MON-167 A Mouse Model of Chronic Shiftwork-like Lighting Exposure Identifies Adverse Pregnancy Outcomes in Female Mice Independent of Estrous Cycle Regularity

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Abstract Disclosure: A.M. Yaw: None. B. Van Loh: None. A.K. McLane-Svoboda: None. K. Jang: None. K. Jursch: None. D. Nguyen: None. H.M. Hoffmann: None. Nighttime and rotating shiftwork are linked to numerous health risks, including disrupted menstrual cycles and adverse pregnancy outcomes; however, the underlying mechanistic causes are unknown. One feature of shiftwork, exposure to mistimed light, provides a mechanism where shiftwork disrupts the circadian (24h) timekeeping system causing reduced fertility. Light modulates the reproductive axis via vasoactive intestinal peptide (VIP) neurons in the brain’s suprachiasmatic nucleus (SCN). The SCN translates environmental light information to neuronal and endocrine signals aligning circadian rhythms in the body to the time of day, an alignment that is essential for successful ovulation and female fertility. To understand if light-induced circadian disruption deregulates the reproductive axis, we developed a mouse model of rotating light shifts (RL) that alters the timing of light by advancing and delaying the 12h light-12h dark cycle for 6h every 4 days for 5-9 weeks, mimicking light exposures observed in shift workers. To determine if RL impacted estrous cyclicity, female mice underwent vaginal lavage for 14 days. Half of the RL females did not complete one estrous cycle and were deemed abnormal (RL-abnormal). The females that maintained estrous cyclicity (RL-cyclic), had similar estrous cycle lengths and comparable metestrus progesterone (P4) levels to controls. In contrast, RL-abnormal females had reduced P4, indicating reduced ovarian function. To assess if RL impacted the reproductive axis at the level of the brain, we evaluated SCN circadian rhythms via bioluminescent tissue explants (Per2::luciferase). RL reduced recording success of SCN explants. Successful control and RL-cyclic SCN explants exhibited similar tissue timekeeping, but RL-abnormal SCN explants did not cluster at a consistent time of day, indicating a reduced ability to adapt to RL. As SCN VIP neurons can modulate gonadotropin-releasing hormone (GnRH) release, which drives the luteinizing hormone (LH) surge to trigger ovulation, we examined the number of VIP+ cells in the SCN. We found that RL-abnormal, but not RL-cyclic, had reduced VIP+ immunostaining and reductions in LH release following a GnRH injection. To understand if RL impacts pregnancy, we mated the mice. There were no differences in pregnancy rates, but more RL females experienced labor dystocia (71%) independent of cyclicity, compared to controls (0%). Our model recapitulates a phenomenon present in female shift workers, where ∼50% experience menstrual disorders and suggests that differences in SCN function may underlie a resilience to estrous cycle disruption. Interestingly, this resilience does not protect against adverse pregnancy outcomes, including labor dystocia. Future mechanistic studies of the pregnant uterus in our model will be important next steps towards understanding how RL cause dystocia. Presentation: Monday, July 14, 2025

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