Increased DNA damage and repair deficiency in granulosa cells are associated with ovarian aging in rhesus monkey
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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.
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.
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.
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.
KeywordsOvarian aging DNA double-strand break Rhesus monkey BRCA1
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.
- 5.Lei L., Spradling A.C. Female mice lack adult germ-line stem cells but sustain oogenesis using stable primordial follicles. Proc Natl Acad Sci U S A 2013;110:8585–90.Google Scholar
- 11.Soleimani R, Heytens E, Darzynkiewicz Z, Oktay K. Mechanisms of chemotherapy-induced human ovarian aging: double strand DNA breaks and microvascular compromise. Aging (Albany NY). 2011;3:782–93.Google Scholar
- 12.Titus S, Li F, Stobezki R, Akula K, Unsal E, Jeong K, et al. Impairment of BRCA1-related DNA double-strand break repair leads to ovarian aging in mice and humans. Sci Transl Med. 2013;5:172ra121.Google Scholar
- 37.Johnson J, Keefe DL. Ovarian aging: breaking up is hard to fix. Sci Transl Med. 2013;5:172fs175.Google Scholar
- 52.Starborg M, Gell K, Brundell E, Hoog C. The murine Ki-67 cell proliferation antigen accumulates in the nucleolar and heterochromatic regions of interphase cells and at the periphery of the mitotic chromosomes in a process essential for cell cycle progression. J Cell Sci. 1996;109(Pt 1):143–53.PubMedGoogle Scholar
- 54.Scalercio S.R., Brito A.B..., Domingues S.F., Santos R.R., Amorim C.A. Immunolocalization of growth, inhibitory, and proliferative factors involved in initial ovarian folliculogenesis from adult common squirrel monkey (Saimiri collinsi). Reprod Sci 2015;22:68–74.Google Scholar