Inhibition of Fetal Prostate Development by Dioxin

描述（由申请人提供）：子宫内暴露于2,3,7,8-四氯二苯并-对二恶英（TCDD）通过抑制胎儿泌尿生殖窦（UGS）的前列腺上皮芽形成（出芽）而损害小鼠腹侧前列腺发育。虽然是UGS的上皮成分产生前列腺芽，但它是周围的UGS间质（UGM），它包含驱动出芽的雄激素受体（AR）和介导TCDD抑制出芽的芳烃受体（AhR）。拟议的研究将通过使用染色质免疫沉淀（ChlP）测定来鉴定UGM中作为AR和AhR直接靶点的基因，该测定可鉴定与转录因子积极结合的基因启动子。本研究还将通过对整个UGS基因表达的DNA微阵列分析，鉴定雄激素和tcdd响应的基因表达。研究人员将分析野生型和ar缺陷（Tfm）雄性C57BL/6J胎儿在妊娠15 - 16天（TCDD抑制出芽的关键窗口期）子宫内暴露于载药或TCDD的ugs。目前关于tcdd诱导的萌芽抑制机制的信息很少。这项工作将通过确定UGS暴露于TCDD后最早的AhR-DNA结合事件，促进识别参与出芽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.