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）通过阻断胎儿腹侧泌尿生殖窦（vUGS）中前列腺导管上皮芽的形成而损害小鼠腹侧前列腺发育。TCDD对vUGS芽的抑制需要在妊娠15 ~ 16天激活芳烃受体（Ahr）。初步数据显示，TCDD在此期间诱导了类维甲酸代谢细胞色素P450 (Cyp) 2c39基因，并降低了类维甲酸响应Homeobox (Hox) a13基因（预计Hoxd13也会降低）。该研究将检验TCDD通过Ahr-和cyp2c39依赖性维甲酸降低Hoxa13/d13表达来抑制vUGS芽形成的假设。本研究将证明TCDD暴露于C57B1/6J雄性小鼠胎儿会局部增加vUGS Cyp2c39基因表达，局部降低生物活性类维生素a水平，局部降低Hoxa13/d13基因表达。本研究将证明维甲酸是前列腺芽形成所必需的，Cyp2c39过表达时维甲酸不足会损害UGS前列腺芽形成。此外，本研究将证明vgs中维甲酸代谢的增加是TCDD抑制腹侧前列腺出芽的关键机制，通过短暂降低Cyp2c39表达或在TCDD培养的UGS器官中补充维甲酸可以恢复出芽。

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.