Ghrelin Prevents Cisplatin-Induced Testicular Damage by Facilitating Repair of DNA Double Strand Breaks Through Activation of p53 in Mice
Ghrelin Prevents Cisplatin-Induced Testicular Damage by Facilitating Repair of DNA Double Strand Breaks Through Activation of p53 in Mice
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DOI：
10.1095/biolreprod.115.129759
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发表时间：
2015-07-01
影响因子：
3.6
通讯作者：
Lamb, Dolores J.
中科院分区：
文献类型：
--
作者：
Garcia, Jose M.;Chen, Ji-an;Lamb, Dolores J.
顺铂给药会诱导 DNA 损伤，导致生殖细胞凋亡和随后的睾丸萎缩。尽管接受顺铂化疗的男性癌症患者中有 50% 会出现长期继发性不育，但目前还没有预防化疗后生精失败的药物治疗。在正常情况下，睾丸 p53 促进细胞周期停滞，从而为减数分裂期间的 DNA 修复和重新洗牌提供时间。然而，其在顺铂引起的不孕症中的作用尚未研究。施用生长素释放肽可改善小鼠顺铂施用后的生精障碍，但介导这些作用的机制尚未明确。本研究的目的是确定顺铂引起的睾丸损伤后 ghrelin 和 p53 在睾丸中的作用机制。在这里，我们发现顺铂通过抑制涉及γ-H2AX和共济失调毛细血管扩张突变蛋白激酶的p53依赖性DNA修复机制来诱导生殖细胞损伤。结果，睾丸重量、精子数量和活力下降，精子 DNA 损伤也随之增加。 Ghrelin 给药通过恢复 γ-H2AX、共济失调性毛细血管扩张突变和 p53 的正常表达来预防这些后遗症，从而修复 DNA 双链断裂。总之，这些发现表明，ghrelin 有潜力通过恢复 p53 依赖性 DNA 修复机制来预防或减少顺铂和其他化疗药物引起的不孕症。
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.