Physiological effects of altered Se transport and Se tissue distribution in selenoprotein P knock out mice - studies on the impact of gender on the phenotype

硒（Se）主要存在于血浆中的可溶性糖蛋白，即硒蛋白P（SePP）中。我们通过靶向破坏SEPP基因座来产生活的SePP-KO小鼠。这些小鼠表现出一个复杂的表型相对于生长，生存，健身，生育能力等SePP-KO小鼠的主要特点是由改变Se-分布之间的器官和干扰的表达的其他硒蛋白，表明SePP的功能作为Se-载体和-转运。该表型表现出简单的基因-剂量关系。此外，主要的影响是以针对性别的方式出现的。在这里，最引人注目的例子是我们在大约30%的雄性SePP-KO小鼠中观察到的雄性不育和自发死亡。同样，雄性SePP-KO小鼠表现出更明显的生长缺陷、脂肪量减少和更明显的共济失调。这些发现指出了一个尚未解决的问题，即硒的性别特异性影响很少受到重视。因此，我们计划详细比较雄性和雌性SePP-KO小鼠的表型。雄性和雌性SePP-KO小鼠的内分泌腺是否受到不同的影响？是否存在改善女性表型的基因表达的性别特异性差异？或者，女性特定的激素/维生素E水平是否可以防止硒供应受限时产生的不良影响？由于也有提示，从临床医学描述性别特异性的影响硒的病理生理条件下，我们相信，这些研究将适合澄清一些潜在的机制。

Selenium (Se) is mainly contained in plasma within a soluble glycoprotein, i.e. selenoprotein P (SePP). We generated viable SePP-KO mice by targeted disruption of the SEPP locus. These mice display a complex phenotype with respect to growth, survival, fitness, fertility, etc. SePP-KO mice are mainly characterized by an altered Se-distribution among the organs and by disturbed expression of the other selenoproteins indicating that SePP functions as a Se-carrier and -transporter. The phenotype displays a simple gene-dose relationship. Moreover, the major effects emerged in a gender-specific manner. Here, the most striking examples were male infertility and spontaneous fatalities that we observed in around 30% of male SePP-KO mice. Likewise male SePP-KO mice displayed more pronounced growth defects, reduced fat mass and more pronounced ataxia. These findings point to an unresolved issue, i.e. sex-specific effects of Se that have rarely received major attention, yet. Thus we plan to compare the phenotype of male and female SePP-KO mice in detail. Are the endocrine glands affected differently in male and female SePP-KO mice? Are there gender-specific differences in gene expression that ameliorate the female phenotype? Or do female-specific hormones/hormone-levels protect from the adverse effects that arise when the Se supply is limiting? Since there are also hints from clinical medicine describing gender-specific effects of Se in pathophysiological conditions, we believe that these studies will be suited to clarify some of the underlying mechanisms.