"Androgen receptors in fishes, endocrine, toxicological and evolutionary significance"

雄激素或雄性激素对于所有脊椎动物的雄性和雌性的性发育和功能至关重要。雄激素的作用是通过雄激素受体介导的，雄激素受体被认为在所有有颌脊椎动物中都是保守的。已知只有硬骨鱼拥有两种雄激素受体。这可能是硬骨鱼与其他有颌脊椎动物分裂后基因组复制的结果。然而，并非所有硬骨鱼都保留了两种雄激素受体，而第二种不同受体的功能仍然是个谜。这项研究旨在解决与鱼类雄激素受体调节相关的三个基本问题。第一个问题是“拥有两种雄激素受体的物种的内分泌功能和信号机制是什么？”这将通过敲低细胞培养物中受体的表达或检查报告基因生物测定中受体的功能来确定信号转导机制来进行检查。这反过来需要了解与雄激素调节基因上游受体结合的反应元件——这是鱼类中完全未探索过的领域。第二个问题，“拥有两种受体的进化优势是什么？”，将通过评估仅具有一种或两种雄激素受体的鱼类的繁殖特征来进行检查。这将需要为这两种受体开发快速分子生物学筛选策略，并将其应用于广泛的不同鱼类。最后，鉴于已知许多生殖内分泌干扰物质会进入环境，“我们试图了解两种雄激素受体的毒理学意义是什么？”这将通过比较两种受体与已知内分泌毒物的结合、检查这些化合物对细胞培养物中雄激素调节基因产物的影响以及比较两种鱼类对一种或两种受体的反应来进行检查。这项研究将增进我们对鱼类进化的了解，并将提供知识和工具来更好地预测和诊断对我们环境的影响。

Androgens, or male hormones, are essential for sexual development and function in both males and females of all vertebrates. The effects of androgens are mediated through androgen receptors that are thought to be conserved in all jawed vertebrates. Only teleost fishes are known to possess two androgen receptors. This likely occurred as a result of a genome duplication after the split of teleost fishes from other jawed vertebrates. However, not all teleost fishes have retained two androgen receptors and the function of the second distinct receptor remains an enigma. This research proposes to address three fundamental questions associated with androgen receptor regulation in fishes. The first question is "what is the endocrine function and signaling mechanism of two androgen receptors in those species that possess them?" This will be examined by determining the mechanism of signal transduction by either knocking down receptor expression in cell culture, or examining the function of the receptors in reporter gene bioassays. This will in turn require an understanding of the responsive elements that bind the receptor upstream of androgen-regulated genes - an area completely unexplored in fishes. The second question, "what is the evolutionary advantage of having two receptors?", will be examined by evaluating the reproductive traits of fishes with either just one, or two androgen receptors. This will entail developing a rapid molecular biology screening strategy for both receptors, and applying this to a wide range of diverse fish species. Finally, given the many reproductive-endocrine disrupting substances that are known to enter the environment, "we seek to know what the toxicological significance of two androgen receptors could be?" This will be examined by comparing the binding both receptors to known endocrine toxicants, examining the effects of those compounds on androgen-regulated gene products in cell culture, and by comparing the responses of two species of fish, with either one, or two receptors. This research will grow our understanding of the evolution of fishes and will provide knowledge and tools to better predict and diagnose impacts on our environment.