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Reconciling the nutritional and glucocorticoid hypotheses of fetal programming

Elizabeth C Cottrell1, Megan C Holmes, Dawn E Livingstone

  • 1Endocrinology Unit, Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK. elizabeth.cottrell@manchester.ac.uk

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|February 11, 2012
PubMed

Insights

Maternal low-protein diets and placental 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2) deficiency both impair fetal growth by increasing fetal glucocorticoids. However, these conditions act independently, with low-protein diets affecting the fetal adrenal axis directly.

Area of Science:

  • Developmental biology
  • Endocrinology
  • Nutritional science

Background:

  • Fetal growth restriction (FGR) is linked to adult cardiometabolic and neuropsychiatric issues.
  • Maternal malnutrition (e.g., low-protein diet) and stress-induced glucocorticoid exposure can cause FGR and long-term offspring abnormalities.
  • Placental 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2) deficiency, which inactivates glucocorticoids, has been proposed as a unifying mechanism for FGR.

Purpose of the Study:

  • To investigate the roles of glucocorticoids and placental 11β-HSD2 in dietary programming leading to FGR.
  • To determine if placental 11β-HSD2 deficiency is the primary mechanism for FGR induced by maternal low-protein diets.

Main Methods:

  • Pregnant mice were fed either a control or an isocaloric low-protein (LP) diet throughout gestation.
  • Placental 11β-HSD2 activity and fetal glucocorticoid levels were assessed.
  • Studies involved heterozygous 11β-HSD2(+/-) crosses to differentiate dietary effects from genetic deficiency.

Main Results:

  • The LP diet reduced fetal weight by 17% near term and altered fetal glucocorticoid levels.
  • While LP diets reduced placental 11β-HSD2 activity near term, earlier ages showed increased activity, suggesting 11β-HSD2-independent mechanisms for glucocorticoid overexposure.
  • LP diet-induced FGR was independent of placental 11β-HSD2 deficiency, instead activating the fetal hypothalamic-pituitary-adrenal axis.

Conclusions:

  • Maternal malnutrition and placental 11β-HSD2 deficiency are distinct pathways that retard fetal growth.
  • Both pathways involve increased fetal glucocorticoid exposure, but from different sources.
  • Dietary programming of FGR is primarily mediated by direct effects on the fetal adrenal axis, not solely by placental 11β-HSD2 function.

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