Shift work is detrimental to many facets of female reproductive health, extending beyond just fertility but also affecting menstrual health, reproductive hormones, and pregnancy. To better understand how the circadian disruption that occurs during shift work impacts reproductive health, we must firstunderstand the regulation of the suprachiasmatic nucleus (SCN) of the hypothalamus, which is the pacemaker and synchronizer of circadian rhythms. The goal of this dissertation is to determine how the regulation of the SCN by homeodomain transcription factors or mistimed light exposure impacts circadian rhythms, female fertility, and estrous cycles in a mouse model. First, we explored the post-developmental roles of the homeodomain transcription factors SIX3 and SIX6 within neuromedin-S–expressing neurons of the SCN. Conditional deletion of Six6 had no measurable effect on circadian or reproductive function, while deletion of Six3 resulted in shortened circadian behavioral rhythms and impaired sperm motility, suggesting distinct and non-redundant roles for these transcription factors in maintaining adult SCN function and reproductive output. Building on the importance of transcriptional regulation in SCN neurons, we next investigated the role of the SCN-enriched transcription factor VAX1 in Vasoactive Intestinal Peptide (VIP)-expressing neurons, which are critical for synchronizing circadian output to downstream systems. Female mice lacking Vax1 in SCN VIP neurons exhibited weakened SCN rhythms, disrupted estrous cyclicity, reduced estrogen, and increased depressive-like behavior. Finally, to model an environmental form of circadian disruption, we used a rotating light (RL) paradigm that mimics human shift work. While some mice maintained regular cycles (RL-C), others became acyclic (RL-A), despite identical light exposure. Compared to control lighting and RL-C mice, RL-A mice had a reduction in circulating progesterone, a blunted luteinizing hormone response to exogenous gonadotropin releasing hormone, and fewer maturing follicles in the ovary. Interestingly, while both RL-C and RL-A groups had comparable conception rates to controls, exposure to RL resulted in reduced litter sizes, suggesting gestational risks independent of estrous cyclicity. Together, these findings provide insight into how circadian disruption, whether genetic or light-induced, may contribute to irregular reproductive cycles, hormone imbalance, and poor reproductive outcomes in women.
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