Anderson C A, Clark R L
Department of Safety Assessment, Merck Sharp and Dohme Research Laboratories, West Point, Pennsylvania 19486.
Teratology. 1990 Nov;42(5):483-96. doi: 10.1002/tera.1420420505.
The normal histogenesis of the rat genital tubercle and the effect of exposure in utero to the 5 alpha-reductase inhibitor finasteride (L-652,931; MK-0906; Proscar) on that process were studied. In normal males and females, the genital tubercle was first seen on Day 14.25 of gestation. It contained a urethral plate which extended from the cloaca (and after Day 15.25, from the urogenital sinus) to the tip of the tubercle. On Day 18.25 the glans lamellae, which would separate the glans penis or the clitoris from the prepuce, began to develop in both sexes. Also on Day 18.25 a dense, midline plate of mesenchymal cells was first evident between the urogenital sinus and the rectum in normal males. This plate acted as a wedge, first increasing the separation between the rectum and the urogenital sinus, and subsequently separating the urethral plate from the surface epithelium in the genital tubercle. As a result, by Day 21.25 the urethra in males followed an "S"-shaped course, extending from the pelvis through the center of the glans penis to an orifice near the tip of the genital tubercle. In females, in which a mesenchymal plate did not develop, the urethral orifice remained at the base of the tubercle, and the clitoris contained the remnants of the urethral plate, extending as an open groove from the urethral orifice to the tip of the tubercle. Finasteride did not affect development of the genital tubercle in females. However, in males exposed to finasteride in utero, there was variable failure of the mesenchymal wedge to develop. As a result, the urethral plate remained in contact with the surface epithelium and eventually opened to form a groove on the ventral surface of the glans penis (hypospadias). Also, the persistence of the urethral plate along the ventral midline in finasteride-treated male fetuses and its subsequent opening as a groove interfered with development of the glans lamellae, causing displacement of the frenulum distally on the glans penis and the development of a cleft in the prepuce.
研究了大鼠生殖结节的正常组织发生过程，以及子宫内暴露于5α-还原酶抑制剂非那雄胺（L-652,931；MK-0906；保列治）对该过程的影响。在正常雄性和雌性大鼠中，妊娠第14.25天首次可见生殖结节。它包含一个尿道板，该尿道板从泄殖腔（妊娠第15.25天后，从泌尿生殖窦）延伸至结节顶端。在第18.25天，两性均开始发育将阴茎头或阴蒂与包皮分开的龟头板层。同样在第18.25天，正常雄性大鼠的泌尿生殖窦与直肠之间首次出现一层致密的中线间充质细胞板。该板起到楔子的作用，首先增加直肠与泌尿生殖窦之间的距离，随后将尿道板与生殖结节表面上皮分离。结果，到第21.25天，雄性大鼠的尿道呈“S”形，从骨盆延伸穿过阴茎头中心至生殖结节顶端附近的开口处。在雌性大鼠中，由于未发育间充质板，尿道口仍位于结节基部，阴蒂包含尿道板的残余部分，从尿道口延伸为一条开放的沟至结节顶端。非那雄胺不影响雌性生殖结节的发育。然而，在子宫内暴露于非那雄胺的雄性大鼠中，间充质楔发育出现不同程度的失败。结果，尿道板仍与表面上皮接触，最终开口形成阴茎头腹侧表面的一条沟（尿道下裂）。此外，在非那雄胺处理的雄性胎儿中，尿道板沿腹中线持续存在并随后开口形成一条沟，干扰了龟头板层的发育，导致阴茎头系带向远端移位以及包皮出现裂隙。
