Development of an Epigenetic Biomarker for Prediction of Fetal Alcohol Spectrum D

项目摘要 在美国，产前酒精暴露是导致出生缺陷的主要可预防原因， 产生了一系列的神经行为和身体异常统称为 胎儿酒精谱系障碍（FASD）。早期干预和治疗方案已被 显示减少一些长期的不利影响，但这取决于识别 有胎儿损伤风险的儿童，在大多数情况下无法检测到。许多受影响的儿童 FASD没有表现出明显的产前酒精相关出生缺陷的身体迹象， 在及时和准确诊断方面带来了挑战。迫切需要掌握 开发生物标志物，可以检测婴儿严重暴露于酒精的整个过程 怀孕，特别是在第一个三个月，当胎儿的大脑最容易受到 致畸剂，以预测那些有神经行为和发育风险的人， 与FASD相关的残疾。产前酒精暴露已被证明会改变DNA 已知基因的甲基化模式在发育中发挥重要作用并有助于 胚胎发育异常，表明酒精相关的DNA改变 从新生儿血斑样本中鉴定出的甲基化图谱，可以用作酒精 新生儿中的生物标志物。结合美国药物测试实验室拥有的技术 开发用于检测血液中的直接乙醇生物标志物磷脂酰乙醇（PEth） 与产前酒精暴露相关的筛查表观遗传变化的点提供了一个 研究酒精暴露发生的新生物标志物的创新方法 这可能预示着胎儿损伤。第一阶段的目标是 项目是确定利用新生儿血斑筛查酒精诱导的 DNA甲基化改变，并确定这些表观遗传修饰是否与 检测PEth。差异甲基化的候选区域的选择将是 通过新生儿血斑样本DNA的全基因组甲基化扫描确定 从已知在子宫内接触酒精的婴儿中收集，并将其与未接触酒精的婴儿进行比较。 暴露的对照品。如果产前酒精暴露与一组定义的 差异甲基化的DNA位点，使用表观遗传标记检测的可行性， 新生儿将有胎儿损伤的风险，这些表观遗传模式可能 作为FASD的可能的预测生物标志物进行进一步检查。发展和 实施定量DNA甲基化筛选测定，以分析 在该I期研究中鉴定的差异甲基化将是II期研究的目标。

PROJECT SUMMARY Prenatal alcohol exposure is the leading preventable cause of birth defects in the United States, producing an array of neurological, behavioral and physical abnormalities collectively known as fetal alcohol spectrum disorders (FASD). Early intervention and treatment programs have been shown to reduce some of the long-term adverse effects, but this is dependent on identifying children at risk of fetal damage which is not detected in most cases. Many children affected by FASD do not exhibit obvious physical indications of prenatal alcohol-associated birth defects, creating challenges in making timely and accurate diagnoses. There is a critical need for development of biomarkers that can detect babies heavily exposed to alcohol throughout pregnancy, particularly during the first trimester when the fetal brain is most vulnerable to teratogens, to predict those at risk for developing the neurobehavioral and developmental disabilities associated with FASD. Prenatal alcohol exposure has been shown to alter DNA methylation patterns of genes known to play important roles in development and contribute to abnormal embryonic development, suggesting that alcohol-associated alterations in DNA methylation profiles, identified from neonatal blood spot samples, could be used as an alcohol biomarker in neonates. Coupling the technology United States Drug Testing Laboratories has developed for detection of the direct alcohol biomarker phosphatidylethanol (PEth) in blood spots with screening epigenetic changes associated with prenatal alcohol exposure provides an innovative approach to examine novel biological markers of alcohol exposure occurring throughout pregnancy that may be predictive of fetal damage. The objective of this Phase I project is to determine the feasibility of using neonatal blood spots to screen alcohol-induced DNA methylation alterations and establish whether these epigenetic modifications correlate with detection of PEth. The selection of candidate regions of differential methylation will be determined by whole-genome methylation scanning of DNA from neonatal blood spot samples collected from infants with known exposure to alcohol in utero and comparing them with non- exposed controls. If prenatal alcohol exposure is significantly associated with a defined set of differentially methylated DNA sites, the feasibility of using epigenetic markers to detect newborns at risk of fetal damage will have been established and these epigenetic patterns could be further examined as possible predictive biomarkers of FASD. Development and implementation of a quantitative DNA methylation screening assay, to analyze sites of differential methylation identified in this Phase I study, would be the goal of a Phase II study.