Miyagawa Shinichi, Yatsu Ryohei, Kohno Satomi, Doheny Brenna M, Ogino Yukiko, Ishibashi Hiroshi, Katsu Yoshinao, Ohta Yasuhiko, Guillette Louis J, Iguchi Taisen
Okazaki Institute for Integrative Bioscience (S.M., R.Y., Y.Og., T.I.), National Institute for Basic Biology, National Institutes of Natural Sciences, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi 444-8787, Japan; Department of Obstetrics and Gynecology (S.K., B.M.D., L.J.G.), Medical University of South Carolina and Hollings Marine Laboratory, Charleston, South Carolina 29412; Department of Life Environmental Conservation (H.I.), Faculty of Agriculture, Ehime University, Matsuyama, Ehime 790-8566, Japan; Department of Biological Sciences (Y.K.), Hokkaido University, Sapporo 060-0810, Japan; and Department of Veterinary Medicine (Y.Oh.), Faculty of Agriculture, Tottori University, Tottori, Tottori 680-8553, Japan.
Endocrinology. 2015 Aug;156(8):2795-806. doi: 10.1210/en.2015-1037. Epub 2015 May 14.
Androgens are essential for the development, reproduction, and health throughout the life span of vertebrates, particularly during the initiation and maintenance of male sexual characteristics. Androgen signaling is mediated by the androgen receptor (AR), a member of the steroid nuclear receptor superfamily. Mounting evidence suggests that environmental factors, such as exogenous hormones or contaminants that mimic hormones, can disrupt endocrine signaling and function. The American alligator (Alligator mississippiensis), a unique model for ecological research in that it exhibits environment-dependent sex determination, is oviparous and long lived. Alligators from a contaminated environment exhibit low reproductive success and morphological disorders of the testis and phallus in neonates and juveniles, both associated with androgen signaling; thus, the alterations are hypothesized to be related to disrupted androgen signaling. However, this line of research has been limited because of a lack of information on the alligator AR gene. Here, we isolated A mississippiensis AR homologs (AmAR) and evaluated receptor-hormone/chemical interactions using a transactivation assay. We showed that AmAR responded to all natural androgens and their effects were inhibited by cotreatment with antiandrogens, such as flutamide, p,p'-dichlorodiphenyldichloroethylene, and vinclozolin. Intriguingly, we found a spliced form of the AR from alligator cDNA, which lacks seven amino acids within the ligand-binding domain that shows no response to androgens. Finally, we have initial data on a possible dominant-negative function of the spliced form of the AR against androgen-induced AmAR.
雄激素对于脊椎动物整个生命周期的发育、繁殖和健康至关重要，尤其是在男性性征的起始和维持过程中。雄激素信号由雄激素受体（AR）介导，AR是类固醇核受体超家族的成员。越来越多的证据表明，环境因素，如外源性激素或模拟激素的污染物，会扰乱内分泌信号和功能。美国短吻鳄（密西西比鳄）是生态研究的独特模型，因为它表现出环境依赖性性别决定，是卵生且寿命长。来自受污染环境的短吻鳄繁殖成功率低，新生儿和幼体的睾丸和阴茎出现形态紊乱，两者都与雄激素信号有关；因此，这些改变被认为与雄激素信号紊乱有关。然而，由于缺乏关于短吻鳄AR基因的信息，这一研究方向受到了限制。在这里，我们分离出了密西西比鳄AR同源物（AmAR），并使用反式激活测定法评估受体 - 激素/化学物质的相互作用。我们发现AmAR对所有天然雄激素都有反应，并且与抗雄激素（如氟他胺、p,p'-二氯二苯二氯乙烯和乙烯菌核利）共同处理时其作用受到抑制。有趣的是，我们从短吻鳄cDNA中发现了一种AR的剪接形式，它在配体结合域内缺少七个氨基酸，对雄激素无反应。最后，我们有关于AR剪接形式对雄激素诱导的AmAR可能具有显性负性功能的初步数据。
