Abstract：
Cranial radiotherapy is a major treatment for leukemia and brain tumors. Our previous study found abscopal effects of cranial irradiation could cause spermatogenesis disorder in mice. However, the exact mechanisms are not yet fully understood. In the study, adult male C57BL/6 mice were administrated with 20 Gy X-ray cranial irradiation (5 Gy per day for 4 days consecutively) and sacrificed at 1, 2 and 4 weeks. Tandem Mass Tag (TMT) quantitative proteomics of testis was combined with bioinformatics analysis to identify key molecules and signal pathways related to spermatogenesis at 4 weeks after cranial irradiation. GO analysis showed that spermatogenesis was closely related to oxidative stress and inflammation. Severe oxidative stress occurred in testis, serum and brain, while serious inflammation also occurred in testis and serum. Additionally, the sex hormones related to hypothalamic-pituitary-gonadal (HPG) axis were disrupted. PI3K/Akt pathway was activated in testis, which upstream molecule SCF/C-Kit was significantly elevated. Furthermore, the proliferation and differentiation ability of spermatogonial stem cells (SSCs) were altered. These findings suggest that cranial irradiation can cause spermatogenesis disorder through brain-blood-testicular cascade oxidative stress, inflammation and the secretory dysfunction of HPG axis, and SCF/C-kit drive this process through activating PI3K/Akt pathway.
摘要：
头颅放疗是白血病和脑肿瘤的主要治疗方法。我们先前的研究发现，颅骨照射的远视效应可能导致小鼠精子发生障碍。然而,确切的机制尚未完全了解。在研究中,成年雄性C57BL/6小鼠接受20GyX射线颅骨照射（每天5Gy，连续4天），并在第1、2和4周处死。在头颅照射后4周，将睾丸串联质量标签（TMT）定量蛋白质组学与生物信息学分析相结合，以鉴定与精子发生相关的关键分子和信号通路。GO分析表明，精子发生与氧化应激和炎症密切相关。严重的氧化应激发生在睾丸，血清和大脑，而严重的炎症也发生在睾丸和血清中。此外,与下丘脑-垂体-性腺（HPG）轴相关的性激素被破坏。PI3K/Akt通路在睾丸中被激活，上游分子SCF/C-Kit显著升高。此外，精原干细胞（SSC）的增殖和分化能力发生改变。这些发现表明，颅骨照射可通过脑-血-睾丸级联氧化应激引起精子发生障碍，炎症和HPG轴的分泌功能障碍，SCF/C-kit通过激活PI3K/Akt途径驱动这一过程。
