College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.
Department of Cancer Biology, Beckman Research Institute, City of Hope, 91010, CA, USA.
Free Radic Biol Med. 2019 Jun;137:74-86. doi: 10.1016/j.freeradbiomed.2019.04.009. Epub 2019 Apr 12.
Busulfan is a widely used chemotherapeutic drug for chronic myelogenous leukemia and bone marrow transplantation. As a cell cycle nonspecific alkylation agent, busulfan has a severe side effect on germ cells, especially on spermatogonia before meiosis. Studies have revealed that busulfan causes DNA strand crosslinks in spermatogonia and induces apoptosis, and many corresponding strategies have been developed to ameliorate the side effects. However, fertility maintenance after busulfan treatment is still a challenging project in the clinic. Here, we demonstrated that continuous injection of melatonin effectively alleviated germline cytotoxicity both in recipient mice and cultured spermatogonia, and busulfan/melatonin recipient mice produced normal litters. We further revealed that melatonin rescues spermatogonia from apoptosis by neutralizing reactive oxidative species (ROS) induced by busulfan and recovered the phosphorylation of ATM and p53 to normal levels, and as a result apoptosis in spermatogonial progenitor cells was avoided. This study reports that pineal gland hormone melatonin effectively protects spermatogonia from the stress of chemotherapy and oxidation and reveals the underlying molecular mechanisms, which will provide an important hint for fertility protection in clinic.
白消安是一种广泛用于慢性髓性白血病和骨髓移植的化疗药物。作为一种细胞周期非特异性烷化剂，白消安对生殖细胞有严重的副作用，特别是对减数分裂前的精原细胞。研究表明，白消安在精原细胞中引起 DNA 链交联，并诱导细胞凋亡，并且已经开发出许多相应的策略来改善其副作用。然而，白消安治疗后的生育力维持仍然是临床中的一个挑战项目。在这里，我们证明了连续注射褪黑素可有效减轻受者小鼠和培养的精原细胞中的生殖细胞毒性，并且白消安/褪黑素受者小鼠产生了正常的后代。我们进一步揭示了褪黑素通过中和白消安诱导的活性氧 (ROS) 来挽救精原细胞免于凋亡，并恢复 ATM 和 p53 的磷酸化至正常水平，从而避免了精原细胞祖细胞的凋亡。这项研究报告称，松果腺激素褪黑素可有效保护精原细胞免受化疗和氧化应激的影响，并揭示了潜在的分子机制，这将为临床生育力保护提供重要提示。
