Méndez Natalia, Corvalan Fernando, Halabi Diego, Vasquez Abigail, Vergara Karina, Noriega Hector, Ehrenfeld Pamela, Sanhueza Katiushka, Seron-Ferre Maria, Valenzuela Guillermo J, Torres-Farfan Claudia
Escuela de Medicina, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile.
Laboratory of Developmental Chronobiology, Instituto de Anatomía, Histología y Patología, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile.
J Pineal Res. 2024 Nov;76(8):e70015. doi: 10.1111/jpi.70015.
Gestational chronodisruption, increasingly common due to irregular light exposure, disrupts maternal-fetal circadian signaling, leading to long-term health issues in offspring. We utilized a chronic photoperiod shifting model (CPS) in pregnant rats to induce chronodisruption and investigated the potential mitigating effects of maternal melatonin supplementation (CPS + Mel). Male and female offspring were evaluated at 3 ages (90, 200, and 400 days of age) for metabolic profiles, hormonal responses, cytokine levels, and adipose tissue activity. Our findings indicate that gestational chronodisruption leads to increased birth weight by approximately 15% in male and female offspring and increased obesity prevalence in male offspring, accompanied by a 30% reduction in nocturnal melatonin levels and a significant disruption in corticosterone rhythms. Male CPS offspring also exhibited decreased lipolytic activity in white adipose tissue, with a 25% reduction in glycerol release compared to controls, indicating impaired metabolic flexibility. In contrast, female offspring, while less affected metabolically, showed a 25% increase in adipose tissue lipolytic activity and higher levels of pro-inflammatory cytokines such as IL-6 (increased by 40%). Scheduled melatonin supplementation in chronodisrupted mothers, administered throughout gestation, effectively normalized birth weights in both sexes, reduced obesity prevalence in males by 18%, and improved lipolytic activity in male offspring, bringing it closer to control levels. In females, melatonin supplementation moderated cytokine levels, reducing IL-6 by 35% and restoring IL-10 levels to near-control values. These results highlight the importance of sex-specific prenatal interventions, particularly the role of melatonin in preventing disruptions to fetal metabolic and inflammatory pathways caused by gestational chronodisruption. Melatonin treatment would prevent maternal circadian rhythm misalignment, thereby supporting healthy fetal development. This study opens new avenues for developing targeted prenatal care strategies that align maternal and fetal circadian rhythms, mitigating the long-term health risks associated with chronodisruption during pregnancy.
由于光照不规律，孕期生物钟紊乱日益常见，它会破坏母婴昼夜节律信号，导致后代出现长期健康问题。我们利用孕鼠慢性光周期转换模型（CPS）诱导生物钟紊乱，并研究了母体补充褪黑素（CPS + Mel）的潜在缓解作用。在3个年龄阶段（90日龄、200日龄和400日龄）对雄性和雌性后代进行评估，检测其代谢特征、激素反应、细胞因子水平和脂肪组织活性。我们的研究结果表明，孕期生物钟紊乱导致雄性和雌性后代出生体重增加约15%，雄性后代肥胖患病率增加，同时夜间褪黑素水平降低30%，皮质酮节律显著紊乱。雄性CPS后代白色脂肪组织的脂解活性也降低，甘油释放量比对照组减少25%，表明代谢灵活性受损。相比之下，雌性后代虽然代谢受影响较小，但脂肪组织脂解活性增加25%，促炎细胞因子如IL-6水平升高（增加40%）。在整个孕期对生物钟紊乱的母亲定时补充褪黑素，有效使两性出生体重恢复正常，使雄性肥胖患病率降低18%，并改善了雄性后代的脂解活性，使其接近对照水平。对雌性而言，补充褪黑素可调节细胞因子水平，使IL-6降低35%，并将IL-10水平恢复至接近对照值。这些结果凸显了针对性别差异的产前干预的重要性，特别是褪黑素在预防孕期生物钟紊乱对胎儿代谢和炎症途径造成破坏方面的作用。褪黑素治疗可防止母体昼夜节律失调，从而支持胎儿健康发育。这项研究为制定使母婴昼夜节律同步的针对性产前护理策略开辟了新途径，可降低孕期生物钟紊乱相关的长期健康风险。
