Oral Presentation ESA-SRB 2023 in conjunction with ENSA

Conditional loss of Brca1 in oocytes causes accelerated ovarian ageing and subfertility in mice (#66)

Amy Winship 1 , Lauren Alesi 1 , Jessica Stringer 1 , Yasmin Lewis 1 , Lisa Tu 1 , Elyse Swindells 1 , Saranya Giridharan 1 , Wilcox Cao 1 , Xuebi Cai 1 , Nadeen Zerafa 1 , Martha Hickey 2 3 , Karla Hutt 1
  1. Department of Anatomy & Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
  2. Gynaecology Research Centre, Royal Women's Hospital, Parkville
  3. Department of Obstetrics and Gynaecology, The University of Melbourne, Parkville

An estimated one in 350 women carry germline BRCA1/2 mutations, which confer increased risk of developing breast and ovarian cancer and may also contribute to subfertility. In this study we addressed a longstanding question in the field regarding the functional consequences of BRCA1 inactivation in oocytes. We generated mice with conditional gene deletion of Brca1 using Gdf9-Cre recombinase (WT: Brca1fl/flGdf9+/+; cKO: Brca1fl/flGdf9cre/+). After a comprehensive fertile lifespan breeding trial, the average number of pups per female across all litters was significantly reduced in Brca1 cKO (9.4 pups ± 0.7) compared to WT animals (11.6 pups ± 0.4, p=0.0196), indicating that conditional loss of Brca1 in oocytes leads to subfertility. To determine whether reduced oocyte number contributed, ovarian follicles were enumerated throughout the lifespan. Females of each genotype were endowed with equal numbers of total follicles at postnatal day (PN)5 (range 5392-5562 total follicles/ovary). However, by PN300, the ovarian reserve of primordial follicles was significantly reduced by 47% in Brca1 cKO animals (141 ± 17) versus WT (264 ± 27; p=0.0007). In advanced reproductively aged mice at PN300, oocyte in vitro maturation was reduced by 50% in Brca1 cKO mice compared to WT, demonstrating defective oocyte quality. Serum anti-Müllerian hormone (AMH) concentrations (which is the gold-standard indirect marker of the ovarian reserve used in clinical practice), were not predictive of reduced primordial follicle number in Brca1 cKO mice versus WT. Furthermore, we found no correlation between follicle number or density and serum AMH concentrations in matched samples from premenopausal women with BRCA1/2 mutations. Together, our data demonstrate that BRCA1 is a key regulator of oocyte number and quality in females and suggest that AMH is not a reliable marker of the ovarian reserve in this context.