Identification of Epigenetic Biomarkers Associated with Prenatal Exposure to Substances of Abuse

项目摘要 产前药物使用仍然是一个重大的公共卫生问题，具有明确的后果 在新生儿时期确定的健康问题和出生时确定的其他健康后果， 度过青春期烟草和酒精仍然是最经常使用的物质， 怀孕，其次是大麻，甲基苯丙胺，鸦片和可卡因。的估计 全国药物使用和健康调查表明，超过5%的孕妇使用 一种或多种非法物质。产前接触滥用物质不仅会导致 新生儿戒断综合征（NAS）和出生时的其他并发症，但也可能导致 青少年神经行为和认知发育障碍的数量。后生 机制，包括DNA甲基化，提供了产前暴露之间的机制联系， 和产前期后的健康后果。基因组的改变 产前发育，由于环境暴露于毒素或药物，可以诱导持久的 表观遗传学的变化，可以诱导胎儿的生理变化。虽然多项研究 已经建立了与产前接触烟草相关的独特甲基化特征 和酒精，没有关于产前暴露影响的人类表观遗传学研究报告 非法药物对胎儿表观基因组的影响以及这些干扰如何影响随后的 发展后果。研究以了解表观遗传倾向导致 从药物暴露和识别生物标志物的具体到每种物质是必要的， 确定受影响的新生儿并制定有效的治疗干预措施。第一阶段提案将 是第一个评估新生儿全表观基因组甲基化特征的研究， 已知在子宫内暴露于滥用物质，确定特定的甲基化位点， 显著区别于未暴露的对照组，并检查与出生的相关性 新生儿结局，包括NAS的严重程度。DNA甲基化的差异模式 将在第二阶段研究中进行检查，以检查胎儿 暴露于非法药物，暴露新生儿与健康对照组的甲基化模式， NAS严重程度和婴儿成熟时的发育结果。我们的长期目标是 检查已确定的表观遗传变化与 与产前接触非法药物有关的发育障碍。建立一个 使用新生儿血斑检测胎儿暴露于非法药物的表观遗传生物标志物， 比目前的筛查方法更有益，因为它能够在非常早期预测胎儿损伤。 时间点允许及时诊断和早期干预。

PROJECT SUMMARY Prenatal substance use remains a significant public health concern, with defined consequences established in the neonatal period and additional health consequences identified at birth and through adolescence. Tobacco and alcohol remain the most frequently used substances during pregnancy, followed by marijuana, methamphetamine, opiates and cocaine. Estimates from the National Survey on Drug Use and Health suggest that over five percent of pregnant women use one or more illicit substances. Prenatal exposure to substances of abuse can not only cause neonatal abstinence syndrome (NAS) and other complications at birth, but can also lead to a number of neurobehavioral and cognitive developmental disabilities in adolescence. Epigenetic mechanisms, including DNA methylation, provide a mechanistic link between prenatal exposure and health consequences following the prenatal period. Alterations to the epigenome during prenatal development, due to environmental exposure to toxins or drugs, can induce lasting epigenetic changes that can induce physiological changes to the fetus. While multiple studies have already established unique methylation signatures related to prenatal exposure to tobacco and alcohol, there are no reported human epigenetic studies on the impact of prenatal exposure to illicit drugs on the fetal epigenome and how these perturbations impact subsequent developmental consequences. Research to understand the epigenetic predisposition resulting from drug exposures and identification of biomarkers specific to each substance is necessary to identify affected neonates and tailor effective treatment interventions. This Phase I proposal will be the first study to evaluate whole epigenome methylation signatures from newborns with known exposure to substances of abuse in utero, identify specific methylation sites that are significantly differentiated from non-exposed controls, and examine the correlation with birth outcomes in newborns including severity of NAS. The differential patterns of DNA methylation identified will be examined in a Phase II study to examine the correlation between fetal exposure to illicit drugs, methylation patterns in exposed newborns versus healthy controls, NAS severity, and developmental outcomes as the infants mature. Our long-term goal is to examine a correlation between identified epigenetic changes and an increased risk of the developmental disabilities associated with prenatal exposure to illicit drugs. Establishment of an epigenetic biomarker of fetal exposure to illicit drugs using neonatal blood spots would be more beneficial than current screening methods in its ability to predict fetal damage at a very early time point allowing for prompt diagnosis and early intervention.