Circadian rhythms are endogenous oscillations widely present in living organisms, typically following approximately 24-hour cyclic regulation. These rhythms govern various physiological processes including sleep-wake cycles, hormone secretion, thermoregulation, and metabolism. The central pacemaker located in the suprachiasmatic nucleus of the hypothalamus orchestrates circadian rhythms, synchronizing with external time cues through environmental light signals. Maintaining robust circadian rhythms is crucial for physiological homeostasis, while circadian disruption has been demonstrated to correlate with numerous health issues including metabolic disorders, psychiatric conditions, and impaired immune function. Recent research has focused on the impact of circadian rhythms on the reproductive system, revealing their regulatory roles in sex hormone secretion, follicular development, and embryo implantation. Therefore, investigating how circadian rhythm disruption affects oocyte function and reproductive potential not only helps elucidate underlying molecular mechanisms but also provides new research directions and intervention strategies for addressing declining fertility in women due to modern lifestyle disruptions and reduced livestock reproduction in intensive farming systems.
Through integrated approaches including transcriptomic sequencing, predictive analysis, and rescue experiments, the research team uncovered the molecular mechanism by which circadian disruption impairs fertility through compromised oocyte quality. By establishing a circadian disruption mouse model via constant light exposure, the study identified mitochondrial homeostasis imbalance-induced cytoplasmic maturation defects as a key factor contributing to reduced fertility, with the PTEN/AKT signaling pathway serving as a critical regulatory mechanism.
The study confirmed that light-treated mice exhibited disrupted estrous cycles, aberrant circadian gene expression, and significantly reduced litter sizes and offspring survival rates - phenotypes potentially attributable to impaired oocyte maturation quality, all of which were effectively rescued by melatonin supplementation. GO analysis of oocyte transcriptomes revealed significant enrichment of differentially expressed genes in endoplasmic reticulum protein processing, cytoskeleton assembly, and organelle dynamics, particularly mitochondrial structure and function regulation. Further investigation demonstrated that light exposure reduced perinuclear mitochondrial distribution, decreased membrane potential, suppressed FIS1/p-DRP1-mediated mitochondrial fission, and significantly reduced ATP levels. Concurrently, functions of mitochondria-associated organelles including endoplasmic reticulum and Golgi apparatus were compromised, suggesting disrupted cytoplasmic maturation in oocytes. Exogenous supplementation with mitochondria-targeted antioxidant MitoQ effectively alleviated localization and functional abnormalities in mitochondria and Golgi apparatus, indicating mitochondrial dysfunction plays a central role in circadian disruption-induced oocyte maturation impairment. Screening and prediction identified the PTEN/AKT signaling pathway as a potential core target, with GSEA enrichment analysis, western blotting, and fluorescence labeling confirming significantly reduced AKT levels and activity in oocytes from circadian-disrupted mice. Exogenous AKT activator SC79 supplementation improved maturation rates in circadian-disrupted oocytes while reducing oxidative stress, restoring mitochondrial distribution, and protecting cytoskeletal assembly.
This study demonstrates that oocyte cytoplasmic maturation quality is a critical factor in circadian disruption-induced fertility impairment in female mammals, with the PTEN/AKT signaling pathway serving as a key regulatory target. These findings provide molecular foundations and therapeutic targets for mitigating female reproductive damage caused by circadian rhythm disruptions.
DOI：10.1093/procel/pwaf080