Restraint stress impairs oocyte maturation via dysregulating stage-dependent estradiol-BMAL 1 rhythm in mice

Stress can reduce reproductive capacity by disrupting the maternal clock genes. This study shows that restraint stress dysregulates stage-dependent estradiol-BMAL1 rhythmicity, compromising oocyte maturation and quality.

Stress is an important cause of reduced reproductive capacity, but how stress-induced endocrine disruption affects oocyte maturation through ovarian clock gene expression and metabolic processes remains unclear. Here, we investigated whether restraint stress impaired oocyte maturation by disrupting glucocorticoid signaling and brain and muscle ARNT-like protein 1 (BMAL1)-associated glycolysis in cumulus cells. Restraint stress caused sustained serum corticosterone elevation and increased glucocorticoid receptor expression in cumulus cells. At 29-41 hr post-pregnant mare serum gonadotropin, corresponding to late antral follicle growth, corticosterone declined while ovarian Cyp19a1, Esr2, and Bmal1 increased. Restraint stress suppressed Cyp19a1, Esr2, and Pkm2, thereby disrupting these temporal patterns of change. During germinal vesicle breakdown and subsequent maturation, corticosterone levels declined while oocyte ATP demand, ovarian glycolytic gene, and cumulus cell BMAL1 expression increased. Restraint stress suppressed ovarian Star and Hk2, and reduced cumulus cells BMAL1. Restraint stress also reduced the proliferative capacity of cumulus cells and decreased transzonal projections formation and glucose transporter 1 expression. In vitro, estradiol (E2) supplementation promoted Per2 and Bmal1 expression in cumulus cells and enhanced glycolysis and proliferation, whereas Bmal1 knockdown impaired metabolic support. These findings suggest that stress-induced glucocorticoid elevation suppresses E2 synthesis and blocks BMAL1 upregulation in cumulus cells, thereby impairing cumulus cell proliferation and glycolysis, reducing pyruvate supsply to oocytes, and ultimately causing insufficient oocyte ATP production and decreased nuclear maturation. This study provides a stage-dependent glucocorticoid-E2-Per-Bmal1-glycolysis pathway in cumulus cells for stress-related abnormalities in oocyte maturation.