Effects of maternal cortisol on fetal and neonatal growth and metabolism

描述（由申请人提供）：母体皮质醇浓度通常在妊娠期增加2-3倍。母体皮质醇水平似乎影响胎儿骨骼和内脏的生长。我们以前的数据显示，无论是增加或减少母体皮质醇水平的母羊胎儿生长减少，与临床报告，无论是肾上腺皮质功能减退，阿狄森氏病，或肾上腺皮质功能亢进，库欣综合征，结果在小于胎龄儿。在这些研究中，我们将使用妊娠晚期的妊娠绵羊来测试与母体皮质醇对胎儿生长以及对母体、胎儿和新生儿代谢的影响有关的几个假设。将使用三组母羊：1）正常完整对照母羊，2）切除肾上腺并用皮质醇替代至正常妊娠水平一半但与正常非妊娠母羊相似的母羊，3）输注皮质醇至正常血浆浓度两倍的母羊（相对于对照妊娠母羊）。我们提出了两组研究，以确定对母体和胎儿生理学以及新生儿生理学的影响。我们将检验这样一个假设：母体皮质醇的减少主要通过减少母体的体积扩张、母体心输出量和子宫胎盘血流量的正常增加来改变胎儿的生长和代谢，这对妊娠晚期胎儿的生长加速至关重要，其次是通过减少母体的食物摄入量和母体及胎儿的葡萄糖浓度。我们还将检验相关假设，即这些变化导致新生儿胎儿器官重量成比例减少，脂肪量减少，脂肪组织和肝脏中IGF-I表达减少。我们还将检验以下假设：与对照组相比，这些胎儿的胎儿肾上腺成熟将略微加速，导致分娩略微提前;我们还将检验以下假设：在相对肾上腺皮质功能减退的母羊所生的羔羊中，出生后葡萄糖增加会导致胰岛素反应受损。在平行实验中，我们将测试的假设，增加母体皮质醇，类似于那些由慢性应激产生的，不产生负面影响子宫胎盘血流量，但导致骨骼生长的IGF水平的影响减少，并会导致器官生长的器官特异性变化和生长相关的基因在内脏。我们还将检验这一假设，即增加喂养这些母羊，结合增加母体皮质醇将导致增加母体和胎儿的葡萄糖浓度，增加肥胖，但降低新生儿的葡萄糖和皮质醇浓度在出生后的第一个月内，并降低葡萄糖耐量。

DESCRIPTION (provided by applicant): Maternal cortisol concentrations are normally increased by 2-3 fold in pregnancy. Maternal cortisol levels appear to affect fetal skeletal and visceral growth. Our previous data show reduced growth in fetuses of ewes with either increased or decreased maternal cortisol levels, consistent with clinical reports that either hypoadrenocorticism, Addison's disease, or hyperadrenocorticism, Cushing's syndrome, results in small for gestational age infants. In these studies we will use pregnant sheep in late gestation to test several hypotheses relating to effects of maternal cortisol on fetal growth and on maternal, fetal, and neonatal metabolism. Three groups of ewes will be used: 1) normal intact control ewes, 2) ewes that are adrenalectomized and replaced with cortisol to levels half that of normal pregnancy, but similar to those of normal nonpregnant ewes, 3) ewes infused with cortisol to double normal plasma concentrations relative to the control pregnant ewes. We propose two sets of studies to determine effects on both maternal and fetal physiology, and on neonatal physiology. We will test the hypothesis that reductions in maternal cortisol alter fetal growth and metabolism primarily by reducing maternal volume expansion, and the normal increases in maternal cardiac output and uteroplacental blood flow that are essential for acceleration of fetal growth in the late gestation, and secondarily, by reducing maternal food intake and maternal and fetal glucose concentrations. We also will test the related hypothesis that these changes result in a neonate with proportionate reduction in weight of fetal organs, reduced fat mass and reduced IGF-I expression in adipose tissue and liver. We will also test the hypothesis that fetal adrenal maturation will be slightly accelerated in these fetuses, resulting in slightly earlier delivery as compared to the control groups, and we will test the hypotheses that there will be an impaired insulin response to increases in glucose postnatally in the lambs born of ewes with relative hypoadrenocorticism. In parallel experiments, we will test the hypothesis that increases in maternal cortisol, similar to those produced by chronic stress, do not negatively impact uteroplacental blood flow, but result in reduction in skeletal growth by affects on IGF levels, and will cause organ-specific changes in organ growth and in growth-related genes in the viscera. We also will test the hypothesis that increased feeding in these ewes, in combination with increased maternal cortisol will result in increased maternal and fetal glucose concentrations, with increased adiposity, but reduced neonatal glucose and cortisol concentrations in the period immediately following birth, and reduced glucose tolerance in the first month of life.