Neuroendocrine and Immune Consequences of Circadian Dysregulation in Pregnancy

Hanne M. Hoffmann

Michigan State University

Abstract Text:

Pregnancy relies on precise temporal regulation of hormonal, metabolic, and immune processes to support fetal development and maternal health. Central to this coordination are circadian rhythms, which are approximately 24h rhythms, generated by molecular clocks in nearly all cells and synchronized by the brain’s master pacemaker, the suprachiasmatic nucleus (SCN). Disruption of the body's circadian rhythms is associated with an increased risk of gestational diabetes, preeclampsia, and preterm birth in women. Despite these well-established associations, it remains unclear how circadian disruption causes pregnancy complications. To answer this question, we used transgenic mouse models and mouse models of environment-induced circadian dysregulation. We found that healthy control mice adapted SCN circadian output during pregnancy, which was characterized by changes in hypothalamic and SCN neuropeptide expression and increased sensitivity to light. To determine how this increased sensitivity of the SCN to light impacted pregnancy outcome, we exposed the mice to an irregular light-dark cycle, mimicking shiftwork-like lighting. Females were placed on the irregular light-dark cycle for 4-6 weeks prior to pregnancy, and throughout pregnancy, with samples harvested in mid/late gestation and during labor. We found that the irregular-light dark exposure caused circadian dysregulation in peripheral tissues. As expected, circadian dysregulation was associated with changes in immune function, favoring a predominantly pro-inflammatory phenotype. Importantly, circadian dysregulation caused a significant increase in labor complications, primarily resulting in labor dystocia. To determine if the labor dystocia phenotype was caused by circadian dysregulation, causing immune dysregulation in the uterus, we generated conditional knock-out mice, where the clock gene, Bmal1, was deleted in the myometrium. We identified this conditional knock-out mouse to have increased spontaneous uterine contractions, reduced sensitivity to the labor-promoting hormone oxytocin, dysregulated immune infiltration, and increased sensitivity to infection-induced preterm birth. This work identifies the molecular clock and circadian rhythms as central to a healthy pregnancy and provides a novel target for improving outcomes in complicated pregnancies.