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

胎盘编程 - 妊娠早期地塞米松治疗对胎盘和胎儿卵巢发育的影响。

• 批准号: 145880571
• 负责人: Privatdozent Dr. Thorsten Braun
• 金额: --
• 依托单位: Klinik für Geburtsmedizin (CVK)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/145880571?language=en
• 关键词: Placental; programming; effects; dexamethasone; treatment

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.

孕期外源性剂量的母体糖皮质激素(GC)与特定性别、胎儿生长受限以及胎盘结构和功能的变化有关，这可能对受影响个人的健康产生终身影响(胎儿计划)。在动物和人类的研究中，都描述了适应子宫内环境变化的特定性别策略。我们在绵羊上的动物研究表明，早期母体地塞米松(DEX)治疗作为母体窘迫的模型，不会导致男性胎儿生长受限，而在女性胎儿中，DEX治疗会导致一过性生长减退。在女性中，观察到了对地塞米松治疗的适应策略，特别是关于胎盘的分布和功能、胎儿HPA轴的活动和出生后的应激反应。在女性胎儿中，胎盘对GC的敏感性保持不变，这可能是为了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暴露的增加，胎盘至少暂时变得对GC有抵抗力。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)及其亚型，并应在拟议的研究中进行检查。目前已经描述了8种不同的GR亚型，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。我们怀疑GR的性别敏感性与GR的分布、表达和/或相互作用的不同有关，因为转导刺激GR与其他胎盘GR亚型不同，母亲暴露于地塞米松会影响这些参数。因此，我们建议在绵羊(Ovis Aries)中进行研究，目的是对胎盘GR亚型进行性别和胎盘特异性鉴定和定位，并评估GR亚型在胎儿和胎盘发育中的生理功能，作为性别特异性GC抵抗的可能机制。分子和参数正在与与胎儿和围产儿结局有关的多变量相关性进行比较。功能性GR抗性将通过皮质醇结合试验进行研究。关于GR在胎儿编程的性别特异性适应策略中的作用以及对该机制的典型洞察，以及在人群和个人中如何发生编程错误的有价值的信息，是值得期待的。