The epigenetic impact of in utero opioid exposure on Generation Z

子宫内阿片类药物暴露对 Z 世代的表观遗传影响

基本信息

批准号：
9182548
负责人：
Ruth Landau Cahana
金额：
$ 8万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9182548
关键词：
Abstinence Accounting Admission activity Adult Behavioral Biological Assay Birth CYP2D6 gene Case-Control Studies Cessation of life Characteristics Child Childhood Chronic Clinical Congenital Abnormality DNA DNA Methylation Data Development Diagnosis Disease Dose Drug Addiction Epidemic Epigenetic Process Evaluation Exposure to Fetus Foundations Future Gene Expression Gene Expression Regulation Generations Genes Genetic Genetic Polymorphism Genetic screening method Genotype Gestational Age Goals Hair Health Hepatitis Hospitalization Hyperalgesia Immunization Individual Infant Length Life Liquid Chromatography Long-Term Effects Longitudinal Studies Maintenance Meconium Medicine Metabolism Methods Methylation Mothers Narcotics Neonatal Neonatal Abstinence Syndrome Neonatal Intensive Care Units Newborn Infant Opiate Addiction Opioid Outcome Pain Pathway interactions Perinatal Exposure Pharmaceutical Preparations Pharmacodynamics Pharmacogenetics Phenotype Pilot Projects Predisposition Pregnancy Pregnancy Tests Pregnant Women Premature Birth Process Public Health Regimen Research Risk Safety Saliva Sampling Testing Time Woman addiction base chronic pain cohort design drug withdrawal epigenetic marker genetic predictors genetic variant genome wide methylation improved in utero innovation insight methylation pattern neonatal exposure neonatal outcome neonate opiate tolerance opioid misuse opioid use pain behavior postnatal prevent promoter pyrosequencing response tandem mass spectrometry

项目摘要

Project Summary An alarming rise in opioids prescribed for pain relief during pregnancy has resulted in an increasing number of neonatal intensive care unit (NICU) admissions for neonatal drug withdrawal, also called neonatal abstinence syndrome (NAS). Evidence that these NAS babies are more likely to become ‘addicted’ later in life has emerged in recent years. Although the exact mechanism has not been identified, there is robust evidence that DNA methylation is altered in individuals taking chronic opioids, and polymorphisms and DNA methylation of OPRM1 promoter have recently been shown to influence NAS outcomes. Our hypothesis is that in utero opioid exposure results in epigenetic processes with potentially long term clinical consequences for the fetus/child such as an increased vulnerability to develop an ‘opioid (mis)use disorder’. The rationale for the proposed pilot project is that evaluation of DNA methylation in neonates exposed in utero to opioids will lay the foundation to study the relationship between DNA methylation and other epigenetic processes with specific pain behaviors during childhood and drug addiction later in life. In this pilot exploratory longitudinal case-control study we will evaluate the impact of maternal opioid use for pain relief during pregnancy and consequent prolonged in utero opioid exposure in cases (20 mothers on prescribed opioids for pain relief and their neonate) and controls (20 unexposed mothers/babies). Maternal opioid exposure will be quantified using Liquid Chromatography– Tandem Mass Spectrometry at delivery (hair), and neonatal chronic exposure will be evaluated on meconium and hair samples at birth, and again at 2 months (hair). We propose 3 specific aims: (1) compare neonatal outcomes (NAS outcomes & pain during immunization in particular) between exposed vs unexposed babies, (2) assess neonatal DNA methylation patterns (OPRM1 & COMT promoters, LINE-1) at birth and 2 months and (3) evaluate opioid metabolism and genetic predictors (CYP2D6/3A4, OPRM1 & COMT) of neonatal outcomes and NAS management. Such an approach is innovative as repeated DNA methylation assays in neonates evaluating behavioral and pain phenotypes after in utero opioid exposure have not been undertaken and may (a) provide key insight into the mechanisms/pathways underlying opioid tolerance and drug addition, (b) help propose strategies to improve our ability to diagnose and treat opioid addiction and (c) prevent opioid exposure in individuals identified as being at risk for opioid dependence, tolerance and addiction due to genetic/epigenetic markers. Public Health Statement The proposed research is extremely timely because death from opioids prescribed for pain relief has become an epidemic in the U.S. causing 50 deaths every day and FDA’s recent safety announcement regarding risks associated with pain medicines use during pregnancy emphasizes the current ‘over- exposure’ to opioids in the U.S. Elucidating the long-term effects of in utero opioid exposure is key to further our understanding of the genetic and epigenetic contributions to opioid addiction, and potentially predict and prevent opioid misuse and chronic pain.

项目概要用于缓解怀孕期间疼痛的阿片类药物的惊人增加导致了因新生儿药物戒断（也称为新生儿药物戒断）而入院的新生儿重症监护病房 (NICU) 数量证据表明这些 NAS 婴儿更有可能出现新生儿戒断综合症 (NAS)。近年来出现了晚年“上瘾”的现象，尽管确切的机制尚不清楚。已确定，有强有力的证据表明 DNA 甲基化存在于长期服用阿片类药物的个体中，最近显示 OPRM1 启动子的多态性和 DNA 甲基化会影响我们的假设是，子宫内阿片类药物暴露会导致表观遗传过程。对胎儿/儿童可能产生长期的临床后果，例如更容易受到感染拟议试点项目的基本原理是评估“阿片类药物（滥用）使用障碍”。子宫内接触阿片类药物的新生儿的 DNA 甲基化将为研究这种关系奠定基础 DNA甲基化与儿童时期特定疼痛行为的其他表观遗传过程之间的关系在这项试点探索性纵向病例对照研究中，我们将评估母亲在怀孕期间使用阿片类药物缓解疼痛以及由此导致的宫内阿片类药物持续时间延长的影响病例暴露（20 名服用阿片类药物缓解疼痛的母亲及其新生儿）和对照（20 将使用液相色谱法对母亲的阿片类药物暴露进行量化—— 将评估分娩时的串联质谱（头发）和新生儿慢性暴露出生时以及 2 个月时再次采集胎便和毛发样本（毛发）。我们提出 3 个具体目标：(1)。比较暴露组之间的新生儿结局（特别是 NAS 结局和免疫期间的疼痛）与未暴露的婴儿相比，(2) 评估新生儿 DNA 甲基化模式（OPRM1 和 COMT 启动子， LINE-1) 出生时和 2 个月，(3) 评估阿片类药物代谢和遗传预测因子（CYP2D6/3A4， OPRM1 和 COMT) 的新生儿结局和 NAS 管理是创新的。对新生儿进行重复 DNA 甲基化检测，评估子宫内后的行为和疼痛表型尚未进行阿片类药物暴露，并且可能 (a) 提供有关阿片类药物暴露的重要见解阿片类药物耐受性和药物添加的机制/途径，(b) 帮助提出策略提高我们诊断和治疗阿片类药物成瘾的能力，并 (c) 防止个人接触阿片类药物被确定因遗传/表观遗传而面临阿片类药物依赖、耐受和成瘾的风险标记。公共卫生声明这项拟议的研究非常及时，因为用于缓解疼痛的阿片类药物导致的死亡已经在美国成为一种流行病，每天造成 50 人死亡，FDA 最近的安全公告关于怀孕期间使用止痛药的相关风险强调了当前的“过度使用” 阐明在子宫内阿片类药物暴露的长期影响是关键进一步加深我们对阿片类药物成瘾的遗传和表观遗传贡献的理解，并可能预测和预防阿片类药物滥用和慢性疼痛。