Sex-dependent effects of prenatal alcohol exposure on developmental programming

项目总结 产前酒精暴露(PAE)与发育、认知、行为和身体有关 这些异常被称为胎儿酒精谱系障碍(FASD)。患病率从2/100到5/100不等 儿童和患有FASD的个人每年估计增加2.1万美元的费用，旨在进行治疗 治疗FASD将具有显著的社会效益。我们的目标是通过 哪种酒精会改变发育中的胎儿，并利用这一信息推进有针对性的干预 扭转或减少PAE的长期后果。 PAE是生物体发展的“程序”，产生的变化可以贯穿整个生命周期。在……里面 在许多情况下，PAE的作用是由糖皮质激素(GC)通过糖皮质激素受体介导的 (GRS)，并受生物体性别的影响。我们假设PAE改变了子宫内的 由于PAE对以下方面的不同影响，以针对性别和发展的方式拟订GRS方案 胎盘和胎儿大脑水平的11个β-hsd1和11个β-hsd2，它们催化活性和 不活跃的GC，以及2。)长的非编码RNA生长停滞特异性5(Gas5)，它与GR DNA结合- 结合结构域，抑制GR依赖基因表达。这些研究将确定PAE对 MicroRNA介导的调节GR编程的机制。此外，我们评估了胎盘的作用 外切体作为PAE对胎脑Gas5影响的介体。PAE的作用机制研究进展 胎盘11β-HSD、Gas5和外切体可用于识别1。)用于酒精鉴定的生物标志物 人类怀孕期间的消费，2.)子代结局的预测因子，以及3.)新的目标是 FASD的治疗。

PROJECT SUMMARY Prenatal alcohol exposure (PAE) is associated with developmental, cognitive, behavioral, and physical abnormalities termed Fetal Alcohol Spectrum Disorders (FASD). With a prevalence ranging from 2 to 5 in 100 children and an estimated added annual cost of $21,000 for an individual afflicted with FASD, therapies aimed at treating FASD will be of significant societal benefit. Our goal is to identify molecular mechanisms through which alcohol alters the developing fetus and to use this information to advance targeted interventions that reverse or reduce the long-term consequences of PAE. PAE “programs” development of the organism, producing changes that can persist throughout the lifespan. In many cases, the effects of PAE are mediated by glucocorticoids (GCs) acting via glucocorticoid receptors (GRs) and are influenced by the sex of the organism. We hypothesize that PAE modifies the in utero programming of GRs in a sex- and development-specific manner as the result of differential effects of PAE on placental and fetal brain levels of 1.) 11β-HSD1 and 11β-HSD2, which catalyze interconversion of active and inactive GC, and 2.) the long noncoding RNA Growth arrest-specific 5 (Gas5), which binds to the GR DNA- binding domain, inhibiting GR-dependent gene expression. These studies will identify effects of PAE on microRNA-mediated mechanisms that regulate GR programming. Additionally, we assess the role of placental exosomes as mediators of the effects of PAE on fetal brain Gas5. Elucidation of the effects of PAE on placental 11β-HSDs, Gas5 and exosomes may serve to identify 1.) biomarkers for identification of alcohol consumption during human pregnancy, 2.) predictors of progeny outcomes, and 3.) novel targets for the treatment of FASDs.