BRCA1 deficiency in oocytes compromises ovulation without exacerbating follicle loss after chemotherapy in mice

Does oocyte-specific loss of breast cancer susceptibility gene 1 (Brca1) increase vulnerability to chemotherapy-induced ovarian damage in mice?

This study examined the effects of chemotherapeutic agents, including cyclophosphamide, doxorubicin, paclitaxel and carboplatin, on ovarian function in mice with oocyte-specific Brca1 deletion [conditional knockout (cKO): Brca1^fl/flGdf9^cre/+] and wild-type controls (Brca1^fl/flGdf9^+/+). Young (40-80 postnatal days) and older (180-220 postnatal days) mice received a single dose of chemotherapy or saline, and ovarian reserve, serum anti-Müllerian hormone, and ovulated oocytes were assessed.

In young wild-type mice, doxorubicin depleted the number of primordial follicles significantly (P = 0.0082), whereas cyclophosphamide, paclitaxel and carboplatin at the chosen doses did not reduce the number of primordial follicles significantly. Importantly, loss of primordial follicles was not exacerbated by any chemotherapeutic agent in cKO mice compared with wild-type mice. Follicle atresia and granulosa cell apoptosis were unaffected by treatment or genotype. In older mice, paclitaxel and carboplatin impaired superovulation and reduced the yield of mature (metaphase II) oocytes in cKO mice, while ovarian reserve, including primordial and primary follicles, remained largely preserved.

These results indicate that Brca1 deficiency in mice reduced ovulatory capacity after chemotherapy in older females without altering the number of follicles substantially. These findings underscore the need to consider BRCA1 status in fertility preservation counselling and interventions for women undergoing chemotherapy.