Morgan Joshua T, Robbins Alan K, Mateson Abigail B, Sawamoto Kazuki, Tomatsu Shunji, Gray Dione R, Gleghorn Jason P, Barthold Julia Spencer
Department of Bioengineering, University of California, Riverside, Riverside, CA, United States.
Nemours Biomedical Research, Division of Urology, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, United States.
Front Endocrinol (Lausanne). 2018 Dec 4;9:738. doi: 10.3389/fendo.2018.00738. eCollection 2018.
The process of testicular descent requires androgen and insulin-like 3, hormones secreted by fetal Leydig cells. Knowledge concerning distinct and common functions of these hormones in regulating development of the fetal gubernaculum remains limited and/or conflicting. The current studies were designed to better define characteristics of androgen receptor (AR) expression, function and regulation, as well as the biomechanical properties of normal and cryptorchid gubernaculum during fetal development. We studied fetal gubernacula from Long Evans outbred (LE/wt) rats and an inbred (LE/orl) strain with an inherited form of cryptorchidism associated with an AR signaling defect. Gubernacular cells or whole organs obtained from LE/wt and LE/orl fetal gubernacula underwent AR immunostaining and quantitative image analysis. The effects of dihydrotestosterone (DHT) on AR expression, muscle fiber morphology, hyaluronan (HA) levels and glycosaminoglycan (GAG) content were measured in LE/wt gubernacula. Finally, the spatial mechanics of freshly harvested LE/wt and LE/orl fetal gubernacula were compared using micropipette aspiration. AR is expressed in the nucleus of mesenchymal core, tip and cord cells of the embryonic (E) day 17 and 21 fetal gubernaculum, and is enhanced by DHT in primary cultures of gubernacular mesenchymal cells. Enhanced AR expression at the tip was observed in LE/wt but not LE/orl gubernacula. In studies of whole mount fetal gubernaculum, DHT did not alter muscle fiber morphology, HA content or GAG production. Progressive swelling with reduced cellular density of the LE/wt gubernaculum at E19-21 was associated with increased central stiffness in LE/wt but not in LE/orl fetuses. These data confirm nuclear AR expression in gubernacular mesenchyme with distal enhancement at the tip/cord region in LE/wt but not LE/orl rat fetuses. DHT enhanced cellular AR expression but had no major effects on muscle morphology or matrix composition in the rat fetal gubernaculum . Regional increased stiffness and decreased cell density between E19 and E21 were observed in LE/wt but not LE/orl fetal gubernacula. Developmental differences in cell-specific AR expression in LE/orl fetal gubernacula may contribute to the dysmorphism and aberrant function that underlies cryptorchidism susceptibility in this strain.
睾丸下降过程需要雄激素和胰岛素样3，这两种激素由胎儿睾丸间质细胞分泌。关于这些激素在调节胎儿引带发育中的独特和共同功能的知识仍然有限且/或相互矛盾。当前的研究旨在更好地定义雄激素受体（AR）表达、功能和调节的特征，以及胎儿发育过程中正常和隐睾引带的生物力学特性。我们研究了来自远交系Long Evans（LE/wt）大鼠以及一种近交系（LE/orl）大鼠的胎儿引带，该近交系存在与AR信号缺陷相关的遗传性隐睾症。从LE/wt和LE/orl胎儿引带获取的引带细胞或整个器官进行了AR免疫染色和定量图像分析。在LE/wt引带中测量了双氢睾酮（DHT）对AR表达、肌纤维形态、透明质酸（HA）水平和糖胺聚糖（GAG）含量的影响。最后，使用微量移液器抽吸比较了新鲜收获的LE/wt和LE/orl胎儿引带的空间力学。AR在胚胎（E）第17天和21天胎儿引带的间充质核心、尖端和索状细胞的细胞核中表达，并且在引带间充质细胞的原代培养中被DHT增强。在LE/wt引带而非LE/orl引带中观察到尖端处AR表达增强。在对整个胎儿引带的研究中，DHT未改变肌纤维形态、HA含量或GAG产生。在E19 - 21时，LE/wt引带的渐进性肿胀伴细胞密度降低与LE/wt胎儿而非LE/orl胎儿的中心硬度增加有关。这些数据证实了在LE/wt大鼠胎儿而非LE/orl大鼠胎儿的引带间充质中存在核AR表达，在尖端/索状区域有远端增强。DHT增强了细胞AR表达，但对大鼠胎儿引带的肌肉形态或基质组成没有重大影响。在LE/wt胎儿引带中观察到E19和E21之间区域硬度增加和细胞密度降低，而在LE/orl胎儿引带中未观察到。LE/orl胎儿引带中细胞特异性AR表达的发育差异可能导致该品系中隐睾易感性的畸形和异常功能。
