Ghrelin Prevents Cisplatin-Induced Testicular Damage by Facilitating Repair of DNA Double Strand Breaks Through Activation of p53 in Mice

被引:28
|
作者
Garcia, Jose M. [1 ,3 ,4 ,5 ]
Chen, Ji-an [1 ,2 ]
Guillory, Bobby [1 ,5 ]
Donehower, Lawrence A. [6 ]
Smith, Roy G. [4 ,5 ,7 ]
Lamb, Dolores J. [3 ,4 ,6 ,8 ]
机构
[1] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, CTRID, Div Endocrinol Diabet & Metab,Dept Med,MCL, Houston, TX 77030 USA
[2] Third Mil Med Univ, Coll Prevent Med, Dept Hlth Educ, Chongqing, Peoples R China
[3] Baylor Coll Med, Ctr Reprod Med, Houston, TX 77030 USA
[4] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA
[5] Baylor Coll Med, Huffington Ctr Aging, Houston, TX 77030 USA
[6] Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA
[7] Scripps Res Inst Florida, Dept Metab & Aging, Jupiter, FL USA
[8] Baylor Coll Med, Scott Dept Urol, Houston, TX 77030 USA
关键词
GHSR; growth hormone secretagogue; infertility; testis; HORMONE SECRETAGOGUE RECEPTOR; GERM-CELL CANCER; RAT TESTIS; C57/BL/6J MICE; MESSENGER-RNA; MOUSE TESTIS; FOOD-INTAKE; CHEMOTHERAPY; EXPRESSION; APOPTOSIS;
D O I
10.1095/biolreprod.115.129759
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
Cisplatin administration induces DNA damage resulting in germ cell apoptosis and subsequent testicular atrophy. Although 50 percent of male cancer patients receiving cisplatin-based chemotherapy develop long-term secondary infertility, medical treatment to prevent spermatogenic failure after chemotherapy is not available. Under normal conditions, testicular p53 promotes cell cycle arrest, which allows time for DNA repair and reshuffling during meiosis. However, its role in the setting of cisplatin-induced infertility has not been studied. Ghrelin administration ameliorates the spermatogenic failure that follows cisplatin administration in mice, but the mechanisms mediating these effects have not been well established. The aim of the current study was to characterize the mechanisms of ghrelin and p53 action in the testis after cisplatin-induced testicular damage. Here we show that cisplatin induces germ cell damage through inhibition of p53-dependent DNA repair mechanisms involving gamma-H2AX and ataxia telangiectasia mutated protein kinase. As a result, testicular weight and sperm count and motility were decreased with an associated increase in sperm DNA damage. Ghrelin administration prevented these sequelae by restoring the normal expression of gamma-H2AX, ataxia telangiectasia mutated, and p53, which in turn allows repair of DNA double stranded breaks. In conclusion, these findings indicate that ghrelin has the potential to prevent or diminish infertility caused by cisplatin and other chemotherapeutic agents by restoring p53-dependent DNA repair mechanisms.
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页数:8
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