Two new male contraceptives exert their effects by depleting germ cells prematurely from the testis
Two new male contraceptives exert their effects by depleting germ cells prematurely from the testis
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DOI：
10.1095/biolreprod65.2.449
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发表时间：
2001-08-01
影响因子：
3.6
通讯作者：
Mruk, D
中科院分区：
文献类型：
--
作者：
Cheng, CY;Silvestrini, B;Mruk, D
目前可用的三种男性避孕方法是：1)避孕套等屏障方法；2)扰乱垂体-睾丸轴以影响精子发生的激素法；3)制备针对男性特异性抗原的疫苗的免疫学方法。我们在此描述了另一种方法，在这种方法中，发育中的生殖细胞附着到生精上皮被破坏，从而导致它们过早地释放到管腔中。这反过来又会导致不孕。合成了一系列以1-(2，4-二氯苯基)-吲唑-3-羧酸为核心结构的类似物。对这些化合物进行体内筛选，评估它们诱导睾丸表达的效果，睾丸是一种睾丸标记，其表达与支持-生殖细胞连接的完整性相关。睾丸中睾丸表达的诱导意味着支持-生殖细胞连接的中断，随后生精上皮中的生殖细胞被耗尽。组织学分析证实，两个化合物1-(2，4-dichlorobenzyl)-indazole-3-carbohydrazide(AF-2364)和1-(2，4-二氯苯基)-吲唑-3-丙烯酸(AF-2785)可引起生殖细胞，特别是圆形和细长精子细胞从上皮细胞上脱落，导致其提前释放到管腔内。在附睾精子储备耗尽后的3-7周内，接受几种口服其中一种化合物的成年大鼠成为不育大鼠。根据给药化合物的剂量，大鼠在4-14周内变得不育，然后生育力逐渐回升，这说明了这些新化合物的可逆性和有效性。此外，这些化合物似乎没有损害下丘脑-垂体-睾丸轴，因为与对照组相比，处理组动物的血清促黄体生成素、卵泡刺激素和睾酮水平没有显著变化。此外，血清微量化学结果表明，这两种化合物对动物的肝肾功能没有影响。
The three currently available male contraceptive approaches are 1) the barrier method such as the condom, 2) hormonal methods by disrupting the pituitary-testicular axis so as to impair spermatogenesis, and 3) immunological methods by preparing vaccines against male-specific antigens. We hereby describe an alternative approach in which attachments of developing germ cells onto the seminiferous epithelium are disrupted, thereby inducing their premature release into the tubular lumen. This in turn leads to infertility. A panel of analogues based on the core structure of 1-(2,4-dichlorobenzyl)-indazole-3-carboxylic acid was synthesized. These compounds were subjected to an in vivo screening assay assessing their effects in inducing the expression of testin, a testicular marker whose expression correlates with the integrity of Sertoli-germ cell junctions. An induction of testin expression in the testis signifies a disruption of Sertoli-germ cell junctions that is followed by depletion of germ cells from the seminiferous epithelium. Two compounds, namely 1-(2,4-dichlorobenzyl)-indazole-3-carbohydrazide (AF-2364) and 1-(2,4-dichlorobenzyl)-indazole-3-acrylic acid (AF-2785), were identified that caused detachment of germ cells, in particular round and elongated spermatids, from the epithelium inducing their premature release into the tubular lumen as confirmed by histological analysis. Adult rats receiving several oral doses of either one of these compounds became infertile within 3-7 wk after the epididymal sperm reserve was exhausted. Depending on the dosing of the administered compound, rats became infertile for 4-14 wk before their fertility gradually bounced back, illustrating the reversibility and efficacy of these new compounds. Also, these compounds did not appear to impair the hypothalamus-pituitary-testicular axis because the serum levels of LH, FSH, and testosterone of the treated animals did not change significantly when compared to control rats. in addition, results of serum microchemistry illustrate that liver and kidney function was not affected in animals treated with both compounds.