Endocrine Abstracts (2012) 28 S9.3

The fetus or the placenta? Targets of glucocorticoid programming

Megan Holmes, Caitlin Wyrwoll & Jonathan Seckl

Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.

Prenatal exposure to excess glucocorticoids may be causal in programming mood disorders in later life. In support of this hypothesis, maternal stress, treatment during pregnancy with dexamethasone (which crosses the placenta) or inhibitors of feto-placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), the physiological ‘barrier’ to maternal glucocorticoids, reduces birth weight and programmes offspring cardio-metabolic and affective behaviours. The enzyme 11β-HSD2 appears key to prenatal glucocorticoid programming, but it is expressed in both the placenta and the developing fetal brain, raising the questions: What is the site of 11β-HSD2 expression that is the most important? Secondly, where are the glucocorticoids acting to initiate the programmed effects? By comparing fetal and placental growth of fetal units resulting from crossing 11β-HSD2+/− mice (which produce +/+, +/− and −/− offspring), we demonstrated that placental and fetal growth is inversely correlated with the level of protection from maternal glucocorticoids provided by 11β-HSD2 and is independent of maternal influence. Decreased 11β-HSD2 activity resulted in decreased growth and function of the placenta, delayed growth of the brain and modified developmental expression of key glucocorticoid-regulated genes, which resulted in elevated anxiety and depressive-like behaviour in later life. Hence, placental 11β-HSD2 rather than only protecting the fetus from actions of high glucocorticoid levels, also protects the placental structure and function. However, elevated glucocorticoids in the absence of 11β-HSD2, also affect fetal and postnatal brain development. Here we present evidence from tissue-specific 11β-HSD2 knockouts, that delineates the role of 11β-HSD2 in the brain versus the placenta and provides mechanistic insight to glucocorticoid programming of affective behaviours.

Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding: Declaration of Funding: This work was supported by the Wellcome Trust (Grant number WT 079009).

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