Agras Koray, Willingham Emily, Liu Benchun, Baskin Laurence S
Institute for the Study and Treatment of Hypospadias, Department of Urology, UCSF Children's Medical Center, University of California-San Francisco, San Francisco, CA, USA.
J Urol. 2006 Oct;176(4 Pt 2):1883-8. doi: 10.1016/S0022-5347(06)00613-6.
The ontogeny of androgen receptor expression in male and female mouse genital tubercles, and the effects of in utero ethinyl estradiol exposure on androgen receptor mRNA expression in the hypospadias model were studied.
Androgen receptor mRNA expression was measured in mouse genital tubercles from fetuses and pups collected on gestational days 12, 14, 16 and 18, and from newborns using immunohistochemistry and real-time quantitative polymerase chain reaction. Pregnant dams were exposed to ethinyl estradiol or corn oil as controls from gestational days 12 to 17. Genital tubercles of gestational day 19 fetuses were then examined by further quantitative polymerase chain reaction analysis after identification of the seam area using a dissecting microscope to diagnose hypospadias in males.
Androgen receptor protein was detected in genital tubercles by gestational day 14. Androgen receptor mRNA expression increased gradually in each sex during normal development. However, female genital tubercles expressed a higher level of androgen receptor mRNA throughout development compared to male genital tubercles (p <0.0001). In utero ethinyl estradiol exposure led to a 5.4 and 4.5-fold increase in androgen receptor mRNA in the genital tubercles of female and male embryos (p = 0.004 and 0.001, respectively). Hypospadiac male genital tubercles showed increased androgen receptor mRNA expression compared to control males (p = 0.006). Levels in hypospadiac males did not differ from those in control females but they were less than those in ethinyl estradiol treated females (p >0.05 and 0.01, respectively).
Androgen receptor protein is expressed abundantly in male and female genital tubercles. Androgen receptor mRNA levels are higher in female than in male genital tubercles through development and they increase in response to in utero ethinyl estradiol exposure with ethinyl estradiol treated females having the highest levels of expression, followed by ethinyl estradiol treated hypospadiac males. We infer that higher estrogen in genital tubercles results in a physiological response of increased androgen receptor mRNA expression. We found no direct association between changes in androgen receptor mRNA expression and the presence or absence of hypospadias in males, suggesting that alterations in the expression of proteins other than or in addition to androgen receptor result in anomalous urethral development. This finding supports the idea that the etiology of hypospadias is multifactorial in origin.
研究雄性和雌性小鼠生殖器结节中雄激素受体表达的个体发生，以及子宫内乙炔雌二醇暴露对尿道下裂模型中雄激素受体mRNA表达的影响。
使用免疫组织化学和实时定量聚合酶链反应，测量妊娠第12、14、16和18天收集的胎儿及幼崽以及新生小鼠生殖器结节中的雄激素受体mRNA表达。从妊娠第12天至17天，将怀孕母鼠暴露于乙炔雌二醇或玉米油作为对照。在使用解剖显微镜鉴定缝线区域以诊断雄性尿道下裂后，通过进一步的定量聚合酶链反应分析检查妊娠第19天胎儿的生殖器结节。
在妊娠第14天在生殖器结节中检测到雄激素受体蛋白。在正常发育过程中，雄激素受体mRNA表达在各性别中逐渐增加。然而，与雄性生殖器结节相比，雌性生殖器结节在整个发育过程中表达更高水平的雄激素受体mRNA（p<0.0001）。子宫内乙炔雌二醇暴露导致雌性和雄性胚胎生殖器结节中雄激素受体mRNA分别增加5.4倍和4.5倍（p分别为0.004和0.001）。与对照雄性相比，尿道下裂雄性生殖器结节显示雄激素受体mRNA表达增加（p = 0.006）。尿道下裂雄性的水平与对照雌性无差异，但低于乙炔雌二醇处理的雌性（p分别>0.05和0.01）。
雄激素受体蛋白在雄性和雌性生殖器结节中大量表达。在整个发育过程中，雌性生殖器结节中的雄激素受体mRNA水平高于雄性，并且它们对子宫内乙炔雌二醇暴露有反应而增加，其中乙炔雌二醇处理的雌性表达水平最高，其次是乙炔雌二醇处理的尿道下裂雄性。我们推断生殖器结节中较高的雌激素导致雄激素受体mRNA表达增加的生理反应。我们发现雄激素受体mRNA表达的变化与雄性尿道下裂的存在与否之间没有直接关联，这表明除雄激素受体之外或与之相关的蛋白质表达改变导致尿道发育异常。这一发现支持尿道下裂病因是多因素起源的观点。
