Glucocorticoid programming of the fetus; adult phenotypes and molecular mechanisms.
It has been long recognised that the glucocorticoid administration to pregnant mammals (including humans) reduces offspring birth weight. Epidemiologically, low weight or thinness at birth is associated with an increased risk of cardiovascular and metabolic disorders in adult life. So, does fetal exposure to glucocorticoids produce such 'programming' of adult disorders? Here data are reviewed which show, in rodents and other model species, that antenatal exposure to glucocorticoids reduces offspring birth weight and produces permanent hypertension, hyperglycaemia, hyperinsulinaemia, altered behaviour and neuroendocrine responses throughout the lifespan. This occurs with exogenous (dexamethasone) or endogenous glucocorticoids, the latter achieved by inhibiting 11 beta-hydroxysteroid dehydrogenase type 2, the feto-placental enzymic barrier to maternal glucocorticoids. Processes underlying fetal programming include determination of the 'set point' of the hypothalamic-pituitary-adrenal axis and of tissue glucocorticoid receptor expression. Detailed molecular mechanisms are being dissected. Analogous stress axis hyperreactivity occurs in lower birth weight humans and may be an early manifestation and indicate approaches to manipulation or prevention of the phenotype.
Seckl
J R
JR
Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK. j.seckl@ed.ac.uk
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000328:Adult; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000196:embryology / Q000254:growth & development; D005260:Female; D005317:Fetal Growth Retardation / Q000139:chemically induced; D005333:Fetus / Q000187:drug effects / Q000502:physiology; D005938:Glucocorticoids / Q000009:adverse effects*; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000502:physiology; D008297:Male; D008431:Maternal-Fetal Exchange; D010641:Phenotype; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects
D005938:Glucocorticoids; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases