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.

妊娠中外源剂量的母体糖皮质激素（GC）与胎盘的性别特异性，胎儿生长限制以及结构性和功能变化有关，胎盘的结构和功能变化可能会对受影响个体的健康（胎儿编程）产生终生影响。在动物和人类研究中都描述了适应子宫内部环境改变环境的性别特异性策略。我们在绵羊的动物研究中表明，作为母体困扰的模型，早期的母体地塞米松（DEX）疗法并没有导致雄性胎儿的生长限制，而在雌性胎儿中，DEX治疗导致短暂的生长减少。在女性的适应性策略中，特别是关于胎盘的分布和功能，胎儿HPA轴活动和产后应力反应性的观察到了DEX治疗。尽管在女性胎儿中，保持恒定的胎盘GC敏感性，可能是根据确保生殖能力和物种保护的优先生存策略来维持的，但似乎由于GC暴露增加而导致的雄性胎儿，胎盘至少暂时耐GC。我们了解内源性GC和/或过度暴露于外源性GC会影响胎儿和胎盘发育始于糖皮质激素受体（GR）及其同工型，应在拟议的研究中检查。已经描述了8种以上不同的GR-异型，并怀疑不同的剪接变体具有不同的生物学活性或对生理刺激的反应。我们怀疑对GC的性别特异性敏感性与GRA的不同GR分布，表达和/或相互作用有关，作为转导刺激GR与其他胎盘GR同工型，并且母体DEX暴露会影响这些参数。因此，我们提出了对绵羊（OVIS ARIE）的研究，以性别和胎盘特异性鉴定和胎盘特异性鉴定和定位的目的，以及对胎儿和胎盘发育的生理功能的评估，作为性别特异性GC抗性的可能机制。将分子和参数与与胎儿和围产期结局有关的多元相关性进行比较。将使用皮质醇结合测定法研究功能性GR-抗性。关于GR在胎儿编程和对机制的范式见解的性别适应策略以及在人群和个人的编程错误中如何发展的有价值的信息。