Quercetin Prevents Primordial Follicle Loss via Suppression of PI3K/Akt/Foxo3a Pathway Activation in Cyclophosphamide - Treated Mouse

Abstract Background: Chemotherapy improves survival rates but often causes some adverse effects associated with ovarian damage, characterized by a decreased of primordial follicle stockpiles. Recent studies reveal that chemotherapy may stimulate the PI3K signaling pathway, who has roles in manipulating the dormancy and activation of mammalian primordial follicles, resulting in accelerated primordial follicles activation followed by the loss of ovarian reserve. As an inhibitor of PI3K pathway, whether quercetin has protective properties against chemotherapy - induced follicle loss in mice is worth to be explored. Methods： The effects of quercetin on the mouse model of cyclophosphamide-induced ovarian dysfunction were investigated. Paraffin sections of mouse ovary were stained with hematoxylin and eosin for differential follicles count and TUNEL assay for apoptosis detection. Immunohistochemistry stain with ki67 and Foxo3a were used to evaluate the activation of primordial follicles. The function of PI3K signaling pathway were assessed via the western blot of ovary. Results: Quercetin cotreatment rescued the reduction number of dormant primordial follicles induced by cyclophosphamide. Moreover, analysis of the PI3K/Akt/Foxo3a pathway demonstrated that quercetin co - administration decreased phosphorylation of proteins that stimulate follicle activation in ovary induced by cyclophosphamide. Meanwhile, Quercetin prevents cyclophosphamide - induced apoptosis in early growing follicles and early antral follicles, maintaining AMH level secreted by these follicles, preserving the quiescence of the primordial follicle pool, characterized by the intranuclear staining of Foxo3a in primordial follicle. Conclusions: Quercetin attenuates cyclophosphamide - induced follicle loss by preventing the phosphorylation of PI3K/Akt/Foxo3a pathway members and maintaining AMH level secreted by growing follicles.