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Timed Maternal Melatonin Treatment Reverses Circadian Disruption of the Fetal Adrenal Clock Imposed by Exposure to Constant Light

机译：胎儿肾上腺时钟定时产妇褪黑素治疗昼夜颠倒破坏暴露于恒光强加

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Surprisingly, in our modern 24/7 society, there is scant information on the impact of developmental chronodisruption like the one experienced by shift worker pregnant women on fetal and postnatal physiology. There are important differences between the maternal and fetal circadian systems; for instance, the suprachiasmatic nucleus is the master clock in the mother but not in the fetus. Despite this, several tissues/organs display circadian oscillations in the fetus. Our hypothesis is that the maternal plasma melatonin rhythm drives the fetal circadian system, which in turn relies this information to other fetal tissues through corticosterone rhythmic signaling. The present data show that suppression of the maternal plasma melatonin circadian rhythm, secondary to exposure of pregnant rats to constant light along the second half of gestation, had several effects on fetal development. First, it induced intrauterine growth retardation. Second, in the fetal adrenal in vivo it markedly affected the mRNA expression level of clock genes and clock-controlled genes as well as it lowered the content and precluded the rhythm of corticosterone. Third, an altered in vitro fetal adrenal response to ACTH of both, corticosterone production and relative expression of clock genes and steroidogenic genes was observed. All these changes were reversed when the mother received a daily dose of melatonin during the subjective night; supporting a role of melatonin on overall fetal development and pointing to it as a ‘time giver’ for the fetal adrenal gland. Thus, the present results collectively support that the maternal circadian rhythm of melatonin is a key signal for the generation and/or synchronization of the circadian rhythms in the fetal adrenal gland. In turn, low levels and lack of a circadian rhythm of fetal corticosterone may be responsible of fetal growth restriction; potentially inducing long term effects in the offspring, possibility that warrants further research.
机译：令人惊讶的是，在我们现代的24/7社会中，很少有关于发育性时序发育的影响的信息，如轮班工作的孕妇对胎儿和产后生理的影响。母体和胎儿的昼夜节律系统之间存在重要差异。例如，视交叉上核是母亲的主钟，而不是胎儿的主钟。尽管如此，胎儿的一些组织/器官仍存在昼夜节律性振荡。我们的假设是，孕妇血浆褪黑激素节律会驱动胎儿的昼夜节律系统，进而通过皮质酮节律性信号转导将这一信息依赖于其他胎儿组织。目前的数据表明，在妊娠后半期抑制妊娠大鼠暴露于恒光下继发的母体血浆褪黑素昼夜节律对胎儿发育有多种影响。首先，它引起子宫内生长迟缓。其次，在体内胎儿肾上腺中，它显着影响了时钟基因和时钟控制基因的mRNA表达水平，并且降低了皮质酮的含量并阻止了皮质酮的节律。第三，观察到对ACTH的体外胎儿肾上腺皮质激素产生以及时钟基因和类固醇生成基因的相对表达均发生改变。当母亲在主观的夜晚每天服用褪黑激素时，所有这些改变都可以逆转。支持褪黑激素在整个胎儿发育中的作用，并指出它是胎儿肾上腺的“时间给予者”。因此，本发明结果共同支持褪黑激素的母亲昼夜节律是胎儿肾上腺中昼夜节律的产生和/或同步的关键信号。反过来，低水平和缺乏胎儿皮质酮的昼夜节律可能是胎儿生长受限的原因。可能在后代中引起长期影响，有可能需要进一步研究。

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