Zhou Hongjian, Xu Zhipeng, Jiang Chun, Wu Qiuyue, Zhang Chuanyue, Liu Zhenyu, Zhang Xiaoxue, Li Weiwei, Pang Yujia, Zhang Jing, Pan Wenju, Chen Min, Xia Xinyi
Institute of Laboratory Medicine, Jinling Hospital, First School of Clinical Medicine, Nanjing University School of Medicine, Southern Medical University, Zhongshan East Road 305, Nanjing, Jiangsu, 210002, China.
Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, 210008, China.
Cell Commun Signal. 2025 Jan 31;23(1):58. doi: 10.1186/s12964-025-02067-5.
Ionizing radiation (IR) poses a significant threat to male fertility by inducing substantial changes in the testis, yet the mechanisms underlying IR-induced spermatogenesis disorders remain poorly understood, necessitating the development of more effective radioprotective agents.
We employed Bulk RNA-seq and single-cell RNA-seq (scRNA-seq) on Balb/c mice testes models following IR exposure to assess cellular and transcriptional alterations. Histological examination, sperm concentration and motility analysis, Western blotting (WB), and reverse transcription quantitative PCR (RT-qPCR) were used to evaluate testicular injury. The therapeutic potential of NF-κB agonists was investigated in an IR-induced spermatogenesis disorder model.
A 6 Gy IR dose induced spermatogenesis disorder and suppressed the spliceosome pathway, predominantly affecting the cell abundance of spermatogonia and primary spermatocytes. Bioinformatics analysis revealed that IR induced splicing disorders in differentiation-related genes, thereby impairing the differentiation ability of primary spermatocytes. Mechanistically, This IR-induced disruption was linked to IR-induced inhibition of NF-κB/Rela and Bclaf1 activity. Notably, NF-κB agonists were found to ameliorate this damage via upregulating Bclaf1 and spliceosome-related genes expression, thereby normalizing splicing patterns and rescuing IR-induced spermatogenesis disorders.
This study reveals a novel IR-mediated Rela-Bclaf1-spliceosome regulatory axis in primary spermatocytes and propose Rela as a potential drug target for mitigating IR-induced spermatogenesis disorders. This study not only provides new insights for further research into IR-induced damage and spermatogenic disorders caused by other factors, but also offers potential therapeutic strategies for developing radioprotective agents in cancer radiotherapy.
电离辐射（IR）通过在睾丸中引起实质性变化，对男性生育能力构成重大威胁，然而，IR诱导精子发生障碍的潜在机制仍知之甚少，因此需要开发更有效的辐射防护剂。
我们对受IR照射的Balb/c小鼠睾丸模型进行了批量RNA测序和单细胞RNA测序（scRNA-seq），以评估细胞和转录变化。采用组织学检查、精子浓度和活力分析、蛋白质免疫印迹（WB）和逆转录定量PCR（RT-qPCR）来评估睾丸损伤。在IR诱导的精子发生障碍模型中研究了NF-κB激动剂的治疗潜力。
6 Gy的IR剂量诱导了精子发生障碍，并抑制了剪接体途径，主要影响精原细胞和初级精母细胞的细胞丰度。生物信息学分析表明，IR诱导了分化相关基因的剪接紊乱，从而损害了初级精母细胞的分化能力。从机制上讲，这种IR诱导的破坏与IR诱导的NF-κB/Rela和Bclaf1活性抑制有关。值得注意的是，发现NF-κB激动剂通过上调Bclaf1和剪接体相关基因的表达来改善这种损伤，从而使剪接模式正常化并挽救IR诱导的精子发生障碍。
本研究揭示了初级精母细胞中一种新的IR介导的Rela-Bclaf1-剪接体调控轴，并提出Rela作为减轻IR诱导的精子发生障碍的潜在药物靶点。本研究不仅为进一步研究IR诱导的损伤和其他因素引起的生精障碍提供了新的见解，也为癌症放疗中开发辐射防护剂提供了潜在的治疗策略。
