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11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) rapidly inactivates GCs within the placenta and other fetal tissues, hence serving as a ‘barrier’ to limit exposure of the fetus to maternal GCs, ensuring an appropriate fetal milieu for normal development. The synthetic GC, dexamethasone (Dex) is thought to bypass the 11β-HSD2 ‘barrier’ due to poor substrate specificity. Prenatal administration in rats has been shown to programme low birth weight and anxiety, associated with hypothalamic pituitary adrenal (HPA) axis hyperactivity and the decreased hippocampal gene expression of corticosteroid receptors, an effect thought to underlie the observed behavioural phenotype. Studies described here extend previous findings and show that prenatal Dex programmes enhanced fear-potentiation reflecting heightened state anxiety. These effects were associated with enhanced c-fos mRNA expression following mild stress exposure within the frontal and cingulated cortex, indicating increased cellular activation. We have used a second model of GC programming which involves crossing mice heterozygous for 11β-HSD2-null allele, generating offspring of three genotypes in the same litter (11β-HSD2+/+, +/- and -/-), allowing direct study of excessive fetal exposure to GCs, independent of altered maternal physiology and/or behaviour, thus providing a unique programming model. In our studies, 11β-HSD2-null mutants displayed reduced birthweight, increased anxiety-related behaviour and mild cognitive deficits, despite normal circulating corticosterone and limbic expression of HPA axis-associated genes. However, dysregulated expression of these candidate genes during the early postnatal period was evident, indicative of an altered developmental trajectory. In addition to programmed effects on the brain and behaviour, 11β-HSD2 null mice exhibit reduced fat deposition, acute weight maintenance deficits and spontaneous hypoactivity despite evidence of normal glucose homeostasis. These metabolic findings emphasize the crucial interactions of early-life programming effects of GCs with the adult GC environment.

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