Effects of CDB-4022 on Leydig cell function in adult male rats.
Effects of CDB-4022 on Leydig cell function in adult male rats.
复制标题
CDB-4022 对成年雄性大鼠 Leydig 细胞功能的影响。
DOI：
10.1095/biolreprod.106.059204
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发表时间：
2007
影响因子：
3.6
通讯作者：
Clark,BarbaraJ
中科院分区：
文献类型：
--
作者：
Chen,Yu-Chyu;Cochrum,RenateK;Tseng,MichaelT;Ghooray,DushanT;Moore,JosephP;Winters,StephenJ;Clark,BarbaraJ
CDB-4022是一种茚并吡啶，可抑制成年雄性大鼠的精子发生并减少精子素分泌。在本研究中，我们研究了CDB-4022对Leydig细胞功能的影响。单次口服CDB-4022（2.5 mg/kg）7天后导致血清睾酮水平降低2倍，与溶剂处理的大鼠相比，Cyp 17 a1 mRNA和蛋白水平以及17 α羟化酶酶活性降低。与较低的血清睾酮水平一致，通过CDB-4022处理，垂体LH和Fshb mRNA水平分别增加3.2倍和2.3倍。垂体促性腺激素细胞的超微结构分析显示，扩张的内质网（ER）和分泌颗粒在CDB-4022治疗的大鼠，分泌活性增强的特点。相反，CDB-4022增加血清孕酮水平，testicularStarmRNA和蛋白质表达，以及每个睾丸的Leydig细胞数量。在CDB-4022处理的大鼠中检测不到血清白蛋白B水平，而血清激活素A水平与对照相似，表明CDB-4022处理的大鼠具有升高的激活素A：白蛋白B比率。在hCG刺激的存在下，激活素A直接抑制睾酮分泌，但增强大鼠睾丸间质细胞原代培养物的孕酮分泌。同样，发现用激活素A处理MA-10细胞增强cAMP刺激的孕酮分泌和星星表达。总之，我们的数据表明，CDB-4022治疗抑制CYP 17 A1和刺激星星表达，从而减少睾酮，但增加孕酮的生产。我们提出，激活素A的非对抗作用最有可能有助于CDB-4022治疗后大鼠中的类固醇特征。我们的研究结果建立了CDB-4022作为一个新的模型来检查睾丸内控制机制，调节Leydig细胞基因的表达和功能。
CDB-4022, an indenopryridine, suppresses spermatogenesis and decreases inhibin secretion in adult male rats. In the present study, we investigated the effects of CDB-4022 on Leydig cell function. A single oral dose of CDB-4022 (2.5 mg/kg) resulted in a 2-fold decrease in serum testosterone levels after 7 days that was paralleled by a decrease inCyp17a1mRNA and protein levels and 17alpha hydroxylase enzymatic activity compared with vehicle-treated rats. Consistent with the lower serum testosterone levels, pituitaryLhbandFshbmRNA levels were increased 3.2- and 2.3-fold, respectively, by CDB-4022 treatment. Ultrastructural analysis of pituitary gonadotrophs showed distended endoplasmic reticulum (ER) and fewer secretory granules in CDB-4022-treated rats, characteristic of enhanced secretory activity. Conversely, CDB-4022 increased serum progesterone levels, testicularStarmRNA and protein expression, and the number of Leydig cells per testis. Serum inhibin B levels were undetectable in CDB-4022-treated rats, while serum activin A levels were similar to controls, indicating that the CDB-4022-treated rats have an elevated activin A:inhibin B ratio. In the presence of hCG stimulation, activin A directly suppressed testosterone secretion but enhanced progesterone secretion from rat Leydig cell primary cultures. Likewise, treatment of MA-10 cells with activin A was found to enhance cAMP-stimulated progesterone secretion and STAR expression. Together, our data indicate that CDB-4022 treatment inhibits CYP17A1 and stimulates STAR expression, thereby decreasing testosterone but increasing progesterone production. We propose that unopposed actions of activin A most likely contribute to the steroid profile in rats after CDB-4022 treatment. Our findings establish CDB-4022 as a new model to examine intratesticular control mechanisms that modulate Leydig cell gene expression and function.