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Identification of Common and Specific Genes Involved in Mouse Models of Age-Related and Cyclophosphamide-Induced Diminished Ovarian Reserve

  • Reproductive Endocrinology: Original Article
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Abstract

Diminished ovarian reserve (DOR) is an etiologically heterogeneous disorder that usually leads to poor reproductive outcomes. Does a specific or common pathogenesis exist for DOR subtypes with different etiologies? Two frequently used mouse models, age-related DOR (AR-DOR) and cyclophosphamide (CTX)-induced DOR (CTX-DOR), were successfully established, and RNA sequencing was performed on ovarian tissue samples. Differentially expressed genes (DEGs) in each subtype and common DEGs (co-DEGs) in the two subtypes were identified. Subsequently, we performed comprehensive bioinformatics analyses, including an evaluation of immune cell infiltration. Finally, the genes of interest were further validated by performing RT-qPCR and immunohistochemistry. In AR-DOR mice, functional enrichment analyses showed that upregulated DEGs were mainly involved in the inflammatory/immune response, while downregulated DEGs were involved in DNA damage repair. In CTX-DOR mice, the inflammatory/immune response and cell apoptosis played significant roles. Meanwhile, 406 co-DEGs were identified from the two models. The biological functions of these co-DEGs were associated with inflammatory/immune responses. The analysis of immune cell infiltration showed reduced infiltration of Treg cells, as well as increased infiltration of M0 macrophages, NK resting, and T cells CD4 follicular in both DOR subtypes. The results of the validation experiments were consistent with the RNA sequencing data. In conclusion, the inflammatory/immune response might be the common pathogenesis for the two DOR subtypes, while DNA repair and cell apoptosis may have different roles in the two subtypes. These results may provide potential insights for mechanistic research and therapeutic targets of DOR.

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Funding

This work was supported by the National Natural Science Foundation of China (No. 81960278), the Outstanding Youth Funds of Science and Technology Department of Gansu Province (No. 20JR5RA371), the Key Research and Development Program of Gansu Province (No. 20YF3FA031), and Longyuan Youth Innovation and Entrepreneurship Talent Project.

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Authors and Affiliations

  1. The First Clinical Medical College of Lanzhou University, Lanzhou, China

    Ruifen He, Qigang Fan, Yi Li, Qinying Zhu, Dan Hu, Junhong Du & Yijuan **ng

  2. Department of Obstetrics and Gynecology, Key Laboratory for Gynecologic Oncology Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China

    Hongli Li, **aolei Liang & Yongxiu Yang

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  1. Ruifen He
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  2. Qigang Fan
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  3. Yi Li
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  7. Yijuan **ng
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Contributions

Ruifen He, **aolei Liang, and Yongxiu Yang contributed to the central idea and design of work; Qigang Fan, Yi Li, and Qinying Zhu, acquisition of sample and sample processing; Ruifen He, Dan Hu, Junhong Du, and Yijuan **ng, analysis and interpretation of data; Hongli Li, **aolei Liang, and Yongxiu Yang, critical feedback of the manuscript. The original draft was written by Ruifen He.

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Correspondence to **aolei Liang or Yongxiu Yang.

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This study makes the use of male C57BL/6 mice, and all the experimental protocol for the use of animal was approved by the Ethics Committee of the First Hospital of Lanzhou University (LDYYLL2019-44).

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He, R., Fan, Q., Li, Y. et al. Identification of Common and Specific Genes Involved in Mouse Models of Age-Related and Cyclophosphamide-Induced Diminished Ovarian Reserve. Reprod. Sci. 30, 1965–1978 (2023). https://doi.org/10.1007/s43032-022-01161-0

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