TCDD Impairs Prostate Development: Cyp2c39 & Retinoids

描述(由申请人提供)：2，3，7，8-四氯二苯并-对二恶英(TCDD)通过阻断上皮芽的形成而损害小鼠的腹侧前列腺发育，从而在胎儿的腹侧泌尿生殖窦(Vugs)形成前列腺管。TCDD对Vugs芽的抑制需要在妊娠15-16天之间激活芳香烃受体(Ahr)。初步数据表明，在此期间，TCDD在Vugs中诱导了维甲酸代谢细胞色素P450(Cyp)2c39基因，并降低了维甲酸反应性同源盒(Hox)A13基因(预计Hoxd13也会减少)。这项拟议的研究将检验这样的假设，即TCDD通过依赖AhR和Cyp2c39的维甲酸减少Hoxa13/d13的表达来抑制Vugs芽的形成。这项拟议的研究将证明，C57B1/6J雄性小鼠胚胎暴露于TCDD局部增加了Vugs Cyp2c39基因的表达，局部降低了生物活性维甲酸水平，局部降低了Hoxa13/d13基因的表达。这项研究将证明维甲酸是前列腺芽形成所必需的，而在Cyp2c39过度表达损害UGS前列腺芽形成的过程中维甲酸不足。此外，这项研究将证明，Vugs中维甲酸代谢增加是TCDD抑制前列腺腹侧发芽的关键机制，通过瞬时降低Cyp2c39的表达或向与TCDD孵育的UGS器官培养中添加维甲酸，可以恢复发芽。

DESCRIPTION (provided by applicant): 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.