Graphical abstractExpression and function of 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 and 2. 11β-HSD1 is widely expressed throughout the adult CNS and is key to HPA axis function and cognitive decline during ageing. Conversely, the major central effects of 11β-HSD2 are seen in development, as expression of 11β-HSD2 is high in fetal tissues including the neonate brain and placenta. Loss of 11β-HSD2 from the fetus and fetally-derived tissues results in a life-long phenotype of anxiety, consistent with developmental programming.

Fetal glucocorticoid exposure is a key mechanism proposed to underlie prenatal "programming" of adult cardiometabolic and neuropsychiatric disorders. Regulation of fetal glucocorticoid exposure is achieved by the placental glucocorticoid "barrier," which involves glucocorticoid inactivation within the labyrinth zone of the murine placenta by 11beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2). Thus, the absence of placental 11beta-HSD2 may impact on fetal and placental development. The current study investigated transport of amino acids and glucose, key factors required for fetal growth, and vascular development in placentas from 11beta-HSD2(+/+), (+/-), and (-/-) fetuses derived from 11beta-HSD2(+/-) matings. At embryonic d 15 (E15) (term = E19), 11beta-HSD2(-/-) fetal weight was maintained in comparison to 11beta-HSD2(+/+) fetuses. The maintenance of 11beta-HSD2(-/-) fetal weight occurred despite a reduction in placental weight, suggesting that compensatory changes occur in the placenta to maintain function. However, by E18, 11beta-HSD2(-/-) fetal and placental weights were both reduced. Transport studies revealed up-regulation of placental amino acid transport to 11beta-HSD2(-/-) offspring at E15, coinciding with an increase in the expression of the amino acid transporters. Furthermore, at E18, placental glucose transport to 11beta-HSD2(-/-) offspring was markedly reduced, correlating with lower fetal weight and a decrease in glucose transporter 3 expression. Stereological analyses of the labyrinth zone of the placenta revealed that the reduction in placental weight at E18 was associated with restriction of the normal increase in fetal vessel density over the final third of pregnancy. Our data suggest that restriction of fetal growth in 11beta-HSD2(-/-) mice is mediated, at least in part, via altered placental transport of nutrients and reduction in placental vascularization.

Fetal programming is now recognized as a key determinant of the adult phenotype, with major implications for adult-onset diseases including hypertension. Two mediators of fetal programming are maternal nutrition and fetal glucocorticoid exposure. Recent studies show that postnatal dietary manipulations can exacerbate programming effects, but whether programming effects can be attenuated by postnatal dietary manipulations, and thus provide a possible therapeutic strategy, is unknown. In this study, we tested the hypothesis that a postnatal diet enriched with long-chain omega-3 fatty acids attenuates programmed hyperleptinemia and hypertension. Pregnant rats were treated with dexamethasone (Dex) from d 13 to term, and offspring were cross-fostered to mothers on either a standard diet or a diet high in omega-3 fatty acids and remained on these diets postweaning. Maternal Dex reduced birthweight and delayed the onset of puberty in offspring. Hyperleptinemia (associated with elevated leptin mRNA expression in adipose tissue) and hypertension were evident in offspring by 6 months of age in Dex-exposed animals consuming a standard diet, but these effects were completely blocked by a high omega-3 diet. These results demonstrate for the first time that manipulation of postnatal diet can limit adverse outcomes of fetal programming, with programmed hyperleptinemia and hypertension prevented by a postnatal diet enriched with omega-3 fatty acids. This raises the possibility that dietary supplementation with omega-3 fatty acids may provide a viable therapeutic option for preventing and/or reducing adverse programming outcomes in humans.

Epidemiology formed the basis of 'the Barker hypothesis', the concept of 'developmental programming' and today's discipline of the Developmental Origins of Health and Disease (DOHaD). Animal experimentation provided proof of the underlying concepts, and continues to generate knowledge of underlying mechanisms. Interventions in humans, based on DOHaD principles, will be informed by experiments in animals. As knowledge in this discipline has accumulated, from studies of humans and other animals, the complexity of interactions between genome, environment and epigenetics, has been revealed. The vast nature of programming stimuli and breadth of effects is becoming known. As a result of our accumulating knowledge we now appreciate the impact of many variables that contribute to programmed outcomes. To guide further animal research in this field, the Australia and New Zealand DOHaD society (ANZ DOHaD) Animals Models of DOHaD Research Working Group convened at the 2nd Annual ANZ DOHaD Congress in Melbourne, Australia in April 2015. This review summarizes the contributions of animal research to the understanding of DOHaD, and makes recommendations for the design and conduct of animal experiments to maximize relevance, reproducibility and translation of knowledge into improving health and well-being.

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Abstract-Fetal glucocorticoid excess leads to subsequent adult hypertension, but the mechanisms involved in this developmental programming remain largely unknown. In this study we tested the hypothesis that programmed hypertension in rats is linked to altered renal expression of the glucocorticoid receptor, mineralocorticoid receptor, and 11␤-hydroxysteroid dehydrogenase type 2 and components of the intrarenal and adipose renin-angiotensin system. The interactive effects of a postnatal diet enriched in omega-3 fatty acids, which prevents emergence of the hypertensive phenotype, were also examined. Maternal dexamethasone (0.75 g/mL of drinking water from day 13 to term) markedly increased renal expression of the glucocorticoid receptor in 6-month-old offspring, and this was associated with hypomethylation of the glucocorticoid receptor promoter; renal MR was unaffected. In contrast, maternal dexamethasone reduced renal 11␤-hydroxysteroid dehydrogenase type 2 in offspring, but this effect was prevented by a high omega-3 diet. Consistent with these effects, renal Na/K-ATPase-␣1 was elevated in offspring of dexamethasone-treated mothers, but only in those raised on the standard diet. Maternal dexamethasone also programmed increased expression of renal and adipose angiotensin-converting enzyme and renal renin, but among these changes, only that of renal angiotensin-converting enzyme was prevented by the omega-3 diet. Our data support the hypothesis that programmed hypertension is mediated, in part, by increased renal glucocorticoid sensitivity, with consequent stimulatory effects on Na/K-ATPase-␣1 and intrarenal renin-angiotensin system components. Partial prevention of programmed changes in renal gene expression by postnatal dietary omega-3 fatty acids provides insight into how this intervention prevents hypertension induced by fetal glucocorticoid excess. Key Words: prenatal programming Ⅲ hypertension Ⅲ glucocorticoids Ⅲ 11␤-hydroxysteroid dehydrogenase type 2 Ⅲ renin-angiotensin system Ⅲ kidney Ⅲ omega-3 fatty acids D evelopmental programming is now recognized as a key determinant of the adult phenotype, most notably in relation to regulation of blood pressure, insulin sensitivity, and adiposity. 1 Thus, fetal insults, such as undernutrition or glucocorticoid excess, can lead to adult hypertension and insulin resistance, but the mechanisms underlying such programming outcomes remain largely unknown. 2,3 Moreover, the severity of the programmed phenotype can be either reduced or exacerbated by the postnatal environment. Specifically, adult hypertension programmed by fetal undernutrition is worsened by a hypercaloric diet in postnatal life, 4 whereas we recently reported that hypertension programmed by maternal dexamethasone treatment is prevented when offspring are raised on a diet enriched with omega-3 (n-3) fatty acids. 5 This rescue of the programmed phenotype is consistent with the well-recognized, beneficial effects of dietary n-3 fatty acids in relation to human hypertension. 6 Interestingly, hyperleptinemia ...

Fetal glucocorticoid exposure is a key mechanism proposed to underlie prenatal ‘programming’ of adult affective behaviours such as depression and anxiety. Indeed, the glucocorticoid metabolising enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which is highly expressed in the placenta and the developing fetus, acts as a protective barrier from the high maternal glucocorticoids which may alter developmental trajectories. The programmed changes resulting from maternal stress or bypass or from the inhibition of 11β-HSD2 are frequently associated with alterations in the hypothalamic-pituitary-adrenal (HPA) axis. Hence, circulating glucocorticoid levels are increased either basally or in response to stress accompanied by CNS region-specific modulations in the expression of both corticosteroid receptors (mineralocorticoid and glucocorticoid receptors). Furthermore, early-life glucocorticoid exposure also affects serotonergic and catecholamine pathways within the brain, with changes in both associated neurotransmitters and receptors. Indeed, global removal of 11β-HSD2, an enzyme that inactivates glucocorticoids, increases anxiety- and depressive-like behaviour in mice; however, in this case the phenotype is not accompanied by overt perturbation in the HPA axis but, intriguingly, alterations in serotonergic and catecholamine pathways are maintained in this programming model. This review addresses one of the potential adverse effects of glucocorticoid overexposure in utero, i.e. increased incidence of affective behaviours, and the mechanisms underlying these behaviours including alteration of the HPA axis and serotonergic and catecholamine pathways.

Foetal growth restriction (FGR), reflective of an adverse intrauterine environment, confers a significantly increased risk of perinatal mortality and morbidity. In addition, low birthweight associates with adult diseases including hypertension, metabolic dysfunction and behavioural disorders. A key mechanism underlying FGR is exposure of the foetus to glucocorticoids which, while critical for foetal development, in excess can reduce foetal growth and permanently alter organ structure and function, predisposing to disease in later life. Foetal glucocorticoid exposure is regulated, at least in part, by the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which catalyses the intracellular inactivation of glucocorticoids. This enzyme is highly expressed within the placenta at the maternal-foetal interface, limiting the passage of glucocorticoids to the foetus. Expression of 11β-HSD2 is also high in foetal tissues, particularly within the developing central nervous system. Down-regulation or genetic deficiency of placental 11β-HSD2 is associated with significant reductions in foetal growth and birth weight, and programmed outcomes in adulthood. To unravel the direct significance of 11β-HSD2 for developmental programming, placental function, neurodevelopment and adult behaviour have been extensively investigated in a mouse knockout of 11β-HSD2. This review highlights the evidence obtained from this mouse model for a critical role of feto-placental 11β-HSD2 in determining the adverse programming outcomes.