Placental programming - effects of dexamethasone treatment early in pregnancy on placenta and fetal development in ovis aries.

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Exogenous doses of maternal glucocorticoids (GC) in pregnancy are associated with sex-specific, fetal growth restriction and structural and functional changes in the placenta, which potentially can have life-long impact on health of the affected individual (fetal programming). Sex-specific strategies for adapting to a changed environment in utero have been described both in animal and in human studies. We have shown in our animal studies in sheep that early maternal dexamethasone (DEX) therapy, as a model for maternal distress, did not lead to growth restriction in male fetuses, whereas in female fetuses DEX treatment resulted in a transient growth reduction. In females adaptation strategies to DEX treatment were observed in particular with respect to the distribution and function of the placentomes, the fetal HPA axis activity and postnatal stress reactivity. While in female fetuses a constant placental GC sensitivity is maintained, possibly in terms of a preferential survival strategy for ensuring reproductive capacity and species conservation, it seems that in male fetuses due to increased GC exposure, the placenta becomes at least temporarily GC-resistant. Our understanding how endogenous GC and/or overexposure to exogenous GC can influence fetal and placental development begins with the glucocorticoid receptor (GR) and its isoforms and should be examined in the proposed study. More than 8 different GR-isoforms have been described and different splice variants are suspected to have a different biological activity or responsiveness to physiological stimuli. We suspect that the sex-specific sensitivity to GC are related to a different GR distribution, expression and/or interaction of GRa as transduction stimulating GR vs. other placental GR isoforms and that maternal DEX exposure influences those parameters. Therefore we propose studies in sheep (ovis aries) with the objective of sex- and placentome-specific identification and localization of placental GR-isoforms and the evaluation of the physiological function of the GR- isoforms for the fetal and placental development as a possible mechanism of gender-specific GC resistance. Molecular and parameters are being compared with multivariate correlation in relation to fetal and perinatal outcome. Functional GR-resistance will be investigated with a cortisol-binding assay. Valuable information on the role of GR for the sex-specific adaptation strategies of fetal programming and paradigmatic insights into the mechanisms, how in populations and individuals 'programming errors' may develop, are expected.