Biology of Non-steroidal Androgen Receptor Modulators

生殖与发育毒理学实验室的雄激素生物学小组成立于2003年。我们正在研究组织选择性雄激素受体调节剂的药理学。所采用的方法包括利用独特的非类固醇雄激素激动剂和天然荧光的拮抗剂。我们使用基于细胞和动物的分析方法来研究这些化合物的药效学，特别是它们在确定组织选择性机制方面的作用。主要的感兴趣的化合物在可见光下发出荧光，并产生高量子产率的单线态氧物种。在显微镜下照射培养中的活细胞产生一种时间-光和化合物浓度依赖的细胞杀伤效应。通过碘化丙啶染色可见细胞进入渗透期，随后进入溶细胞期，导致细胞死亡。我们正在研究这一途径的机制。第二项研究活动包括研究雄激素受体调节剂在体外控制干细胞分化的作用。已发表的证据表明，雄激素效应将干细胞转移到肌样途径而不是脂肪细胞途径，支持内分泌干扰物作为环境因素影响人类肥胖的作用。这一过程的机制和对雄激素激动剂和拮抗剂的敏感性是目前我们这方面工作的重点。

The Androgen Biology Group in the Laboratory of Reproductive and Developmental Toxicology was established in 2003. We are studying the pharmacology of tissue-selective androgen receptor modulators. The methods employed involve capitalizing upon unique non-steroidal androgen agonists and antagonists that are naturally fluorescent. We use both cell- and animal based assays to investigate the pharmacodynamics of these compounds, with particular reference to their utility to determine the mechanism of tissue selectivity. The principal compound of interest fluoresces in the visible, and also elicits singlet-oxygen species with high quantum yield. Irradiation of live cells in culture on the microscope stage generates a cell-killing effect that is time- light- and compound concentration dependent. Cells progress through a permeable stage visualized via propidium iodide staining, followed subsequently by a cytolytic phase resulting in cell death. We are investigating the mechanism of this pathway. A second research activity involves studies of the role of androgen receptor modulators as controllers of stem cell differentiation in vitro. Published evidence for androgen effects to shift stem cells towards a myoid pathway as opposed to an adipocytic pathway supports a role for endocrine disruptors as environmental factors affecting obesity in humans. The mechanism and sensitivity of this process to androgen agonists and antagonists is currently the focus of this aspect of our work.