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

与产前接触滥用物质相关的表观遗传生物标志物的鉴定

• 批准号: 10325100
• 负责人: Aileen Estelle Baldwin
• 金额: $ 25.09万
• 依托单位: U.S. DRUG TESTING LABORATORIES, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10325100
• 关键词: Adolescence; Adult; Affect; Alcohols; Animals; Behavioral; Biological Assay; Biological Markers; Birth; Blood; Child; Cocaine; Cognitive; DNA; DNA Methylation; DNA analysis; Development; Developmental Disabilities; Diagnosis; Disease susceptibility; Drug Exposure; Drug usage; Early Intervention; Embryonic Development; Enrollment; Environmental Exposure; Epigenetic Process; Exhibits; Exposure to; Fetal Development; Fetus; Genetic Screening; Genome; Goals; Health; Human; Illicit Drugs; Incidence; Infant; Intervention; Laboratories; Lead; Life; Link; Marijuana; Methamphetamine; Methods; Methylation; Modification; Mothers; Neonatal; Neonatal Abstinence Syndrome; Newborn Infant; Opioid; Outcome; Pattern; Pharmaceutical Preparations; Phase; Phenotype; Physiological; Population; Predisposition; Pregnancy; Pregnant Women; Program Development; Property; Public Health; Reporting; Research; Risk; Sampling; Scanning; Severities; Site; Spottings; Substance of Abuse; Surveys; Teratogens; Testing; Time; Tissue Sample; Tobacco; Toxicology; Toxin; Umbilical cord structure; United States; alcohol exposure; base; biomarker identification; bisulfite; critical period; drug testing; effective therapy; epigenetic marker; epigenome; fetal; fetal drug exposure; fetal substance exposure; human study; illicit drug use; in utero; medical specialties; methylation pattern; minimally invasive; neonatal period; neonate; neurobehavioral; phase 1 study; phase 2 study; prenatal; prenatal exposure; prenatal health; pyrosequencing; research and development; screening; specific biomarkers; substance use; tobacco exposure; toxicant; whole genome

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.

项目总结 产前药物使用仍然是一个重大的公共卫生问题，其后果是明确的 在新生儿期建立和在出生时确定的其他健康后果 一直到青春期。烟草和酒精仍然是年内最常用的物质。 怀孕，其次是大麻、甲基苯丙胺、鸦片和可卡因。据估计， 全国药物使用与健康调查显示，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 新生儿禁欲综合征(NAS)和出生时的其他并发症，但也可导致 青春期神经行为和认知发育障碍的数量。表观遗传 包括DNA甲基化在内的机制在产前暴露之间提供了一种机械联系 以及产前后的健康后果。表观基因组的变化 由于暴露在环境中的毒素或药物，产前发育可能导致持久的 能引起胎儿生理变化的表观遗传变化。虽然多项研究 已经建立了与出生前接触烟草有关的独特甲基化特征 和酒精，目前还没有关于产前暴露影响的人类表观遗传学研究的报道 对胎儿表观基因组的非法药物以及这些扰动如何影响后续 发展后遗症。理解表观遗传易感性的研究 从药物暴露和识别每种物质的特定生物标记物是必要的 确定受影响的新生儿并量身定做有效的治疗干预措施。此第一阶段提案将 是第一个评估新生儿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 新生儿的结局包括NAS的严重程度。DNA甲基化的不同模式 将在第二阶段研究中检查确定的胎儿与 接触非法药物，暴露的新生儿与健康对照的甲基化模式， NAS的严重程度，以及婴儿成熟后的发育结果。我们的长期目标是 检查已识别的表观遗传学变化与增加的风险之间的相关性 与产前接触非法药物有关的发育障碍。设立一个 使用新生儿血点的胎儿暴露于非法药物的表观遗传生物标记物将更多 比目前的筛查方法更有利于在非常早的时候预测胎儿损伤 允许及时诊断和早期干预的时间点。