Doxorubicin Exposure Affects Oocyte Meiotic Maturation through DNA Damage-Induced Meiotic Arrest
Doxorubicin Exposure Affects Oocyte Meiotic Maturation through DNA Damage-Induced Meiotic Arrest
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DOI：
10.1093/toxsci/kfz161
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发表时间：
2019-10-01
影响因子：
3.8
通讯作者：
Huo, Li-Jun
中科院分区：
文献类型：
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作者：
Ding, Zhi-Ming;Zhang, Shou-Xin;Huo, Li-Jun
化疗药物的发展提高了癌症患者的生存率，但化疗药物对卵巢功能的不良影响导致年轻女性癌症患者的生育能力丧失。阿霉素(DOX)是一种蒽环类抗肿瘤抗生素，广泛用于多种恶性肿瘤的治疗。最近的研究表明，DOX可引起卵巢损伤，影响卵母细胞成熟，但DOX对卵母细胞减数分裂的作用机制尚不清楚。在这项研究中，我们探讨了DOX在体外诱导卵母细胞减数分裂失败的机制。结果表明，DOX(100 NM)可直接阻断小鼠卵母细胞的减数分裂成熟，减少第一极体排泄。细胞周期分析显示，大多数卵母细胞停滞于中期I期。然而，DOX处理对纺锤体结构没有影响，但对染色体错位有影响。我们观察到DOX处理后，动粒-微管结构受到影响，纺锤体组装检查点被激发。此外，在DOX处理的卵母细胞中发现了严重的DNA损伤，这表明伽马-H_2A.X焦点信号阳性，这可能会引发卵母细胞的早期凋亡。此外，DOX处理后的中期II卵母细胞纺锤体形态紊乱，染色体排列错位。综上所述，DOX有可能通过激活纺锤体组装检查点介导的DNA损伤诱导的减数分裂停滞来破坏卵母细胞的减数分裂成熟。这些发现有助于设计新的治疗方法，以减轻DNA损伤，以保护接受化疗的年轻女性癌症患者的生育能力。
Developments in chemotherapeutics have enhanced the survival rate of cancer patients, however, adverse effects of chemotherapeutics on ovarian functions causes the fertility loss in young female cancer patients. Doxorubicin (DOX), as an anthracycline antitumor antibiotic, is extensively used to cure various malignancies. Recent studies have suggested that DOX can cause ovarian damage and affect the oocyte maturation, nevertheless the mechanism by which DOX on oocytes meiosis is poorly understood. In this study, we explored the mechanism for DOX-induced oocytes meiotic failure in vitro at human relevant exposure levels and time periods. Results described that DOX (100 nM) can interrupt the mouse oocytes meiotic maturation directly with reduced first polar body extrusion. Cell cycle analysis showed that most oocytes were arrested at metaphase I (MI) stage. However, DOX treatment had no effect on spindle structure but chromosomal misalignment. We observed that kinetochore-microtubule structure was affected and the spindle assemble checkpoint was provoked after DOX treatment. Moreover, severe DNA damage was found in DOX-treated oocytes indicated by the positive gamma-H2A.X foci signal, which then may trigger oocytes early apoptosis. Besides, metaphase II oocytes with disorganized spindle morphologies and misaligned chromosomes were observed after DOX treatment. In conclusion, DOX have the potential to disrupt oocyte meiotic maturation through DNA damage induced meiotic arrest mediated by spindle assemble checkpoint activation. These findings can contribute to design the new therapies to alleviate DNA damage to preserve fertility for young female cancer patients with chemotherapeutics.