Inhibition of Fetal Prostate Development by Dioxin

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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.