Coonce Mary M, Rabideau Amanda C, McGee Stacey, Smith Keriayn, Narayan Prema
Department of Physiology, School of Medicine, Southern Illinois University, Carbondale, IL 62901, USA.
Mol Cell Endocrinol. 2009 Jan 27;298(1-2):33-41. doi: 10.1016/j.mce.2008.10.016. Epub 2008 Nov 1.
The actions of luteinizing hormone (LH) mediated through its receptor (LHR) are critical for testicular steroidogenesis and Leydig cell differentiation. We have previously characterized transgenic mice expressing a genetically engineered, constitutively active yoked hormone-receptor complex (YHR), in which a fusion protein of human chorionic gonadotropin (hCG) was covalently linked to LHR. Elevated testosterone levels were detected in male mice expressing YHR (YHR(+)) at 3 and 5 weeks of age, accompanied by decreases in testicular weight and serum levels of LH and follicle stimulating hormone (FSH). Here we report a temporal study to identify testicular genes whose expression is altered in YHR(+) mice during postnatal development. The mRNA expression levels for the steroidogenic enzymes, P450 17alpha-hydroxylase, 17beta-hydroxysteroid dehydrogenase3 and 5alpha-reductase1 were down-regulated in 3- and 5-week-old YHR(+) testis. This result coupled with an immunohistochemical analysis of Leydig cell specific proteins and quantification of Leydig cell numbers identified a decrease in adult Leydig cells in YHR(+) mice. Surprisingly, no change was detected for cytochrome P450 side-chain cleavage or steroidogenic acute regulatory protein RNA levels between WT and YHR(+) mice. In contrast, mRNA levels for insulin-like growth factor binding protein 3 were up-regulated in 3- and 5-week-old YHR(+) mice. The mRNA levels for several germ cell-specific proteins were up-regulated at 5 weeks of age in both WT and YHR(+) mice. We conclude that premature high levels of testosterone alter the expression of a select number of testicular genes and impair the differentiation of adult Leydig cells in mice.
促黄体生成素（LH）通过其受体（LHR）介导的作用对于睾丸类固醇生成和睾丸间质细胞分化至关重要。我们之前已对表达基因工程化的、组成型活性轭合激素 - 受体复合物（YHR）的转基因小鼠进行了表征，其中人绒毛膜促性腺激素（hCG）的融合蛋白与LHR共价连接。在3周龄和5周龄时，表达YHR（YHR(+)）的雄性小鼠中检测到睾酮水平升高，同时睾丸重量以及血清LH和促卵泡生成素（FSH）水平降低。在此我们报告一项时间进程研究，以鉴定在出生后发育过程中YHR(+)小鼠睾丸中表达发生改变的基因。在3周龄和5周龄的YHR(+)睾丸中，类固醇生成酶P450 17α - 羟化酶、17β - 羟类固醇脱氢酶3和5α - 还原酶1的mRNA表达水平下调。这一结果与对睾丸间质细胞特异性蛋白的免疫组织化学分析以及睾丸间质细胞数量的定量分析相结合，确定YHR(+)小鼠中成年睾丸间质细胞数量减少。令人惊讶的是，在野生型（WT）小鼠和YHR(+)小鼠之间，细胞色素P450侧链裂解酶或类固醇生成急性调节蛋白RNA水平未检测到变化。相反，在3周龄和5周龄的YHR(+)小鼠中，胰岛素样生长因子结合蛋白3的mRNA水平上调。在5周龄时，WT小鼠和YHR(+)小鼠中几种生殖细胞特异性蛋白的mRNA水平均上调。我们得出结论，过早出现的高水平睾酮会改变一些特定睾丸基因的表达，并损害小鼠成年睾丸间质细胞的分化。
