Impact of maternal marijuana use on epigenetic regulation of offspring neurodevelopment

项目总结 大麻现在是怀孕期间最常用的非法药物。主要的精神活性成分 大麻，德尔塔-9-四氢大麻酚(THC)，可以访问并结合胎盘中的大麻素受体 和胎儿的大脑。初步数据表明，出生前接触大麻类药物会导致 暴露的后代的胎盘和大脑。这是令人担忧的，因为胎盘在胎儿 通过调节胎儿营养、氧合、炎症信号和 母体暴露在环境中。胎盘功能受损会对大脑发育产生不利影响。 对母体使用大麻的表观遗传反应可能导致基因调控的分子变化 神经发育障碍的后代发育轨迹，包括成瘾、自闭症 谱系障碍、注意缺陷多动障碍和认知障碍。具体地说，产前THC 众所周知，暴露会改变奖赏过程，通过修改腹侧纹状体多巴胺能信号的组蛋白， 影响成瘾的易感性。然而，母体使用THC与其影响之间的机械联系 子代神经发育的表观遗传调控因缺乏体内纵向评估而受阻 其次，由于目前成像能力的限制和组织采样的可行性。我们建议 通过定义子宫内暴露后受扰动的表观遗传调控的轨迹来解决这个问题 胎儿和儿童早期的大脑和行为发育。为此，我们将聘请三名创新的 以及使用我们新的非人类灵长类慢性母体THC使用模型的补充方法：1) 首次对胎盘和胎儿表观遗传调控和发育进行体内纵向成像，2) 出生后对婴儿认知和行为的广泛评估，以及3)复杂的组织研究证实 表观遗传修饰在影像和行为研究中的作用。总而言之，我们的研究将询问 母体使用大麻对胎儿来源的影响以前无法触及的机械性联系 健康、疾病和成瘾风险。我们研究的成功完成将带来1)新的洞察力 母亲使用THC对胎儿和婴儿大脑发育的影响，2)THC诱导的表观遗传学的影响 子代神经发育轨迹的改变和行为调节3)建立一个 全面的、纵向的子代从胎儿到胚胎神经发育的表观遗传调控的体内图谱 儿童早期，以及4)可使用的体外表观遗传和转录评估的特征 作为其他滥用药物和环境暴露的参考。这项研究有可能立即 翻译影响，考虑到产前和出生后大麻使用的高流行率，以及关于 更长期的后代结果和对吸毒成瘾的贡献。这项研究的最终目标是提供 对正在尝试怀孕、怀孕或哺乳期使用大麻的妇女提供适当的指导，以及 供临床医生考虑对产前接触大麻的子女进行早期干预和筛查。

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.