Mechanisms of cell senescence and apoptosis in cyclophosphamide-induced premature ovarian failure in rats
Abstract Background Premature ovarian failure (POF) is a clinical condition characterized by a diminished ovarian reserve occurring before the age of 40, significantly affecting female reproductive health. However, its exact pathogenesis remains unclear. This research aimed to examine the mechanisms...
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BMC
2025-07-01
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| Series: | Journal of Ovarian Research |
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| Online Access: | https://doi.org/10.1186/s13048-025-01759-3 |
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| author | Jiaqi Wu Yanmeng Wei Qiangli Peng Jing Zhu Huacong Shi Ting Zhao Tao Yuan |
| author_facet | Jiaqi Wu Yanmeng Wei Qiangli Peng Jing Zhu Huacong Shi Ting Zhao Tao Yuan |
| author_sort | Jiaqi Wu |
| collection | DOAJ |
| description | Abstract Background Premature ovarian failure (POF) is a clinical condition characterized by a diminished ovarian reserve occurring before the age of 40, significantly affecting female reproductive health. However, its exact pathogenesis remains unclear. This research aimed to examine the mechanisms of cyclophosphamide (CTX)-induced senescence and apoptosis in the ovarian and cerebral cortex tissues of rats to provide insights into delaying aging and protecting female reproductive health. Methods A rat model of POF was established by intraperitoneal injection of CTX. Model efficacy was evaluated by measuring ovarian volume, weight, estrogen, and anti-Müllerian hormone levels. Serum marker changes were detected via enzyme-linked immunosorbent assay (ELISA). Senescence and apoptosis in cerebral cortical and ovarian tissues were observed using β-galactosidase (SA-β-gal) staining and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Western Blot and quantitative polymerase chain reaction (RT-qPCR) were employed to detect the expression levels of cell senescence- and apoptosis-related proteins and genes, verifying the correlation between POF and cellular senescence/apoptosis. Results High-dose CTX induced POF. In rats with POF, the levels of anti-Müllerian hormone (AMH), estradiol (E2), and vitamin D (VD) significantly decreased (P < 0.0001), whereas the levels of testosterone (T) and insulin (INS) significantly increased (P < 0.0001). The number of senescent and apoptotic-positive cells in the ovarian and cerebral cortex tissues of rats with POF was substantially augmented (P < 0.05; P < 0.01). Additionally, the expression of senescence-related proteins cyclin-dependent kinase inhibitor 1 A (CDKN1A), cyclin-dependent kinase inhibitor 2 A (CDKN2A), tumor protein p53 (P53), apoptosis-related protein BCL2-Associated X Protein (Bax), and cysteine-aspartic acid protease 3 (caspase 3) was upregulated. In contrast, the expression of the anti-apoptotic protein BCL-2 was downregulated. The changes ranged from 1.7- to 7.1-fold. These findings demonstrated that high-dose CTX injection leads to cellular senescence and apoptosis, resulting in ovarian pathology. Conclusion High-dose CTX induced POF in rats, resulting in aging and apoptosis in the cerebral cortex and ovarian tissues. Therefore, inhibiting cellular senescence and apoptosis may be a potential approach for restoring ovarian reserve function in POF. |
| format | Article |
| id | doaj-art-b5d3ee638fba45a9926eb6b45771ba55 |
| institution | DOAJ |
| issn | 1757-2215 |
| language | English |
| publishDate | 2025-07-01 |
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| series | Journal of Ovarian Research |
| spelling | doaj-art-b5d3ee638fba45a9926eb6b45771ba552025-08-20T03:06:01ZengBMCJournal of Ovarian Research1757-22152025-07-0118111110.1186/s13048-025-01759-3Mechanisms of cell senescence and apoptosis in cyclophosphamide-induced premature ovarian failure in ratsJiaqi Wu0Yanmeng Wei1Qiangli Peng2Jing Zhu3Huacong Shi4Ting Zhao5Tao Yuan6Department of Gynecology, The First People’s Hospital of Yunnan ProvinceDepartment of Gynecology, The First People’s Hospital of Yunnan ProvinceDepartment of Gynecology, Yunnan Provincial Hospital of Traditional Chinese MedicineDepartment of Gynecology, The First People’s Hospital of Yunnan ProvinceDepartment of Gynecology, The First People’s Hospital of Yunnan ProvinceDepartment of Gynecology, The First People’s Hospital of Yunnan ProvinceDepartment of Gynecology, The First People’s Hospital of Yunnan ProvinceAbstract Background Premature ovarian failure (POF) is a clinical condition characterized by a diminished ovarian reserve occurring before the age of 40, significantly affecting female reproductive health. However, its exact pathogenesis remains unclear. This research aimed to examine the mechanisms of cyclophosphamide (CTX)-induced senescence and apoptosis in the ovarian and cerebral cortex tissues of rats to provide insights into delaying aging and protecting female reproductive health. Methods A rat model of POF was established by intraperitoneal injection of CTX. Model efficacy was evaluated by measuring ovarian volume, weight, estrogen, and anti-Müllerian hormone levels. Serum marker changes were detected via enzyme-linked immunosorbent assay (ELISA). Senescence and apoptosis in cerebral cortical and ovarian tissues were observed using β-galactosidase (SA-β-gal) staining and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Western Blot and quantitative polymerase chain reaction (RT-qPCR) were employed to detect the expression levels of cell senescence- and apoptosis-related proteins and genes, verifying the correlation between POF and cellular senescence/apoptosis. Results High-dose CTX induced POF. In rats with POF, the levels of anti-Müllerian hormone (AMH), estradiol (E2), and vitamin D (VD) significantly decreased (P < 0.0001), whereas the levels of testosterone (T) and insulin (INS) significantly increased (P < 0.0001). The number of senescent and apoptotic-positive cells in the ovarian and cerebral cortex tissues of rats with POF was substantially augmented (P < 0.05; P < 0.01). Additionally, the expression of senescence-related proteins cyclin-dependent kinase inhibitor 1 A (CDKN1A), cyclin-dependent kinase inhibitor 2 A (CDKN2A), tumor protein p53 (P53), apoptosis-related protein BCL2-Associated X Protein (Bax), and cysteine-aspartic acid protease 3 (caspase 3) was upregulated. In contrast, the expression of the anti-apoptotic protein BCL-2 was downregulated. The changes ranged from 1.7- to 7.1-fold. These findings demonstrated that high-dose CTX injection leads to cellular senescence and apoptosis, resulting in ovarian pathology. Conclusion High-dose CTX induced POF in rats, resulting in aging and apoptosis in the cerebral cortex and ovarian tissues. Therefore, inhibiting cellular senescence and apoptosis may be a potential approach for restoring ovarian reserve function in POF.https://doi.org/10.1186/s13048-025-01759-3Premature ovarian failureCyclophosphamideApoptosisCellular senescence |
| spellingShingle | Jiaqi Wu Yanmeng Wei Qiangli Peng Jing Zhu Huacong Shi Ting Zhao Tao Yuan Mechanisms of cell senescence and apoptosis in cyclophosphamide-induced premature ovarian failure in rats Journal of Ovarian Research Premature ovarian failure Cyclophosphamide Apoptosis Cellular senescence |
| title | Mechanisms of cell senescence and apoptosis in cyclophosphamide-induced premature ovarian failure in rats |
| title_full | Mechanisms of cell senescence and apoptosis in cyclophosphamide-induced premature ovarian failure in rats |
| title_fullStr | Mechanisms of cell senescence and apoptosis in cyclophosphamide-induced premature ovarian failure in rats |
| title_full_unstemmed | Mechanisms of cell senescence and apoptosis in cyclophosphamide-induced premature ovarian failure in rats |
| title_short | Mechanisms of cell senescence and apoptosis in cyclophosphamide-induced premature ovarian failure in rats |
| title_sort | mechanisms of cell senescence and apoptosis in cyclophosphamide induced premature ovarian failure in rats |
| topic | Premature ovarian failure Cyclophosphamide Apoptosis Cellular senescence |
| url | https://doi.org/10.1186/s13048-025-01759-3 |
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