogenital sinus (vUGS) of the fetus. vUGS bud inhibition by TCDD requires aryl hydrocarbon receptor (Ahr) activation between gestation days 15-16. Preliminary data suggest TCDD induces the retinoid-metabolizing Cytochrome P450 (Cyp) 2c39 gene and decreases the retinoid-responsive Homeobox (Hox) a13 gene in vUGS during this period (it is anticipated Hoxd13 is also reduced). The proposed research will examine the hypothesis that TCDD inhibits vUGS bud formation by an Ahr- and Cyp2c39-dependent reduction in retinoic acid that decreases Hoxa13/d13 expression. The proposed research will demonstrate TCDD exposure of C57B1/6J male mouse fetuses locally increases vUGS Cyp2c39 gene expression, locally decreases biologically active retinoid levels, and locally decreases Hoxa13/d13 gene expression. This research will demonstrate retinoic acid is necessary for prostatic bud formation and retinoic acid insufficiency during Cyp2c39 overexpression impairs UGS prostatic bud formation. Furthermore, this research will demonstrate increased retinoic acid metabolism in vUGS is a key mechanism for ventral prostatic budding inhibition by TCDD and budding can be restored by transiently reducing Cyp2c39 expression or supplementing retinoic acid to UGS organ cultures incubated with TCDD.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-DIG-B (21))
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Humble, Michael C
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University of Wisconsin Madison
Schools of Pharmacy
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Allgeier, Sarah H; Lin, Tien-Min; Moore, Robert W et al. (2010) Androgenic regulation of ventral epithelial bud number and pattern in mouse urogenital sinus. Dev Dyn 239:373-85
Vezina, Chad M; Hardin, Heather A; Moore, Robert W et al. (2010) 2,3,7,8-Tetrachlorodibenzo-p-dioxin inhibits fibroblast growth factor 10-induced prostatic bud formation in mouse urogenital sinus. Toxicol Sci 113:198-206
Vezina, Chad M; Lin, Tien-Min; Peterson, Richard E (2009) AHR signaling in prostate growth, morphogenesis, and disease. Biochem Pharmacol 77:566-76
Allgeier, Sarah Hicks; Vezina, Chad M; Lin, Tien-Min et al. (2009) Estrogen signaling is not required for prostatic bud patterning or for its disruption by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Appl Pharmacol 239:80-6
Vezina, Chad M; Allgeier, Sarah H; Fritz, Wayne A et al. (2008) Retinoic acid induces prostatic bud formation. Dev Dyn 237:1321-33
Allgeier, Sarah Hicks; Lin, Tien-Min; Vezina, Chad M et al. (2008) WNT5A selectively inhibits mouse ventral prostate development. Dev Biol 324:10-7
Vezina, Chad M; Allgeier, Sarah Hicks; Moore, Robert W et al. (2008) Dioxin causes ventral prostate agenesis by disrupting dorsoventral patterning in developing mouse prostate. Toxicol Sci 106:488-96
Cook, Crist; Vezina, Chad M; Allgeier, Sarah H et al. (2007) Noggin is required for normal lobe patterning and ductal budding in the mouse prostate. Dev Biol 312:217-30