Persistent DNA Damage in Spermatogonial Stem Cells After Fractionated Low-Dose Irradiation of Testicular Tissue
Persistent DNA Damage in Spermatogonial Stem Cells After Fractionated Low-Dose Irradiation of Testicular Tissue
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DOI：
10.1016/j.ijrobp.2015.04.033
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发表时间：
2015-08-01
影响因子：
7
通讯作者：
Ruebe, Claudia E.
中科院分区：
文献类型：
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作者：
Grewenig, Angelika;Schuler, Nadine;Ruebe, Claudia E.
目的：睾丸精子发生对辐射引起的损伤极为敏感，即使放射治疗对睾丸的低散射剂量也可能造成生殖风险，可能导致与治疗相关的不孕症。辐射诱导的DNA双链断裂（DSBs）是对精子干细胞（ssc）基因组完整性的最大威胁，而ssc对于维持精子发生和防止生殖失败至关重要。方法和材料：在每日100 mGy或10 mGy低剂量辐射下，通过定量测定干细胞生态位内ssc中的53结合蛋白1 （53BP-1）灶，监测小鼠睾丸中辐射诱导的DSBs。DSBs的积累与睾丸生殖细胞群体的增殖、分化和凋亡有关。结果：即使是极低剂量的电离辐射也会通过诱导精原细胞凋亡来阻止精子的发生。精子发生的最终恢复取决于ssc的存活及其增殖和分化的功能能力，以提供足够数量的分化精原细胞。重要的是，在分次低剂量辐射期间，甚至在低剂量辐射后几个月，抗凋亡的SSCs导致53BP-1病灶水平升高，这表明存活的SSCs积累了更多的DNA损伤负荷。结论：ssc在辐射后数周内显示dsb水平升高，如果这些dsb通过分化到精子持续存在，这可能对受精精子的基因组完整性造成严重后果。(C) 2015爱思唯尔公司版权所有。
Purpose: Testicular spermatogenesis is extremely sensitive to radiation-induced damage, and even low scattered doses to testis from radiation therapy may pose reproductive risks with potential treatment-related infertility. Radiation-induced DNA double-strand breaks (DSBs) represent the greatest threat to the genomic integrity of spermatogonial stem cells (SSCs), which are essential to maintain spermatogenesis and prevent reproduction failure.Methods and Materials: During daily low-dose radiation with 100 mGy or 10 mGy, radiation-induced DSBs were monitored in mouse testis by quantifying 53 binding protein 1 (53BP-1) foci in SSCs within their stem cell niche. The accumulation of DSBs was correlated with proliferation, differentiation, and apoptosis of testicular germ cell populations.Results: Even very low doses of ionizing radiation arrested spermatogenesis, primarily by inducing apoptosis in spermatogonia. Eventual recovery of spermatogenesis depended on the survival of SSCs and their functional ability to proliferate and differentiate to provide adequate numbers of differentiating spermatogonia. Importantly, apoptosis-resistant SSCs resulted in increased 53BP-1 foci levels during, and even several months after, fractionated low-dose radiation, suggesting that surviving SSCs have accumulated an increased load of DNA damage.Conclusions: SSCs revealed elevated levels of DSBs for weeks after radiation, and if these DSBs persist through differentiation to spermatozoa, this may have severe consequences for the genomic integrity of the fertilizing sperm. (C) 2015 Elsevier Inc. All rights reserved.