Impact of maternal marijuana use on epigenetic regulation of offspring neurodevelopment

母亲吸食大麻对后代神经发育的表观遗传调控的影响

• 批准号: 10705157
• 负责人: Jamie Lo
• 金额: $ 52.5万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705157
• 关键词: Address; Affect; Attention deficit hyperactivity disorder; Behavior; Behavioral; Binding; Brain; Cannabinoids; Chronic; Cognition; Corpus striatum structure; Data; Development; Disease; Drug Addiction; Early Intervention; Environmental Exposure; Epigenetic Process; Fetal Development; Fetal Growth; Gene Expression Regulation; Goals; Health; High Prevalence; Infant; Inflammatory; Lactation; Life; Link; Maps; Marijuana; Mediating; Modeling; Modification; Molecular; Morbidity - disease rate; Outcome; Placenta; Play; Pregnancy; Psychotropic Drugs; Regulation; Risk; Role; Secondary to; Signal Transduction; THC exposure; Tetrahydrocannabinol; Tissue Sample; Tissues; Woman; addiction; autism spectrum disorder; behavioral study; cannabinoid receptor; cognitive disability; drug of abuse; early childhood; early screening; epigenetic regulation; fetal; fetal marijuana exposure; fetus nutrition; histone modification; illicit drug use; imaging capabilities; imaging study; in utero; in vivo; in vivo imaging; innovation; insight; marijuana use; maternal marijuana use; neurodevelopment; nonhuman primate; novel; offspring; postnatal; pregnant; prenatal; response; reward processing; transcriptomics; translational impact; transmission process; trying to conceive

PROJECT SUMMARY Marijuana is now the most commonly used illicit drug in pregnancy. The main psychoactive compound of marijuana, delta-9-tetrahydrocannabinol (THC), can access and bind to cannabinoid receptors in the placenta and fetal brain. Preliminary data suggest that prenatal cannabinoid exposure results in epigenetic changes in the placenta and brains of exposed offspring. This is concerning because the placenta plays a key role in fetal growth and development by mediating fetal nutrition, oxygenation, inflammatory signaling, and transmission of maternal environmental exposures. Compromises to placental function can adversely affect brain development. Epigenetic responses to maternal marijuana use likely result in molecular alterations in gene regulation of offspring developmental trajectories towards neurodevelopmental morbidity, including addiction, autism spectrum disorder, attention deficit hyperactivity disorder, and cognitive disabilities. Specifically, prenatal THC exposure is known to alter reward processing, by histone modification of ventral striatal dopaminergic signaling, affecting addiction vulnerability. However, a mechanistic link between maternal THC use and its impact on offspring epigenetic regulation of neurodevelopment is impeded by the lack of in vivo longitudinal assessment secondary to the limitations of current imaging capabilities and feasibility of tissue sampling. We propose to address this problem by defining a trajectory of perturbed epigenetic regulation following in utero THC exposure across fetal and early childhood brain and behavioral development. To this end, we will employ three innovative and complementary approaches using our novel, non-human primate model of chronic maternal THC use: 1) first-in-kind, longitudinal in vivo imaging of placental and fetal epigenetic regulation and development, 2) extensive postnatal assessment of infant cognition and behavior, and 3) sophisticated tissue studies confirming the role of epigenetic modifications in the imaging and behavioral studies. In summary, our study will interrogate the previously inaccessible mechanistic links underlying the impact of maternal marijuana use on fetal origins of health, disease and addiction risk. The successful completion of our study will result in 1) new insights into the impact of maternal THC use on the developing fetal and infant brain, 2) the impact of THC-induced epigenetic alterations on trajectories of offspring neurodevelopment and behavioral regulation 3) the creation of a comprehensive, longitudinal in vivo map of offspring epigenetic regulation of neurodevelopment from fetal life to early childhood, and 4) characterization of ex vivo epigenetic and transcriptomic assessments that can be used as a reference for other drugs of abuse and environmental exposures. This study has the potential for immediate translational impact, given the high prevalence of prenatal and postnatal marijuana use and limited data on longer-term offspring outcomes and contribution to drug addiction. The study’s ultimate goal is to provide appropriate guidance for women using marijuana who are trying to conceive, are pregnant, or are lactating, and for clinicians to consider early intervention and screening of offspring exposed prenatally to marijuana.

项目摘要 大麻现在是怀孕中最常用的非法药物。主要的心理活性化合物 大麻，Delta-9-四氢大麻酚（THC）可以访问并与plopeta中的大麻素受体结合 和胎儿大脑。初步数据表明，产前大麻素暴露会导致表观遗传变化 裸露后代的斑点和大脑。这很关注，因为Plopeta在胎儿中起关键作用 通过介导胎儿营养，氧合，炎症信号传导和传播来生长和发育 产妇环境暴露。妥协对位置功能可能会对大脑发育产生不利影响。 对母体大麻使用的表观遗传反应可能导致基因调节的分子改变 后代发育轨迹朝着神经发育发病率，包括成瘾，自闭症 频谱障碍，注意力缺陷多动障碍和认知障碍。具体而言，产前THC 已知暴露是通过腹侧纹状体多巴胺能信号的组蛋白修饰来改变奖励处理的， 影响成瘾脆弱性。但是，母体THC使用及其对其影响之间的机械联系 缺乏体内纵向评估阻碍了神经发育的后代表观遗传调节 其次是当前成像能力的局限性和组织采样的可行性。我们建议 通过在子宫暴露中定义扰动表观遗传调节的轨迹来解决此问题 跨越胎儿和幼儿的大脑以及行为发展。为此，我们将采用三种创新 并使用我们的新型非人类私人模型的慢性材料使用：1） 胎盘和胎儿表观遗传学调节与发育的最初，纵向体内成像，2） 对婴儿认知和行为的大量产后评估，以及3）复杂的组织研究证实 表观遗传修饰在成像和行为研究中的作用。总而言之，我们的研究将讯问 以前无法访问的机械联系是产妇大麻对胎儿起源的影响的基础 健康，疾病和成瘾风险。我们的研究的成功完成将导致1）对 母体THC使用对发育中的胎儿和婴儿大脑的影响，2）THC诱导的表观遗传学的影响 对后代神经发育和行为法规的轨迹的改变3）创建 从胎儿生命到神经发育的后代表观遗传调节的全面的，纵向的体内图 幼儿和4）可以使用的体内表观遗传学和转录组的表征 作为其他滥用和环境暴露药物的参考。这项研究有可能立即 鉴于产前和产后大麻使用的高流行率，并且对 长期的后代结果和对吸毒成瘾的贡献。该研究的最终目标是提供 适当的指导妇女使用试图怀孕，怀孕或正在哺乳的大麻的妇女 临床医生可以考虑早期干预和筛查在产前暴露于大麻的后代。

项目成果

Cannabis Use and Perinatal Health-Reply.

大麻使用和围产期健康回复。

• DOI: 10.1001/jama.2023.23239
• 发表时间: 2024
• 期刊: JAMA
• 作者: Lo,JamieO;Hedges,JasonC;Metz,TorriD
• 通讯作者: Metz,TorriD

Cannabis Use in Pregnancy and Neonatal Outcomes: A Systematic Review and Meta-Analysis.

大麻在妊娠和新生儿结局中的使用：系统评价和荟萃分析。

• DOI: 10.1089/can.2022.0262
• 发表时间: 2024
• 期刊: Cannabis and cannabinoid research
• 影响因子: 3.8
• 作者: Lo,JamieO;Shaw,Beth;Robalino,Shannon;Ayers,ChelseaK;Durbin,Shauna;Rushkin,MeganC;Olyaei,Amy;Kansagara,Devan;Harrod,CurtisS
• 通讯作者: Harrod,CurtisS

Impact of Prenatal Cannabis Use Disorder on Perinatal Outcomes.

产前大麻使用障碍对围产期结局的影响。

• DOI: 10.1097/adm.0000000000001123
• 发表时间: 2023
• 期刊: Journal of addiction medicine
• 影响因子: 5.5
• 作者: Prewitt,KristinC;Hayer,Sarena;Garg,Bharti;Benson,AshleyE;Hedges,MadelineA;Caughey,AaronB;Lo,JamieO
• 通讯作者: Lo,JamieO

Expectant management of preterm premature rupture of membranes at 34 weeks: a cost effectiveness analysis.

• DOI: 10.1080/14767058.2021.2017874
• 发表时间: 2022-12
• 期刊: JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE
• 影响因子: 1.8
• 作者: Powell, Jacqueline M.;Frank, Zoe C.;Clark, Grace, V;Lo, Jamie O.;Caughey, Aaron B.
• 通讯作者: Caughey, Aaron B.