Inhibition of Fetal Prostate Development by Dioxin

描述(由申请人提供)：在宫内暴露于2，3，7，8-四氯二苯并-对二恶英(TCDD)通过抑制来自胎儿泌尿生殖窦(UGS)的前列腺上皮芽形成(萌芽)而损害小鼠的腹侧前列腺发育。虽然是UGS的上皮成分产生了前列腺芽，但周围的UGS间充质(UGM)含有驱动发芽的雄激素受体(AR)和介导TCDD抑制发芽的芳香烃受体(AhR)。这项拟议的研究将通过染色质免疫沉淀(ChlP)分析确定UGM中作为AR和AhR直接靶标的那些基因，该分析识别主动与转录因子结合的基因启动子。这项研究还将通过对整个UGS基因表达的DNA微阵列分析，确定其表达是雄激素和TCDD反应的基因。UGSS将分析从野生型和AR缺陷(TFM)的男性C57BL/6J胎儿在宫内接触车辆或TCDD在怀孕15天至16天，这是TCDD抑制萌发的关键窗口。目前关于TCDD诱导的萌发抑制机制的信息很少。这项工作将有助于通过识别UGS暴露于TCDD后最早的AhR-DNA结合事件来识别参与萌发抑制的关键信号级联。

DESCRIPTION (provided by applicant): In utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) impairs ventral prostate development in mice by inhibiting prostatic epithelial bud formation (budding) from the fetal urogenital sinus (UGS). While it is the epithelial component of the UGS that gives rise to prostatic buds, it is the surrounding UGS mesenchyme (UGM) that contains the androgen receptors (AR) that drive budding and the aryl hydrocarbon receptors (AhR) that mediate budding inhibition by TCDD. The proposed research will identify those genes in the UGM that are direct targets of the AR and the AhR through the use of chromatin immunoprecipitation (ChlP) assays, which identify gene promoters actively bound to transcription factors. This research will also identify genes whose expression is androgen- and TCDD-responsive through DNA microarray analysis of whole UGS gene expression. UGSs will be analyzed from wild-type and AR-deficient (Tfm) male C57BL/6J fetuses exposed in utero to vehicle or TCDD during day 15 to day 16 of gestation, the critical window for budding inhibition by TCDD. Little information is currently available regarding the mechanisms of TCDD-induced budding inhibition. This work will facilitate the identification of key signaling cascades involved in budding inhibition by identifying the earliest AhR-DNA binding events following exposure of the UGS to TCDD.