Rapamycin inhibits spermatogenesis by changing the autophagy status through suppressing mechanistic target of rapamycin-p70S6 kinase in male rats.
Rapamycin inhibits spermatogenesis by changing the autophagy status through suppressing mechanistic target of rapamycin-p70S6 kinase in male rats.
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雷帕霉素通过抑制雄性大鼠雷帕霉素-p70S6激酶的机制靶点改变自噬状态来抑制精子发生
DOI：
10.3892/mmr.2017.7120
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发表时间：
2017-10
影响因子：
3.4
通讯作者：
Liu X
中科院分区：
文献类型：
--
作者：
Liu S;Huang L;Geng Y;He J;Chen X;Xu H;Li R;Wang Y;Ding Y;Liu X
雷帕霉素（西罗莫司）是一种抗增殖药物，作为免疫抑制剂和潜在的抗癌药物已广泛应用于临床。某些报告表明雷帕霉素可能通过损害精子质量而导致男性不育。本研究探讨了雷帕霉素引起男性不育的机制，并研究了停药雷帕霉素是否可以恢复大鼠精子数量。雄性Sprague-Dawley大鼠（n=100）随机分为5组：3个雷帕霉素处理组（2、4和6 mg/kg）和2个对照组[空白和二甲基亚砜（DMSO）]。睾丸器官系数、精子数量和苏木精-伊红染色分析表明，雷帕霉素治疗显着破坏了生精小管的结构并减少了精子数量。睾丸组织中雷帕霉素机械靶标 (mTOR) 和 Ki67 的免疫组织化学，以及磷酸化 p70S6K 和 p70S6K 的蛋白质印迹，支持了雷帕霉素通过抑制精原细胞增殖导致精子减少的假设。不幸的是，停止雷帕霉素治疗24周后，只有2 mg/kg组的精子数量恢复到正常水平。此外，据我们所知，本研究首次证明低剂量雷帕霉素会激活大鼠睾丸中的自噬。这可能是细胞应对外界压力的一种自我保护机制。因此，低剂量组大鼠的睾丸中可以恢复精子发生。高剂量雷帕霉素导致自噬蛋白过度消耗，且损伤无法补偿。此外，还发现用雷帕霉素处理后细胞凋亡增加。总之，本研究表明雷帕霉素通过抑制p70S6K磷酸化并改变自噬状态来抑制精子发生，最终减少精子数量。这些研究结果为雷帕霉素的临床应用提供了重要指导。
Rapamycin (sirolimus) is an antiproliferative drug that has been widely used in the clinic as an immunosuppressant and a potential anticancer agent. Certain reports have indicated that rapamycin may induce male infertility through impairing sperm quality. The present study investigated the mechanism of male infertility caused by rapamycin and examined whether withdrawal of rapamycin could recover the number of sperm in rats. Male Sprague-Dawley rats (n=100) were divided randomly into 5 groups: 3 rapamycin-treated groups (2, 4 and 6 mg/kg) and 2 control groups [Blank and dimethyl sulfoxide (DMSO)]. Organ coefficients of the testes, number of sperm and hematoxylin-eosin staining analyses demonstrated that rapamycin treatment markedly damaged the structure of the seminiferous tubule and reduced the number of sperm. Immunohistochemistry of mechanistic target of rapamycin (mTOR) and Ki67 in testes tissue, and western blotting of phosphorylated-p70S6K and p70S6K, supported the hypothesis that rapamycin causes sperm reduction through inhibiting proliferation of spermatogonia. Unfortunately, 24 weeks after cessation of rapamycin treatment, only the number of sperm in 2 mg/kg group was restored back to the normal level. In addition, to the best of our knowledge, the present study was the first to demonstrate that low doses rapamycin leads to activation of autophagy in rat testes. This may be a self-protective mechanism of the cell in response to external stress. Thus, spermatogenesis can be recovered in the testes from rats in the low dose group. High doses of rapamycin resulted in excessive consumption of autophagy proteins, and the damage could not be compensated. In addition, it was revealed that cell apoptosis increased after treatment with rapamycin. In conclusion, the present study demonstrated that rapamycin inhibits spermatogenesis through suppressing phosphorylation of p70S6K and changing the autophagy status, ultimately reducing the number of sperm. These findings provide important guidance for the clinical application of rapamycin.
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影响因子：
4.8
作者：
Petiot, A;Ogier-Denis, E;Codogno, P
通讯作者：
Codogno, P
影响因子：
2
作者：
Boobes, Yousef;Bernieh, Bassam;Abouchacra, Samra
通讯作者：
Abouchacra, Samra
DOI：
10.1053/beem.2000.0093
发表时间：
2000-09-01
影响因子：
7.4
作者：
Sharpe, RM
通讯作者：
Sharpe, RM
影响因子：
5.3
作者：
Fingar, DC;Richardson, CJ;Blenis, J
通讯作者：
Blenis, J
影响因子：
6.1
作者：
Liu, GuangYi;Han, Fei;Chen, JiangHua
通讯作者：
Chen, JiangHua