Mechanisms of dioxin effects on prostate development

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DESCRIPTION (provided by applicant): This project will examine the mechanisms by which dioxin exposure disrupts development of the prostate. Dioxin toxicity is mediated by the aryl hydrocarbon receptor (AhR). Prenatal exposure to dioxin in rodents leads to a permanent decrease in prostate gland weight and permanent changes in prostatic gene expression. An understanding of the mechanisms of these effects of dioxin on prostate development could have relevance for both environmental toxicology and human prostate disease. Since the developing prostate is responsive to both androgens and estrogens, studying the role of AhR in prostate development may lead to a greater understanding of the interactions between the AhR and steroid hormone signaling pathways. In addition, study of the perturbation of prostate growth by AhR may shed light on the native roles of AhR in regulation of cell proliferation and differentiation. This study will address three hypotheses. First, the effects of dioxin on prostate development result from direct effects on prostate cells. Second, the effects of dioxin on prostate development are mediated by interactions between mesenchymal and epithelial cells. Third, the effects of dioxin on prostate development involve changes in activity and expression of androgen receptor (AR), estrogen receptor (ER), and the growth factors epidermal growth factor (EGF) and transforming growth factor beta l (TGF-beta l). These hypotheses will be tested by examination of the effects of dioxin on primary cultures of prostate cells collected from developing rats. Epithelial and mesenchymal cells will be tested separately and together using a co-culture system that allows cells to communicate chemically while remaining physically isolated. Gene expression will be measured using real time rtPCR. Activity of AhR, AR, and ER will be measured using transiently transfected reporter systems.