Open Access

Rapamycin inhibits spermatogenesis by changing the autophagy status through suppressing mechanistic target of rapamycin-p70S6 kinase in male rats

  • Authors:
    • Shangjing Liu
    • Longxian Huang
    • Yanqing Geng
    • Junlin He
    • Xuemei Chen
    • Hao Xu
    • Rong Li
    • Yingxiong Wang
    • Yubin Ding
    • Xueqing Liu
  • View Affiliations

  • Published online on: July 31, 2017     https://doi.org/10.3892/mmr.2017.7120
  • Pages: 4029-4037
  • Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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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October-2017
Volume 16 Issue 4

Print ISSN: 1791-2997
Online ISSN:1791-3004

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Copy and paste a formatted citation
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Spandidos Publications style
Liu S, Huang L, Geng Y, He J, Chen X, Xu H, Li R, Wang Y, Ding Y, Liu X, Liu X, et al: Rapamycin inhibits spermatogenesis by changing the autophagy status through suppressing mechanistic target of rapamycin-p70S6 kinase in male rats. Mol Med Rep 16: 4029-4037, 2017
APA
Liu, S., Huang, L., Geng, Y., He, J., Chen, X., Xu, H. ... Liu, X. (2017). Rapamycin inhibits spermatogenesis by changing the autophagy status through suppressing mechanistic target of rapamycin-p70S6 kinase in male rats. Molecular Medicine Reports, 16, 4029-4037. https://doi.org/10.3892/mmr.2017.7120
MLA
Liu, S., Huang, L., Geng, Y., He, J., Chen, X., Xu, H., Li, R., Wang, Y., Ding, Y., Liu, X."Rapamycin inhibits spermatogenesis by changing the autophagy status through suppressing mechanistic target of rapamycin-p70S6 kinase in male rats". Molecular Medicine Reports 16.4 (2017): 4029-4037.
Chicago
Liu, S., Huang, L., Geng, Y., He, J., Chen, X., Xu, H., Li, R., Wang, Y., Ding, Y., Liu, X."Rapamycin inhibits spermatogenesis by changing the autophagy status through suppressing mechanistic target of rapamycin-p70S6 kinase in male rats". Molecular Medicine Reports 16, no. 4 (2017): 4029-4037. https://doi.org/10.3892/mmr.2017.7120