Alterations of gene expression in adult male rat testis and pituitary shortly after subacute administration of the antiandrogen flutamide.
Alterations of gene expression in adult male rat testis and pituitary shortly after subacute administration of the antiandrogen flutamide.
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DOI：
10.1262/jrd.49.275
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发表时间：
2003-08
期刊：
影响因子：
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通讯作者：
S. Ohsako;K. Kubota;Shuichi Kurosawa;K. Takeda;W. Qing;R. Ishimura;C. Tohyama
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文献类型：
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作者：
S. Ohsako;K. Kubota;Shuichi Kurosawa;K. Takeda;W. Qing;R. Ishimura;C. Tohyama
在抗雄激素药物诱导的雄性生殖系统基因表达谱改变的过程中，在亚急性给药众所周知的抗雄激素药物氟替卡松（FM）后不久，对成年大鼠睾丸或垂体中表达的28个基因进行了检查。雄性大鼠经口给予FM（25 mg/kg/天）6天。在FM首次给药后第8天（D8），睾丸内睾酮（T）水平显著增加，但D36的每日精子产量显著降低。用半定量RT-PCR方法检测D8时睾丸和垂体基因mRNA水平。在6种睾丸类固醇生成酶基因中，P450侧链裂解酶、P450 17 α/C（17-20）裂解酶和3 β-羟基类固醇脱氢酶I型（3 β HSD）基因的mRNA显著增加，而17 β-羟基类固醇脱氢酶III型略有减少。在检测的三种类固醇受体中，雄激素受体（AR）和糖皮质激素受体（GR）mRNA在睾丸中显著下调（分别为29%和35%），但雌激素受体α没有变化。促性腺激素受体和支持细胞特异性基因的表达没有明显变化，但乳糖苷酶-c mRNA（生殖细胞特异性基因）的表达略有增加。在三个即刻早期基因中，c-myc mRNA增加约1.4倍。另一方面，在垂体中，LH β和FSH β亚基以及促性腺激素释放激素受体的mRNA显著增加。这些结果表明，亚急性FM给药首先影响下丘脑/垂体激素基因表达，然后改变促性腺激素分泌，随后诱导睾丸类固醇生成酶基因的过度表达。然而，尽管睾丸内T水平较高，但3 β HSD的显著上调和AR mRNA的下调可能是由保留在睾丸中的羟基芴醇的拮抗作用解释的。观察到的基因表达的改变的概况将提供重要的信息，为成年雄性动物的抗雄激素化学品的筛选。
In the course of profiling alterations of gene expression in the male reproductive system induced by anti-androgenic agents, 28 genes expressed in the testis or pituitary of adult rats were examined shortly after subacute administration of the well-known anti-androgen, flutamide (FM). FM (25 mg/kg/day) was orally administered to male rats for six days. On day 8 (D8) after the first dose of FM, intratesticular testosterone (T) levels had dramatically increased, but daily sperm production on D36 was significantly decreased. The mRNA levels of testicular and pituitary genes on D8 were measured by semiquantitative RT-PCR. Among the six testicular steroidogenic enzyme genes, the mRNAs of the P450 side chain cleavage, P450 17 alpha/C(17-20) lyase, and 3beta-hydroxysteroid dehydrogenase type I (3betaHSD) genes significantly increased, whereas 17beta-hydroxysteroid dehydrogenase type III slightly decreased. Among the three steroid receptors examined, androgen receptor (AR) and glucocorticoid receptor (GR) mRNAs were significantly down-regulated (29% and 35%, respectively) in the testis, but there was no change in estrogen receptor alpha. There were no clear changes in expression of the gonadotropin receptors and Sertoli cell specific genes, but a slight increase was observed in expression of the lactose dehydrogenase-c mRNA, a germ cell specific gene. Among the three immediate early genes, c-myc mRNA was increased approximately 1.4-fold. In the pituitary, on the other hand, mRNAs for LHbeta and FSHbeta subunits and gonadotropin releasing hormone receptor had increased significantly. These results show that subacute FM administration first affected hypothalamus/pituitary hormone gene expression, then altered gonadotropin secretion, and subsequently induced over-expression of testicular steroidogenic enzyme genes. However, the significant up-regulation of 3betaHSD and down-regulation of AR mRNAs, despite the higher level of intratesticular T, might be explained by an antagonistic action of hydroxyflutamide retained in the testis. The profiles of alterations in gene expression observed will provide important information for the screening of adult male animals for anti-androgenic chemicals.