MRC Centre for Reproductive Health, The Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom.
PLoS One. 2012;7(5):e37064. doi: 10.1371/journal.pone.0037064. Epub 2012 May 17.
Reproductive disorders that are common/increasing in prevalence in human males may arise because of deficient androgen production/action during a fetal 'masculinization programming window'. We identify a potentially important role for Chicken Ovalbumin Upstream Promoter-Transcription Factor II (COUP-TFII) in Leydig cell (LC) steroidogenesis that may partly explain this. In rats, fetal LC size and intratesticular testosterone (ITT) increased ~3-fold between e15.5-e21.5 which associated with a progressive decrease in the percentage of LC expressing COUP-TFII. Exposure of fetuses to dibutyl phthalate (DBP), which induces masculinization disorders, dose-dependently prevented the age-related decrease in LC COUP-TFII expression and the normal increases in LC size and ITT. We show that nuclear COUP-TFII expression in fetal rat LC relates inversely to LC expression of steroidogenic factor-1 (SF-1)-dependent genes (StAR, Cyp11a1, Cyp17a1) with overlapping binding sites for SF-1 and COUP-TFII in their promoter regions, but does not affect an SF-1 dependent LC gene (3β-HSD) without overlapping sites. We also show that once COUP-TFII expression in LC has switched off, it is re-induced by DBP exposure, coincident with suppression of ITT. Furthermore, other treatments that reduce fetal ITT in rats (dexamethasone, diethylstilbestrol (DES)) also maintain/induce LC nuclear expression of COUP-TFII. In contrast to rats, in mice DBP neither causes persistence of fetal LC COUP-TFII nor reduces ITT, whereas DES-exposure of mice maintains COUP-TFII expression in fetal LC and decreases ITT, as in rats. These findings suggest that lifting of repression by COUP-TFII may be an important mechanism that promotes increased testosterone production by fetal LC to drive masculinization. As we also show an age-related decline in expression of COUP-TFII in human fetal LC, this mechanism may also be functional in humans, and its susceptibility to disruption by environmental chemicals, stress and pregnancy hormones could explain the origin of some human male reproductive disorders.
男性生殖障碍在人群中越来越常见，其可能是由于胎儿“雄性化编程窗口”期间雄激素产生/作用不足所致。我们发现鸡卵清蛋白上游启动子转录因子 II（COUP-TFII）在睾丸间质细胞（LC）类固醇生成中可能具有重要作用，这在一定程度上可以解释这一现象。在大鼠中，e15.5-e21.5 期间胎儿 LC 大小和睾丸内睾酮（ITT）增加了约 3 倍，同时 LC 中表达 COUP-TFII 的比例逐渐下降。暴露于邻苯二甲酸二丁酯（DBP）的胎儿中，DBP 可诱导雄性化障碍，剂量依赖性地阻止了 LC COUP-TFII 表达随年龄的正常下降以及 LC 大小和 ITT 的正常增加。我们发现，胎鼠 LC 中的核 COUP-TFII 表达与类固醇生成因子-1（SF-1）依赖性基因（StAR、Cyp11a1、Cyp17a1）的 LC 表达呈负相关，因为它们的启动子区域存在 SF-1 和 COUP-TFII 的重叠结合位点，但不影响没有重叠位点的 SF-1 依赖性 LC 基因（3β-HSD）。我们还发现，一旦 LC 中的 COUP-TFII 表达关闭，DBP 暴露会重新诱导其表达，同时抑制 ITT。此外，其他降低大鼠胎儿 ITT 的处理（地塞米松、己烯雌酚（DES））也维持/诱导 LC 核中 COUP-TFII 的表达。与大鼠不同，DBP 既不会导致胎儿 LC COUP-TFII 持续存在，也不会降低 ITT，而 DES 暴露于小鼠中维持胎儿 LC 中 COUP-TFII 的表达并降低 ITT，与大鼠相同。这些发现表明，COUP-TFII 的抑制解除可能是促进胎儿 LC 产生更多睾酮以驱动雄性化的重要机制。正如我们还在人胎儿 LC 中显示出 COUP-TFII 表达随年龄的相关性下降，该机制在人类中也可能具有功能，其对环境化学物质、应激和妊娠激素的敏感性破坏可能解释了一些人类男性生殖障碍的起源。
