However, we do identify several CpG sites within the placenta at which an individual’s DNA methylation levels do significantly predict those observed in the fetal cortex, raising the intriguing possibility of using the epigenetic status of placenta to predict corresponding changes in the brain. Overall, these findings provide novel evidence for the epigenetic regulation of HSD11B2 as a potential mechanism linking maternal stress during gestation, dysregulation of placental gene expression, and neurodevelopmental outcomes in offspring. Though placental 11ß-HSD2 can function as an enzymatic buffer against the deleterious effects of exposure to maternal glucocorticoids, it is clear that this enzyme can be down-regulated by adverse prenatal experiences, thus limiting its capacity to protect the developing fetus. However, the nature and timing of these experiences is an important consideration in predicting the direction of the effects on 11ß-HSD2. For example, acute stress in pregnant rats has been found to increase the activity of placental 11ß-HSD2 and similarly in humans, betamethasone treatment within 72 hours of parturition leads to increased 11ß-HSD2 enzymatic activity. Up-regulation of placental 11ß-HSD2 may thus be an adaptive response to elevated maternal glucocorticoids. In contrast, chronic exposure to maternal glucocorticoids may lead to reduced placental 11ß-HSD2, increased exposure of fetal tissues to glucocorticoids, and neurodevelopmental and metabolic phenotypes associated with glucocorticoid programming. BAY 73-4506 Heightened glucocorticoid exposure during fetal development may promote lung development and thus increase survival following pre-term birth – an obstetric outcome predicted by maternal stress. Thus, though heightened anxiety and HPA activity may be considered maladaptive, these outcomes may be the cost of promoting survival amongst the offspring of gestationally stressed females. One possible strategy to buffer the brain against these neurodevelopmental consequences would be to increase 11ß-HSD2 within the brain. Though we do not find an increase in hypothalamic or cortical HSD11B2 mRNA levels, the stress-induced DNA hypomethylation of this gene that we observe in hypothalamic tissue may be an epigenetic precursor to these buffering effects. Time course analysis of HSD11B2 gene expression and DNA methylation throughout the prenatal stress exposure and into the postnatal period may thus be a key strategy for determining the dynamics of glucocorticoid programming mechanisms. Investigation of the epigenetic regulation of HSD11B2 has previously been explored outside the context of studies on maternal stress. In humans and in rats, the promoter and first exon of the HSD11B2 gene are rich in CpG sites and DNA methylation levels at CpG sites within this region are related to the expression of this gene. Pharmacological hypomethylation of HSD11B2 through in vitro or in vivo treatment with the DNA methyltransferase inhibitor 5-aza29-deoxycytidine has been found to increase HSD11B2 expression.