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FOR 1369: Sulfated Steroids in Reproduction

FOR 1369：生殖中的硫酸类固醇

基本信息

批准号：
152381467
负责人：
金额：
--
依托单位：
Institut für Veterinär-Anatomie, -Histologie und Embryologie
依托单位国家：
德国
项目类别：
Research Units
财政年份：
2010
资助国家：
德国
起止时间：
2009-12-31 至 2017-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/152381467?language=en
关键词：
1369 Sulfated Steroids Reproduction

项目摘要

The classical dogma is that steroid hormones must be available in an unbound, free form in order to interact with the respective receptor and to initiate a biological response. Steroid glucuronides and sulfates, which are predominantly formed in the liver or kidney, are generally considered as biologically inactive metabolites intended for elimination. However, in pregnant cows huge amounts of estrone sulfate (E1S) are secretory products of the placenta. Similarly in the stallion and boar the testes secrete large amounts of conjugated estrogens, in particular E1S. The discovery of the co-localisation of estrogen receptors, estrogen sulfatase and sulfotransferase in the same tissue responsible for estrogen synthesis as shown by the expression of aromatase sheds new light on this situation and gives rise to new hypotheses on the role of conjugated estrogens in reproduction and reproductive diseases. There is increasing evidence that hydrolysis of sulfated estrone and dehydroepiandrosterone catalysed by steroid sulfatase is an important alternative source of precursors for the local supply of estrogens and androgens, respectively. Thus, in addition to the provision of steroid hormones by the secretory activity of a given cell or gland, a second system controlling the availability of biologically active steroids on the cellular level might be established due to the expression of steroid sulfatase and/or sulfotransferase in certain organs, like the placenta, mammary gland, ovary or the testis. The existence of such a system, however, would also require that sulfoconjugated steroids may penetrate the plasma membrane of a target cell in order to get hydrolysed and to become biologically active. The fact that - other than free steroids - conjugated steroids will not passively pass the lipid cell membrane barrier, questioned the existence of such a secondary local regulatory system. This situation has changed with the discovery of membrane uptake carriers for sulfoconjugated steroids such as the sodium dependent organic anion transporter (SOAT). SOAT has shown to have high substrate specificity for steroid sulfates and is highly expressed in reproductive tissues such as testis and placenta. The Research Unit focusses around this hypothesis of a local regulatory system concerning the provision of biologically active steroids by using steroid sulfates as precursors or by targeting biological activity through sulfoconjugation of free steroids. Thus, as a completely new aspect in veterinary reproductive endocrinology, this Research Unit addresses the hydrolysis and transmembrane transport of sulfated steroids as additional levels of control of steroid actions.

经典的教条是类固醇激素必须以未结合的游离形式存在，以便与相应的受体相互作用并引发生物反应。类固醇葡萄糖醛酸和硫酸盐主要在肝脏或肾脏中形成，通常被认为是用于消除的生物学无活性代谢产物。然而，在怀孕的奶牛中，大量的硫酸雌酮（E1 S）是胎盘的分泌产物。同样，在种马和公猪的睾丸分泌大量的结合雌激素，特别是E1 S。发现雌激素受体，雌激素硫酸酯酶和磺基转移酶在同一组织中负责雌激素合成的芳香化酶的表达，揭示了这种情况的新的光，并产生了新的假设共轭雌激素在生殖和生殖疾病的作用。越来越多的证据表明，类固醇硫酸酯酶催化的硫酸化雌酮和脱氢表雄酮的水解是雌激素和雄激素的前体的重要替代来源。因此，除了通过给定细胞或腺体的分泌活性提供类固醇激素之外，由于类固醇硫酸酯酶和/或磺基转移酶在某些器官（如胎盘、乳腺、卵巢或睾丸）中的表达，可以建立在细胞水平上控制生物活性类固醇的可用性的第二系统。然而，这种系统的存在还需要磺基缀合的类固醇可以穿透靶细胞的质膜，以便水解并变得具有生物活性。事实上，除了游离类固醇-结合类固醇将不会被动地通过脂质细胞膜屏障，质疑这样的二级局部调节系统的存在。这种情况已经改变了发现膜摄取载体磺基共轭类固醇，如钠依赖性有机阴离子转运蛋白（SOAT）。SOAT已显示对类固醇硫酸盐具有高底物特异性，并且在生殖组织如睾丸和胎盘中高度表达。该研究单位的重点围绕这一假设的本地监管系统有关提供生物活性类固醇通过使用类固醇硫酸盐作为前体或通过靶向生物活性通过磺基共轭的游离类固醇。因此，作为兽医生殖内分泌学的一个全新方面，该研究单位将硫酸化类固醇的水解和跨膜转运作为类固醇作用的额外控制水平。