(250) A Mouse Model of Irregular-light:dark Exposure Identifies Adverse Pregnancy Outcomes in Female Mice Independent of Estrous Cycle Regularity

Hanne M Hoffmann¹, Sierra Moore¹, Jacquelyn Dal Bon¹, Brooke M Van Loh¹, Autumn K McLane-Svoboda¹, Krystal Jang¹, Kierra Jursch¹, Duong Nguyen¹, Aaron C. Sue¹, Thomas O’Halloran¹, Alexandra M Yaw¹ 

¹Michigan State University East Lansing

 

Abstract Text:

In women, irregular sleep patterns and 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 irregular sleep patterns and shiftwork is exposure to light during the night. This nocturnal light exposure is a mechanism by which light can drive disruptions to the body’s circadian (24h) timekeeping system, causing reproductive malfunction. Light modulates the reproductive axis via vasoactive intestinal peptide 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 reproductive function. To understand how light-induced circadian disruption deregulates the reproductive axis, we developed a mouse model of irregular-light: dark cycles (i-LD) which alters the timing of light by advancing and delaying the 12h light-12h dark cycle for 6h every 4 days for 5-9 weeks. To determine if i-LD impacted estrous cyclicity, female mice underwent vaginal lavage for 14 days. Half of the i-LD females did not complete one estrous cycle and were deemed abnormal (i-LD abnormal). The females that maintained estrous cyclicity (i-LD cyclic), had similar estrous cycle lengths and comparable metestrus progesterone (P4) levels to controls. In contrast, i-LD abnormal females had reduced P4, indicating reduced ovarian function. To assess if i-LD impacted the reproductive axis at the level of the brain, we evaluated SCN circadian rhythms via bioluminescent tissue explants (Per2::luciferase). I-LD reduced recording success of SCN explants. Successful control and i-LD-cyclic SCN explants exhibited similar tissue timekeeping, but i-LD-abnormal SCN explants did not cluster at a consistent time of day, indicating a reduced ability to adapt to i-LD. The SCN modulates gonadotropin-releasing hormone release, which drives the luteinizing hormone (LH) surge to trigger ovulation. To test gonadotrope sensitivity to gonadotropin-releasing hormone, we challenged the mice with gonadotropin-releasing hormone and found a reduced release of LH in i-LD females. To understand if i-LD impacted pregnancy, we mated the mice. There were no differences in pregnancy rates, but more i-LD females experienced labor dystocia (71%) independent of cyclicity, compared to controls (5%), suggesting uterine contractile malfunction. Essential trace elements, such as manganese (Mn) and zinc (Zn), have been implicated uterine inertia, but it is unclear how trace elements may modulate function at the level of the uterus or the placenta. We used triple quadrupole ICP-MS to determine if TE change in maternal serum or the uterus between late gestation and labor of mice in control and i-LD. In control mice, no differences in Mn or Zn were detected in maternal serum, and Zn, but not Mn, decreased in the myometrium during the transition from late pregnancy to labor, a time-point where the myometrium becomes highly contractile. Current work is investigating how i-LD impacts trace elements levels in the laboring uterus and the impact of i-LD on the placenta. Together, our model recapitulates a phenomenon present in women with irregular sleep cycles, where ~50% of shift workers 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.