Caffeine-induced activated glucocorticoid metabolism in the hippocampus causes hypothalamic-pituitary-adrenal axis inhibition in fetal rats

PLoS One. 2012;7(9):e44497. doi: 10.1371/journal.pone.0044497. Epub 2012 Sep 6.

Abstract

Epidemiological investigations have shown that fetuses with intrauterine growth retardation (IUGR) are susceptible to adult metabolic syndrome. Clinical investigations and experiments have demonstrated that caffeine is a definite inducer of IUGR, as children who ingest caffeine-containing food or drinks are highly susceptible to adult obesity and hypertension. Our goals for this study were to investigate the effect of prenatal caffeine ingestion on the functional development of the fetal hippocampus and the hypothalamic-pituitary-adrenal (HPA) axis and to clarify an intrauterine HPA axis-associated neuroendocrine alteration induced by caffeine. Pregnant Wistar rats were intragastrically administered 20, 60, and 180 mg/kg · d caffeine from gestational days 11-20. The results show that prenatal caffeine ingestion significantly decreased the expression of fetal hypothalamus corticotrophin-releasing hormone. The fetal adrenal cortex changed into slight and the expression of fetal adrenal steroid acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme (P450scc), as well as the level of fetal adrenal endogenous corticosterone (CORT), were all significantly decreased after caffeine treatment. Moreover, caffeine ingestion significantly increased the levels of maternal and fetal blood CORT and decreased the expression of placental 11β-hydroxysteroid dehydrogenase-2 (11β-HSD-2). Additionally, both in vivo and in vitro studies show that caffeine can downregulate the expression of fetal hippocampal 11β-HSD-2, promote the expression of 11β-hydroxysteroid dehydrogenase 1 and glucocorticoid receptor (GR), and enhance DNA methylation within the hippocampal 11β-HSD-2 promoter. These results suggest that prenatal caffeine ingestion inhibits the development of the fetal HPA axis, which may be associated with the fetal overexposure to maternal glucocorticoid and activated glucocorticoid metabolism in the fetal hippocampus. These results will be beneficial in elucidating the developmental toxicity of caffeine and in exploring the fetal origin of adult HPA axis dysfunction and metabolic syndrome susceptibility for offspring with IUGR induced by caffeine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 2 / genetics
  • Animals
  • Caffeine / pharmacology*
  • DNA Methylation
  • Female
  • Glucocorticoids / pharmacology*
  • Hippocampus / drug effects*
  • Hippocampus / embryology
  • Hippocampus / metabolism
  • Hypothalamo-Hypophyseal System / drug effects*
  • Pituitary-Adrenal System / drug effects*
  • Pregnancy
  • Rats
  • Rats, Wistar

Substances

  • Glucocorticoids
  • Caffeine
  • 11-beta-Hydroxysteroid Dehydrogenase Type 2

Grant support

This work was supported by grants from the National Natural Science Foundation of China (Nos. 30830112, 81072709, and 81202240), the Key Grant Project of the Chinese Ministry of Education (No. V200801), the Hubei Province Science Foundation for Innovation Group of China (No. 2009CDA079), the Specialized Research Fund for the Doctoral Program of Higher Education of China (No. 20110141120055) and the Postdoctoral Science Foundation of China (No. 20110491196). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.