Prenatal marijuana: Impact on infant neurobehavior, stress, & epigenetic mechanisms

项目总结/摘要 大麻是美国孕妇最常使用的非法药物， 在12名赞成使用的孕妇中，贫穷、年轻、服务不足的母亲中的比例高达1/4。与 减少法律的和医疗制裁，增加可用性，并增加美国大麻的效力， 很有可能增加母亲使用和胎儿接触。据我们所知，目前没有 NIH资助的产前大麻使用和后代发育或人类的前瞻性人类研究 研究产前大麻与后代发育之间的生物学途径。我们会进行 关于母亲产前使用大麻对婴儿的具体影响的深入、前瞻性调查 神经行为，包括退缩的迹象，婴儿的应激反应，和表观遗传调节， 内源性大麻素和糖皮质激素途径。涉及前瞻性评估的核心方法 妊娠大麻使用者（使用≥ 2X/周）和烟草匹配的对照组（n = 125/组）， 妊娠，随后在2岁时对婴儿神经行为和应激反应进行发育敏感性测量 天，1和6个月。一个重要的创新是我们关注胎盘的表观遗传调控 内源性大麻素和糖皮质激素途径作为产前大麻和婴儿之间联系的介质 神经行为发育我们的研究还提供了许多创新，以确保严格性，包括一对一， 一个匹配的烟草使用在大麻和对照组，倾向建模方法， 允许因果推理，精确敏感的生物标志物和大麻暴露的综合分类， 对婴儿神经行为和应激反应进行复杂的、对发育敏感的测量， 衡量关键替代途径。我们的目的是：（1）描述母亲使用大麻的影响 对婴儿神经行为的影响，包括戒断症状，（2）描述产前大麻对 婴儿糖皮质激素应激反应在头6个月，（3）表征产前的影响， 大麻对胎盘糖皮质激素和内源性大麻素途径的表观遗传调节，以及（4）测试 提出了连接产前大麻和婴儿神经行为的胎盘表观遗传途径。据我们所知， 这项拟议的研究将是第一次全面调查产前使用大麻对妇女的影响。 婴儿神经行为发育以及关键的合理生物学途径。我们的研究与众不同， 其重点是一种非常普遍但研究不足的滥用药物和创新方法以及新的生物 由我们集团开创的道路。拟议研究的结果将为产科提供关键数据。 提供者和孕妇，并将告知政策，法规和公共卫生信息 关于孕妇和育龄妇女使用大麻的问题。结果也将阐明最早的 产前大麻暴露风险的生物标志物及其对确定新治疗靶点的意义 来保护暴露的后代

Project Summary/Abstract Marijuana (cannabis sativa) is the most commonly used illicit substance by pregnant women in the US, with 1 in 12 pregnant women endorsing use and rates as high as 1 in 4 in poor, young, underserved mothers. With decreasing legal and medical sanctions, increasing availability, and increasing potency of US cannabis, there is high potential for increasing maternal use and fetal exposure. To our knowledge, there are currently no NIH-funded prospective human studies of prenatal cannabis use and offspring development or human studies of biological pathways linking prenatal cannabis and offspring development. We will conduct an intensive, prospective investigation of the specific effects of maternal prenatal cannabis use on infant neurobehavior including signs of withdrawal, infant stress response, and epigenetic regulation of endocannabinoid and glucocorticoid pathways. Central methodology involving prospective assessment of pregnant cannabis users (use ≥ 2X/week) and a tobacco-matched comparison group (n=125/group) across gestation followed by developmentally-sensitive measures of infant neurobehavior and stress response at 2 days, 1 and 6 months. An important innovation is our focus on epigenetic regulation of placenta endocannabinoid and glucocorticoid pathways as mediators of links between prenatal cannabis and infant neurobehavioral development. Our study also offers numerous innovations to ensure rigor, including one-on- one matching for tobacco use across cannabis and comparison groups, a propensity modeling approach to allow causal inference, exquisitely sensitive biomarkers and integrative classification of cannabis exposure, sophisticated, developmentally-sensitive measures of infant neurobehavior and stress response, and measurement of key alternative pathways. Our aims are: (1) to characterize effects of maternal cannabis use on infant neurobehavior including signs of withdrawal, (2) to characterize the impact of prenatal cannabis on infant glucocorticoid stress response over the first 6 months, (3) to characterize the impact of prenatal cannabis on epigenetic regulation of placenta glucocorticoid and endocannabinoid pathways, and (4) to test proposed placenta epigenetic pathways linking prenatal cannabis and infant neurobehavior. To our knowledge, the proposed study would be the first comprehensive investigation of the impact of prenatal cannabis use on infant neurobehavioral development as well as key plausible biological pathways. Our study is distinguished by its focus on a highly prevalent but understudied drug of abuse and innovative methods and novel biological pathways pioneered by our group. Results from the proposed study will provide critical data for obstetric providers and pregnant women, and will inform policy, regulations, and public health messaging regarding cannabis use by pregnant and reproductive age women. Results will also elucidate the earliest biomarkers of risk from prenatal cannabis exposure, with implications for identifying novel therapeutic targets to protect exposed offspring.