Karolczak M, Küppers E, Beyer C
Abteilung Anatomie und Zellbiologie, Universität Ulm, Germany.
J Neuroendocrinol. 1998 Apr;10(4):267-74. doi: 10.1046/j.1365-2826.1998.00200.x.
Androgen metabolites synthesized by neural aromatase and 5alpha-reductase are implicated in many aspects of mammalian brain development and, in particular, in the masculinization of distinct central nervous system structures and brain functions. The present study was designed to determine (1) the developmental profile of aromatase- and 5alpha-reductase type I mRNA expression in the mouse hypothalamus and (2) to relate ontogenetic sex differences in aromatase activity which have been described in the past to sex-specific aromatase gene expression. In addition, we analysed the effect of androgens on the perinatal regulation of hypothalamic aromatase and 5alpha-reductase type I mRNA expression. By applying semiquantitative reverse transcription-polymerase chain reaction analysis, we found hypothalamic aromatase mRNA expression to be developmentally regulated and to display sex differences at birth and on postnatal day 15 with higher mRNA levels in males. Newborn males and females, which were treated in utero with the androgen receptor antagonist cyproterone actetate, exhibited significantly reduced aromatase mRNA levels compared with untreated controls. In contrast to aromatase, expression levels of hypothalamic 5alpha-reductase mRNA did not reveal a clear-cut developmental profile or sex differences, and no regulatory role for androgens in controlling 5alpha-reductase mRNA expression was found. In conclusion, these results demonstrate perinatal sex differences in hypothalamic aromatase- but not 5alpha-reductase gene expression and suggest that sex differences in perinatal aromatase activity are reflected by corresponding differences in mRNA levels. Androgens are found to control brain estrogen formation pretranslationally at the level of aromatase gene expression. Our findings imply that sex differences in androgen availability and responsiveness are important regulatory factors for aromatase expression in the developing male hypothalamus.
由神经芳香化酶和5α-还原酶合成的雄激素代谢产物与哺乳动物大脑发育的许多方面有关，特别是与不同中枢神经系统结构和脑功能的男性化有关。本研究旨在确定：（1）小鼠下丘脑芳香化酶和I型5α-还原酶mRNA表达的发育情况；（2）将过去描述的芳香化酶活性的个体发育性别差异与性别特异性芳香化酶基因表达联系起来。此外，我们分析了雄激素对围产期下丘脑芳香化酶和I型5α-还原酶mRNA表达的调节作用。通过应用半定量逆转录-聚合酶链反应分析，我们发现下丘脑芳香化酶mRNA表达受发育调控，在出生时和出生后第15天表现出性别差异，雄性的mRNA水平更高。在子宫内用雄激素受体拮抗剂醋酸环丙孕酮处理的新生雄性和雌性，与未处理的对照组相比，芳香化酶mRNA水平显著降低。与芳香化酶不同，下丘脑5α-还原酶mRNA的表达水平没有显示出明确的发育情况或性别差异，也没有发现雄激素在控制5α-还原酶mRNA表达方面的调节作用。总之，这些结果表明围产期下丘脑芳香化酶基因表达存在性别差异，而5α-还原酶基因表达不存在性别差异，提示围产期芳香化酶活性的性别差异反映在mRNA水平的相应差异上。发现雄激素在芳香化酶基因表达水平上对脑雌激素形成进行翻译前控制。我们的研究结果表明，雄激素可用性和反应性的性别差异是发育中的雄性下丘脑芳香化酶表达的重要调节因素。
