Mechanisms of dioxin effects on prostate development

描述(由申请者提供)：本项目将检查机械装置 暴露于二恶英会扰乱前列腺的发育。二恶英毒性 是由芳香烃受体(AhR)介导的。产前接触二恶英 在啮齿动物身上导致永久的前列腺重量减轻和永久的 前列腺基因表达的变化。对其作用机制的理解 这些二恶英对前列腺发育的影响可能与两者相关。 环境毒理学和人类前列腺疾病。自发展以来， 前列腺癌对雄激素和雌激素都有反应，研究 AHR在前列腺发育中的作用可能有助于更好地理解 AhR和类固醇激素信号通路之间的相互作用。在……里面 此外，研究AhR对前列腺生长的干扰可能有助于 AhR在调节细胞增殖和修复中的天然作用 差异化。这项研究将解决三个假设。首先，影响 二恶英对前列腺发育的影响源于对前列腺细胞的直接作用。 第二，二恶英对前列腺发育的影响是通过 间充质细胞与上皮细胞之间的相互作用。第三，对中国经济的影响 二恶英对前列腺发育的影响涉及其活性和表达的改变 雄激素受体(AR)、雌激素受体(ER)与生长因子 表皮生长因子和转化生长因子-βL l)。这些假设将通过检测二恶英对环境的影响来检验。 从发育中的大鼠采集的前列腺细胞的原代培养。上皮性 和间充质细胞将单独和一起使用联合培养进行测试 一种允许细胞在保持物理状态的同时进行化学通信的系统 与世隔绝。基因表达将使用实时RT-PCR进行测量。的活动 AHR、AR和ER将使用瞬时转基因报告进行测量 系统。

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.