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DNA repair in primordial follicle oocytes following cisplatin treatment

  • Reproductive Physiology and Disease
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

Genotoxic chemotherapy and radiotherapy can cause DNA double stranded breaks (DSBs) in primordial follicle (PMF) oocytes, which then undergo apoptosis. The development of effective new fertility preservation agents has been hampered, in part, by a limited understanding of DNA repair in PMF oocytes. This study investigated the induction of classical DSB repair pathways in the follicles of wild type (WT) and apoptosis-deficient Puma-/- mice in response to DSBs caused by the chemotherapy agent cisplatin.

Methods

Adult C57BL/6 WT and Puma-/- mice were injected i.p. with saline or cisplatin (5 mg/kg); ovaries were harvested at 8 or 24 h. Follicles were counted, and H2A histone family member (γH2AX) immunofluorescence used to demonstrate DSBs. DNA repair protein RAD51 homolog 1 (RAD51) and DNA-dependent protein kinase, catalytic subunit (DNA-PKcs) immunofluorescence were used to identify DNA repair pathways utilised.

Results

Puma-/- mice retained 100% of follicles 24 h after cisplatin treatment. Eight hours post-treatment, γH2AX immunofluorescence showed DSBs across follicular stages in Puma-/- mice; staining returned to control levels in PMFs within 5 days, suggesting repair of PMF oocytes in this window. RAD51 immunofluorescence eight hours post-cisplatin was positive in damaged cell types in both WT and Puma-/- mice, demonstrating induction of the homologous recombination pathway. In contrast, DNA-PKcs staining were rarely observed in PMFs, indicating non-homologous end joining plays an insignificant role.

Conclusion

PMF oocytes are able to conduct high-fidelity repair of DNA damage accumulated during chemotherapy. Therefore, apoptosis inhibition presents a viable strategy for fertility preservation in women undergoing treatment.

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Data Availability

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.

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Acknowledgements

The authors acknowledge the facilities, scientific and technical assistance of Monash Micro Imaging, the Monash Animal Research Platform, and the Monash Histology Platform, Monash University, Victoria, Australia.

Funding

This work was supported by fellowships and grants from the National Health and Medical Research Council Australia (Project Grant #1007027, Program Grant #1016701, and Fellowship KJH #1050130); National Breast Cancer Foundation (#NC14-001). This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS.

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Authors and Affiliations

  1. Department of Obstetrics & Gynaecology, University of Melbourne, Parkville, Australia

    Quynh-Nhu Nguyen, Jock K. Findlay & Martha Hickey

  2. Ovarian Biology Laboratory, Monash Biomedicine Discovery Institute, Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, 3800, Australia

    Quynh-Nhu Nguyen, Nadeen Zerafa & Karla J. Hutt

  3. Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, Australia, and Monash University, Clayton, Australia

    Jock K. Findlay

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Contributions

QNN planned experiments, obtained ethics approvals, conducted experiments, analysed data, and prepared the manuscript. NZ provided laboratory support and assisted with experiments. MH and JKF provided supervision, assisted in planning experiments, and revised the manuscript. KJH provided supervision, gave assistance with ethics applications, project funding, laboratory resources and infrastructure, planned experiments, and prepared the manuscript.

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Correspondence to Karla J. Hutt.

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All animal experiments and procedures were carried out in accordance with the NHMRC Australian Code of Practice for the Care and Use of Animals and approved by the Monash University School of Biomedical Sciences (MARP/2017/077) and the Monash Medical Centre Animal Ethics (MMCB/2014/13) Committees.

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Nguyen, QN., Zerafa, N., Findlay, J.K. et al. DNA repair in primordial follicle oocytes following cisplatin treatment. J Assist Reprod Genet 38, 1405–1417 (2021). https://doi.org/10.1007/s10815-021-02184-3

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