ENVIRONMENTAL ANTI-ANDROGENS AND AR AUTOREGULATION

雄激素受体(AR)在调节男性泌尿生殖道正常发育和维持生殖功能所必需的基因表达方面起着重要作用。AR作为一种配体激活的转录因子发挥作用，并与许多人类病理有关，最明显的是前列腺癌。AR也经历自我调节，这是雄激素调节AR mRNA转录和AR蛋白稳定性的过程。这种作用可能是细胞改变其对雄激素反应的一种机制。我的赞助人和其他人已经证明，AR mRNA水平可能与雄激素敏感性有关。工业化学品和所谓的“环境内分泌干扰物”可能会干扰雄激素介导的活动。人类男性生殖道畸形、男性不育症和女性乳腺癌发病率的增加可能部分是由于这些化合物的抗雄激素作用。研究表明，两种这样的化学物质，DDE(杀虫剂DDT的代谢物)和M2(杀菌剂长春新灵的代谢物)抑制AR DNA结合和随后的靶基因反式激活。此外，其他实验室也发现，这些化学物质可能具有激动剂活性，特别是在高浓度下。这项建议旨在评估DDE和M2对AR自身调节的影响，以及预先暴露于这些化学物质对细胞对雄激素的反应的影响。两种不同的雄激素靶向组织模型LNCaP(前列腺癌)和T47D(乳腺癌)将用于这些研究。我们的长期目标是阐明这些环境抗雄激素影响AR自身调节和反应性的机制，以及这些影响可能如何与有害和发育病理相关联。

Androgen receptors (ARs) play an important role in regulating the expression of genes necessary for normal development of the male urogenital tract and for the maintenance of reproductive function. AR functions as a ligand-activated transcription factor and has been implicated in a number of human pathologies, most notably prostate cancer. AR also undergoes autoregulation, a process by which androgens regulate AR mRNA transcription and AR protein stability. This action may be a mechanism by which cells can alter their responsiveness to androgens. My sponsor and others have shown that AR mRNA levels may correlate with androgen sensitivity. Industrial chemicals and the so-called "environmental endocrine disruptors" may interfere with androgen-mediated activities. The increasing incidence of human male genital tract malformations, male infertility, and female breast cancer may be due in part to antiandrogenic effects of these compounds. Studies suggest that two such chemicals, DDE (a metabolite of the pesticide DDT) and M2 (a metabolite of the fungicide vinclozolin) inhibit AR DNA-binding and the subsequent transactivation of target genes. Also, other laboratories have found that these chemicals may possess agonist activities, especially at high concentrations. This proposal seeks to assess the effects of DDE and M2 on AR autoregulation as well as the effects of pre-exposure to these chemicals on cellular responsiveness to androgen. Two different models of androgen target tissues, LNCap (prostate cancer) and T47D (breast cancer), will be used for these studies. Our long- term goal is to elucidate the mechanisms by which these environmental antiandrogens affect AR autoregulation and responsiveness and how these effects may be associated with detrimental and developmental pathologies.