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

妊娠期母体糖皮质激素（GC）的外源性剂量与性别特异性、胎儿生长限制以及胎盘的结构和功能变化有关，这可能对受影响个体的健康产生终身影响（胎儿编程）。在动物和人类研究中都描述了适应子宫内环境变化的性别特异性策略。我们在绵羊的动物研究中表明，作为母亲痛苦的模型，母体早期地塞米松（DEX）治疗不会导致男性胎儿的生长限制，而在女性胎儿中，DEX治疗会导致短暂的生长减少。在雌性动物中，我们观察了它们对DEX的适应策略，特别是在胎盘的分布和功能、胎儿HPA轴的活性和产后应激反应方面。而在女性胎儿中，胎盘对GC保持恒定的敏感性，可能是出于确保生殖能力和物种保护的优先生存策略，而在男性胎儿中，由于GC暴露增加，胎盘至少暂时具有GC抗性。我们对内源性GC和/或过度暴露于外源性GC如何影响胎儿和胎盘发育的理解始于糖皮质激素受体（GR）及其异构体，并应在提议的研究中进行检查。超过8种不同的gr -异构体已经被描述，不同的剪接变体被怀疑具有不同的生物活性或对生理刺激的反应性。我们怀疑性别特异性的GC敏感性与不同的GR分布、表达和/或GRa与其他胎盘GR异构体的相互作用有关，而母体的DEX暴露会影响这些参数。因此，我们建议在绵羊（卵巢）中进行研究，目的是对胎盘GR-异构体进行性别和胎盘特异性鉴定和定位，并评估GR-异构体对胎儿和胎盘发育的生理功能，作为性别特异性GC抗性的可能机制。分子和参数正在比较与胎儿和围产期结局的多变量相关性。功能性gr耐药性将通过皮质醇结合试验进行研究。期望获得关于GR在胎儿编程的性别特异性适应策略中的作用的有价值的信息，以及对群体和个体“编程错误”如何发展的机制的范例见解。

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.