SR-18292 Alters Oocyte Competence and Ovarian Transcriptomic Dynamics in Female Mice

Background Mitochondria are essential for ovarian function, steroidogenesis, and oocyte development. However, the role of mitochondrial biogenesis in estrous cyclicity and oocyte competence remains incompletely understood. This study investigated the effects of SR-18292-mediated peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) inhibition on reproductive outcomes and ovarian transcriptomic profiles in female ICR mice. Methods Estrous cyclicity was monitored before, during, and after SR-18292 treatment. Oocyte yield, degeneration, and fertilization outcomes were evaluated following gonadotropin-induced superovulation and in vitro fertilization (IVF). Ovarian transcriptomes were analyzed by RNA sequencing at 48 h after pregnant mare serum gonadotropin (PMSG) and 13 h after human chorionic gonadotropin (hCG) administration, followed by differential gene expression and pathway enrichment analyses. Results SR-18292 treatment disrupted estrous cyclicity, with prolonged or stalled progression at metestrus and diestrus. Treated mice yielded significantly more ovulated oocytes following superovulation, but these oocytes exhibited a greater degeneration rate and almost no successful fertilization compared to the control group. Transcriptomic changes were more pronounced 13 h after hCG than 48 h after PMSG administration. Early transcriptomic responses were associated primarily with activated lipid metabolism, adipocytokine signaling, and hormone-related processes. Moreover, later transcriptomic responses included suppression of mitochondrial respiratory-chain and oxidative phosphorylation-associated gene categories, alongside alterations in metabolic and signaling pathways. Conclusions SR-18292 treatment was associated with disrupted estrous cyclicity, increased ovulatory output, and impaired oocyte competence. Transcriptomic analysis suggests that metabolic, hormone-responsive, and energy-sensing pathways may sustain follicular development and ovulation despite pharmacological modulation of PGC-1α, yet fail to preserve oocyte competence, revealing a potential uncoupling between ovulatory output and oocyte developmental potential. These findings support further investigation into the role of PGC-1α-associated mitochondrial regulation in female reproduction.