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.

妊娠期母体糖皮质激素（GC）的外源性剂量与性别特异性、胎儿生长受限以及胎盘的结构和功能变化相关，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，早期母体地塞米松（DEX）治疗作为母体痛苦的模型，不会导致雄性胎儿的生长受限，而在雌性胎儿中，DEX治疗导致短暂的生长减少。在雌性中，观察到对DEX处理的适应策略，特别是关于胎盘的分布和功能、胎儿HPA轴活性和产后应激反应。虽然在雌性胎仔中保持恒定的胎盘GC敏感性，可能是为了确保生殖能力和物种保护的优先生存策略，但在雄性胎仔中，由于GC暴露增加，胎盘至少暂时具有GC抗性。我们了解内源性GC和/或外源性GC过度表达如何影响胎儿和胎盘发育始于糖皮质激素受体（GR）及其亚型，应在拟议的研究中进行检查。已经描述了超过8种不同的GR-同种型，并且怀疑不同的剪接变体具有不同的生物活性或对生理刺激的响应性。我们怀疑性别特异性的敏感性GC与不同的GR分布，表达和/或相互作用的GR α作为转导刺激GR与其他胎盘GR亚型和母体DEX暴露影响这些参数。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节特异性鉴定和定位，并评价GR-亚型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。分子和参数与胎儿和围产期结局的多变量相关性进行了比较。将采用皮质醇结合试验研究功能性GR抗性。有价值的信息GR的作用，胎儿编程和范式的机制，如何在人群和个人的编程错误的适应策略可能会发展，预期。