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

项目总结 在美国，产前酒精暴露是导致出生缺陷的主要可预防原因， 产生一系列神经、行为和生理异常，统称为 胎儿酒精谱系障碍(FASD)。早期干预和治疗计划一直是 显示可以减少一些长期的不良影响，但这取决于确定 儿童面临胎儿损伤的风险，这在大多数情况下是没有检测到的。许多儿童受到 FASD没有显示出明显的产前酒精相关出生缺陷的体征， 这给及时准确的诊断带来了挑战。迫切需要 开发可在整个过程中检测重度酒精暴露的婴儿的生物标志物 怀孕，尤其是在怀孕的前三个月，此时胎儿的大脑最容易受到 致畸物质，以预测那些有发展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 已知在发育过程中发挥重要作用并有助于 胚胎发育异常，表明与酒精相关的DNA变化 从新生儿血斑样本中鉴定出的甲基化特征可用作酒精 新生儿的生物标志物。结合美国药物检测实验室拥有的技术 用于检测血液中直接酒精生物标志物磷脂酰乙醇(PEH)的开发 筛查与产前酒精暴露相关的表观遗传学变化的斑点提供了 检测酒精暴露发生的新生物标志物的创新方法 在整个怀孕期间，这可能预示着胎儿的损伤。这一阶段的目标是 该项目是确定使用新生儿血斑来筛查酒精诱导的可行性 DNA甲基化改变，并确定这些表观遗传修饰是否与 佩斯的检测。差异甲基化的候选区域的选择将是 新生儿血斑DNA全基因组甲基化扫描检测 从已知在宫内接触酒精的婴儿中收集，并将他们与非 暴露的控件。如果产前酒精暴露与一组明确的 差异甲基化DNA位点，使用表观遗传标记检测 有胎儿损伤风险的新生儿将被确定，这些表观遗传模式可能 可进一步作为FASD的预测生物标志物。发展和 实施定量DNA甲基化筛查试验，以分析 在这项第一阶段研究中确定的差异甲基化将是第二阶段研究的目标。

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.