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Journal of Assisted Reproduction and Genetics

, Volume 32, Issue 7, pp 1069–1078 | Cite as

Increased DNA damage and repair deficiency in granulosa cells are associated with ovarian aging in rhesus monkey

  • Dongdong Zhang
  • Xiaoqian Zhang
  • Ming Zeng
  • Jihong Yuan
  • Mengyuan Liu
  • Yu Yin
  • Xueqing Wu
  • David L. Keefe
  • Lin Liu
Reproductive Physiology and Disease

Abstract

Purpose

Ovarian aging is closely tied to the decline in ovarian follicular reserve and oocyte quality. During the prolonged reproductive lifespan of the female, granulosa cells connected with oocytes play critical roles in maintaining follicle reservoir, oocyte growth and follicular development. We tested whether double-strand breaks (DSBs) and repair in granulosa cells within the follicular reservoir are associated with ovarian aging.

Methods

Ovaries were sectioned and processed for epi-fluorescence microscopy, confocal microscopy, and immunohistochemistry. DNA damage was revealed by immunstaining of γH2AX foci and telomere damage by γH2AX foci co-localized with telomere associated protein TRF2. DNA repair was indicated by BRCA1 immunofluorescence.

Results

DSBs in granulosa cells increase and DSB repair ability, characterized by BRCA1 foci, decreases with advancing age. γH2AX foci increase in primordial, primary and secondary follicles with advancing age. Likewise, telomere damage increases with advancing age. In contrast, BRCA1 foci in granulosa cells of primordial, primary and secondary follicles decrease with monkey age. BRCA1 positive foci in the oocyte nuclei also decline with maternal age.

Conclusions

Increased DSBs and reduced DNA repair in granulosa cells may contribute to ovarian aging. Discovery of therapeutics that targets these pathways might help maintain follicle reserve and postpone ovarian dysfunction with age.

Keywords

Ovarian aging DNA double-strand break Rhesus monkey BRCA1 

Notes

Acknowledgments

This work was supported by MOST of China National Basic Research Program (2010CB94500), National Natural Science Foundation of China (31430052), and PCSIRT (No. IRT13023). The authors have no competing interests to declare.

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

10815_2015_483_MOESM1_ESM.docx (2.8 mb)
ESM 1 (DOCX 2818 kb)

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Dongdong Zhang
    • 1
    • 2
  • Xiaoqian Zhang
    • 1
  • Ming Zeng
    • 1
  • Jihong Yuan
    • 1
  • Mengyuan Liu
    • 1
  • Yu Yin
    • 1
  • Xueqing Wu
    • 2
  • David L. Keefe
    • 3
  • Lin Liu
    • 1
  1. 1.State Key Laboratory of Medicinal Chemical Biology; Collaborative Innovation Center for Biotherapy, College of Life SciencesNankai UniversityTianjinChina
  2. 2.Reproductive Medicine CenterMaternity and Child Health Care Hospital and Children’s Hospital of Shanxi ProvinceTaiyuanChina
  3. 3.Department of Obstetrics and GynecologyNew York University Langone Medical CenterNew YorkUSA

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