Timed maternal melatonin treatment reverses circadian disruption of the fetal adrenal clock imposed by exposure to constant light

PLoS One. 2012;7(8):e42713. doi: 10.1371/journal.pone.0042713. Epub 2012 Aug 13.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors / genetics
  • Adrenal Glands / drug effects
  • Adrenal Glands / embryology*
  • Adrenal Glands / physiology
  • Adrenal Glands / radiation effects
  • Adrenocorticotropic Hormone / pharmacology
  • Animals
  • Circadian Clocks / drug effects*
  • Circadian Clocks / radiation effects*
  • Circadian Rhythm / drug effects
  • Circadian Rhythm / radiation effects
  • Corticosterone / blood
  • Early Growth Response Protein 1 / genetics
  • Female
  • Fetus / drug effects
  • Fetus / embryology
  • Fetus / physiology*
  • Fetus / radiation effects
  • Gene Expression Regulation, Developmental / drug effects
  • Gene Expression Regulation, Developmental / radiation effects
  • Light / adverse effects*
  • Melatonin / pharmacology*
  • Mothers*
  • Period Circadian Proteins / genetics
  • Phosphoproteins / genetics
  • Pregnancy
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Melatonin / genetics
  • Time Factors

Substances

  • ARNTL Transcription Factors
  • Early Growth Response Protein 1
  • Per2 protein, rat
  • Period Circadian Proteins
  • Phosphoproteins
  • RNA, Messenger
  • Receptors, Melatonin
  • steroidogenic acute regulatory protein
  • Adrenocorticotropic Hormone
  • Melatonin
  • Corticosterone

Grant support

This work was supported by Grant 1080649 from Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT). Dr. Abarzua-Catalan was supported by a PhD-Fellowship from Commission Nacional de Investigación Cientifica y Tecnológica (CONICYT), Chile. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.