Sex-Specific Metabolic Effects of Gestational Chronodisruption and Maternal Melatonin Supplementation in Rat Offspring

Abstract

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.