Timed maternal melatonin treatment reverses circadian disruption of the fetal adrenal clock imposed by exposure to constant light.
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.
Instituto de Anatomía, Histología y Patología, Universidad Austral de Chile, Valdivia, Chile.
Natalia
N
Mendez
Lorena
L
Abarzua-Catalan
Nelson
N
Vilches
Hugo A
HA
Galdames
Carlos
C
Spichiger
Hans G
HG
Richter
Guillermo J
GJ
Valenzuela
Maria
M
Seron-Ferre
Claudia
C
Torres-Farfan
D056930:ARNTL Transcription Factors / Q000235:genetics; D000311:Adrenal Glands / Q000187:drug effects / Q000196:embryology* / Q000502:physiology / Q000528:radiation effects; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000818:Animals; D057906:Circadian Clocks / Q000187:drug effects* / Q000528:radiation effects*; D002940:Circadian Rhythm / Q000187:drug effects / Q000528:radiation effects; D003345:Corticosterone / Q000097:blood; D051766:Early Growth Response Protein 1 / Q000235:genetics; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000196:embryology / Q000502:physiology* / Q000528:radiation effects; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000528:radiation effects; D008027:Light / Q000009:adverse effects*; D008550:Melatonin / Q000494:pharmacology*; D009035:Mothers; D056950:Period Circadian Proteins / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044094:Receptors, Melatonin / Q000235:genetics; D013997:Time Factors; D000098682:Steroidogenic Acute Regulatory Protein
D056930:ARNTL Transcription Factors; D051766:Early Growth Response Protein 1; C513311:Per2 protein, rat; D056950:Period Circadian Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D044094:Receptors, Melatonin; D000098682:Steroidogenic Acute Regulatory Protein; D000324:Adrenocorticotropic Hormone; D008550:Melatonin; D003345:Corticosterone