Abstract

Sirolimus, also known as rapamycin, and its closely related rapamycin analog (rapalog) Everolimus inhibit “mammalian target of rapamycin complex 1” (mTORC1), whose activity is required for spermatogenesis. Everolimus is Food and Drug Administration approved for treating human patients to slow growth of aggressive cancers and preventing organ transplant rejection. Here, we test the hypothesis that rapalog inhibition of mTORC1 activity has a negative, but reversible, impact upon spermatogenesis. Juvenile (P20) or adult (P>60) mice received daily injections of sirolimus or Everolimus for 30 days, and tissues were examined at completion of treatment or following a recovery period. Rapalog treatments reduced body and testis weights, testis weight/body weight ratios, cauda epididymal sperm counts, and seminal vesicle weights in animals of both ages. Following rapalog treatment, numbers of differentiating spermatogonia were reduced, with concomitant increases in the ratio of undifferentiated spermatogonia to total number of remaining germ cells. To determine if even low doses of Everolimus can inhibit spermatogenesis, an additional group of adult mice received a dose of Everolimus ∼6-fold lower than a human clinical dose used to treat cancer. In these animals, only testis weights, testis weight/body weight ratios, and tubule diameters were reduced. Return to control values following a recovery period was variable for each of the measured parameters and was duration and dose dependent. Together, these data indicate rapalogs exerted a dose-dependent restriction on overall growth of juvenile and adult mice and negative impact upon spermatogenesis that were largely reversed; following treatment cessation, males from all treatment groups were able to sire offspring.

中文翻译：

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雷帕霉素类似物依维莫司可逆地损害小鼠雄性生殖细胞的分化和生育能力1。

摘要

西罗莫司，也称为雷帕霉素，及其密切相关的雷帕霉素类似物 (rapalog) 依维莫司抑制“雷帕霉素复合物 1 的哺乳动物靶标”(mTORC1)，其活性是精子发生所必需的。依维莫司被食品和药物管理局批准用于治疗人类患者，以减缓侵袭性癌症的生长并防止器官移植排斥。在这里，我们测试了 rapalog 对 mTORC1 活性的抑制对精子发生具有负面但可逆的影响的假设。幼年 (P20) 或成年 (P>60) 小鼠每天注射西罗莫司或依维莫司，持续 30 天，并在治疗完成或恢复期后检查组织。Rapalog 治疗降低了两个年龄段动物的体重和睾丸重量、睾丸重量/体重比、附睾尾精子计数和精囊重量。rapalog 治疗后，分化的精原细胞数量减少，同时未分化的精原细胞与剩余生殖细胞总数的比例增加。为了确定即使是低剂量的依维莫司也能抑制精子发生，另外一组成年小鼠接受了比用于治疗癌症的人类临床剂量低约 6 倍的依维莫司剂量。在这些动物中，只有睾丸重量、睾丸重量/体重比和肾小管直径减少。恢复期后的对照值对于每个测量参数是可变的，并且是持续时间和剂量依赖性的。总之，这些数据表明 rapalogs 对幼鼠和成年小鼠的整体生长施加了剂量依赖性限制，并对精子发生的负面影响在很大程度上被逆转；