Influence Of Circadian Rhythms On Labor Onset,Fetal Reproductive Systems And Cardiovascular Development

Aims:The current study aimed at 1)To explore the influence of biological clock on human labor onset;2)To explore the mechanism of biological clock–related hormones in regulating ovine blood pressure;3)To explore the circadian rhythm and its regulatory mechanisms in fetal cardiovascular systems;and 4)To evaluate the influence of the circadian rhythm on reproductive systems in the fetus.Methods:A total of 10,663 cases of spontaneous labors were analyzed.The age of pregnant women,baby weight,fetal sex,gestation weeks,and delivery seasons were considered on labor onset.We also analyzed the association of placental clock genes with labor onset.Real time blood pressures and related hormones were monitored in fetal sheep after intravenous administration of melatonin or its receptor inhibitor.The heart rate,blood pressure,and SCN clock genes were monitored in fetal sheep in L:L and L:D cycle models,respectively.The follicle-stimulating hormone,luteinizing hormone,estradiol,progesterone in blood were monitored in fetal sheep in L:L and L:D cycle models,respectively.Results:1.There were significant differences in terms of diurnal circadian rhythms for labor onset(p<0.05)when stratified by delivery season,pregnancy age,gestational week,neonatal sex and neonatal body weight.A trend for night delivery,peaking at 0:00 am,was noted.Preterm delivery exhibited in a 24-hour oscillating model,although its oscillating amplitude was significantly decreased(χ~2=249,p<0.01)as compared with the term delivery.Clock genes,including Per 1,Per 2,Per 3,Clock,Bmal 1,Bmal 2,Cry 1 and Cry2,were expressed in human placenta;MT 1,MT 2 and CRHBP were expressed in human placenta,too.The m RNA expressions of Clock,Cry 2,Bmal 1 and MT 1 were oscillated in a circadian manner in the term placenta.The mRNA expressions of Clock,Cry 2,Bmal1and MT 1 were not rhythmical in a circadian manner in the preterm placenta.The expressions of Per 1,Per 2,Per 3,Cry 1,Bmal 2,MT 2and CRHBP were not rhythmical in a circadian manner in either the term or preterm placenta.2.Blood pressure of fetal sheep was decreased following intravenous administration of melatonin;Fetal blood pressure was increased following administration of Luzindole(melatonin MT 1/MT 2 receptor inhibitor);and remained unchanged following administration of Prazosin(melatonin MT 3 receptor inhibitor).Intravenous administration of melatonin decreased the plasma endothelin levels,which could be blocked by Luzindole.3.The cardiovascular circadian rhythm has been established in late-term fetal sheep.Rhythm peak and trough were different in terms of heart rate and average arterial blood pressure as compared with the maternal sheep.Plasma melatonin levels exhibited in a circadian manner in fetal sheep in L:L cycle model,different from the maternal sheep.The expression of the core clock genes was not significantly changed in the fetal SCN under L:L cycle compared to that in L:D cycle.4.The circulating follicle-stimulating hormone and estradiol levels were up regulated,and the circulating progesterone levels were down regulated in the maternal and fetal sheep in L:L cycle model.The circulating luteinizing hormone levels were up regulated in fetal sheep,and were kept unchanged in the maternal sheep.Conclusion:1.Preterm labor onset oscillated in a 24 hour manner,however,the oscillation amplitude significantly decreased.Arrhythmic expressions of placental clock genes,such as Clock,Cry 2,Bmal1 and MT 1,could be an important factor for preterm labor onset.Clock gene-related hormones might regulate the ovine blood pressure via MT 1/MT 2receptor pathway.The decreased release of endothelin could be involved in the blood pressure regulation.3.The cardiovascular circadian rhythm of fetal sheep in late term has been established and independent of maternal sheep.The circulating melatonin of fetal sheep may not completely come from the maternal.Fetal SCN could participate in the regulation of cardiovascular circadian rhythm at late term.4.The reproductive hormones in fetal sheep were secreted in a circadian manner at late term.Disruption of photoperiod could alter the release of reproductive hormones into blood circulation,affecting the development of reproductive systems in fetal sheep.