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

Abstract

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.

Gestation under chronic constant light leads to extensive gene expression changes in the fetal rat liver

“…The effects of altered photoperiod during pregnancy on fetal development and postnatal physiology are just beginning to be explored (15,32,44,48,49). Here we show that, under constant gestational light conditions, as many as 3,431 transcripts displayed changes in their expression level in the fetal liver.…”

“…We have recently reported that exposure of pregnant rats to constant light from midgestation induces intrauterine growth retardation and marked effects on both fetal adrenal physiology and cardiac transcriptome (15,32). Moreover, in the adult offspring that had been gestated under constant light, we also found increased basal plasma glucose and glucose intolerance (49).…”

“…On the other hand, it is conceivable that the present findings of broad changes in global gene expression secondary to manipulations of gestational lighting may be a consequence of changes in crucial maternal circadian signals crossing the placenta to synchronize fetal peripheral clocks. For instance, using the same model of maternal exposure to constant light, we have previously shown that maternal melatonin plays a key role in the entrainment of the circadian clocks residing in the fetal rat adrenal and hippocampus (32,46,49).…”

“…All fetal livers from Sprague-Dawley rats used in the present study were obtained from larger cohorts that we have previously reported (15,32,49). For RNA isolation from the fetal liver, dams were weighed at E18 (term is ϳ21 days).…”

“…In a parallel cohort, E18 fetal rat livers were collected every 4 h for 24 h from fetuses obtained from pregnant dams maintained under control LD photoperiod (n ϭ 5 per time point). The fetal livers were subsequently subjected to RNA isolation and RT-qPCR to evaluate the 24 h expression pattern of both core clock genes [Period 2 (Per2) and brain and muscle aryl hydrocarbon receptor nuclear translocator like protein 1 (Bmal1)] and clock-controlled genes [early growth response 1 (Egr1) and melatonin receptor 1A (Mtnr1a)] according to an RT-qPCR protocol previously described by us (32).…”