The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2018

DNA repair mechanisms responsible for safeguarding oocyte quality and offspring health (#60)

Jessica Stringer 1 , Nadeen Zerafa 1 , Karla Hutt 1
  1. Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia

As oocytes are among the most long-lived cells in the body, it is essential that genomic integrity is maintained throughout reproductive life to ensure fertility and offspring health. Apoptotic elimination of DNA damaged oocytes is presumed essential to ensure that only high quality oocytes remain in the ovary and to prevent transmission of genetic defects to subsequent generations. However, primordial follicles from apoptosis-deficient mice (TAp63-/-) survive irradiation-induced DNA damage, and females can produce live offspring. Furthermore, we identified both RAD51 and DNA-PKcs foci, key repair factors in the homologous repair and non-homologous end joining repair pathways respectively, in primordial follicle oocytes within 3 hours of irradiation. These observations suggest that despite their propensity for apoptosis, primordial oocytes have the capacity to undertake highly efficient DNA repair. Interestingly, super-ovulated irradiated TAp63-/- females produced significantly less mature oocytes compared to controls (Control 27.2±2.76 vs 0.45Gy 3.88±1.99, p<0.0001), while natural matings resulted in normal preimplantation embryo numbers (Control 6.4±1.97 vs 0.45Gy 5.67±1.33, p=0.8) and litter sizes (Control 4.833±0.75 vs 0.45Gy 5±0.63, p=0.9), without any reduction in number of litters over 6 months (Control 5±0.73 vs 0.45Gy 6±0.73, p=0.4). This indicates that DNA repair within damaged oocytes was sufficient to support embryonic development and sustain fertility. Interestingly, despite no difference in prepubertal weight, postpubertal male offspring from irradiated females were significantly lighter than controls, without any significant difference in body composition analysed by DEXA. In-depth histopathology health assessments of offspring from irradiated TAp63-/- mothers confirmed that all offspring were healthy, with no pathology to explain the difference in male weight. Whole-genome sequencing studies are underway in order to investigate offspring genetic integrity. This is the first study to examine DNA repair in primordial follicle oocytes in detail and represents important progress in our understanding of oocyte quality control and preservation of female fertility.