Understanding the effects of moderate vs. heavy chronic maternal marijuana exposure in a non-human primate model

项目总结 大麻是怀孕期间最常用的非法药物，它与死产有关， 胎盘血流动力学异常和胎儿神经发育后果。然而，中国的文学作品 人类是有限的和相互冲突的；大多数研究是观察性的或回溯性的，并且严重混乱。 由于滥用多种药物和自我报告的偏见。然而，动物模型可以允许进行实验 标准化，最大限度地减少混杂因素，以及主题可变性。以前对啮齿动物和兔子的研究 在1960-1980年代进行的研究提供了一些关于胎盘吸收、分布、胎盘转移、 历史上较低剂量大麻有效成分的代谢和排泄(Delta-9- 四氢大麻酚(THC)。鉴于产前大麻的使用正变得越来越普遍， 显著增强效力，了解产前使用大麻对胎盘的纵向影响 胎儿在体内的药代动力学和结局对于建立证据驱动的建议是至关重要的 怀孕期间使用的安全性。我们团队在建立非人类灵长类动物(NHP)方面拥有丰富的经验 孕妇不良行为的怀孕模式，并拥有建立国家健康保险计划的基础设施和专业知识 标准化产前大麻暴露模型。因为NHP有一个妊娠期，大麻血浆 与人类相似的性情和发育个体发育，包括他们的胎盘结构和 对于胎儿发育而言，NHP是一种适合人类状况的翻译模型。我们建议研究 妊娠期长期、中度与重度接触大麻的影响 当代NHP模式。这一拟议的NHP模型将允许对孕妇、胎儿和 宫内胎盘组织，在人类，尤其是怀孕早期，直接测量是不可行的或合乎道德的 妊娠期间THC及其主要代谢物的水平。组织浓度将与 已知的母亲THC暴露的数量和时间，以确定生物利用度和代谢，通过 三个月，因为母体、胎儿和胎盘的生理学在整个怀孕过程中都会发生变化。此外，我们还将 使用先进的非侵入性体内成像方式，结合超声波和核磁共振技术， 大麻对胎盘血流和氧气供应的直接影响的功能评估。体内 磁共振成像将与体外研究相关联，以将胎盘不利灌注的程度和 氧合作用与胎盘组织损伤程度有关。产前纵向抽样将允许 组织药物浓度与体内成像和后成像检测到的胎盘功能改变的相关性 配对妊娠时间点的出生病理。最终，我们预计这项工作将产生高度- 高质量的母体-胎盘-胎儿药代动力学数据，这是在人类身上无法获得的，这对 产科医生促进对妇女在怀孕期间使用大麻进行适当咨询，并促进 设计未来更大规模的产前大麻研究，以研究其对儿童早期发育的影响。

PROJECT SUMMARY Marijuana is the most commonly used illicit drug in pregnancy, it has been associated with stillbirth, abnormal placental hemodynamics, and fetal neurodevelopmental consequences. However, the literature in humans is limited and conflicting; most studies are observational or retrospective and are heavily confounded by polysubstance abuse and self-reporting bias. Animal models, however, can allow for experimental standardization, minimization of confounders, and subject variability. Previous rodent and rabbit studies performed in the 1960-1980s have provided some information on the absorption, distribution, placental transfer, metabolism and excretion of lower historical doses of the active ingredient of marijuana (delta-9- tetrahydrocannabinol, THC). Given prenatal marijuana use is becoming more commonplace and the significant increase in potency, understanding the longitudinal effect of prenatal marijuana use on placental and fetal pharmacokinetics and outcomes in-vivo is vital to establish evidence-driven recommendations on the safety of use during pregnancy. Our group has extensive experience establishing non-human primate (NHP) pregnancy models of maternal adverse behavior and have the infrastructure and expertise to establish a NHP model of standardized prenatal marijuana exposure. As NHPs have a gestational term, marijuana plasma disposition, and developmental ontogeny similar to humans, including their placental structure and timing of fetal development, the NHP is a suitable translational model of human conditions. We propose to study the effects of chronic moderate versus heavy maternal marijuana exposure in pregnancy using a relevant and contemporary NHP model. This proposed NHP model will permit longitudinal sampling of maternal, fetal and placental tissue in-utero, not feasible or ethical in humans especially early in pregnancy, to directly measure levels of THC and its primary metabolites throughout gestation. Tissue concentrations will be correlated with known quantities and timing of maternal THC exposure to determine bioavailability and metabolism by trimester, since maternal, fetal and placental physiology changes throughout pregnancy. Additionally, we will use advanced, non-invasive, in-vivo imaging modalities, a combination of ultrasound and MRI techniques, for functional assessment of the direct effects of marijuana on placental perfusion and oxygen availability. In-vivo MR imaging will be correlated with in-vitro studies to link the degree of adverse placental perfusion and oxygenation with the extent of placental tissue damage. Antenatal longitudinal sampling would permit correlation of tissue drug concentrations with detected altered placental function on in-vivo imaging and post- natal pathology at matched gestational time points. Ultimately, we anticipate that this work will generate high- quality maternal-placental-fetal pharmacokinetic data, not achievable in humans, that is essential for obstetricians to facilitate appropriate counseling of women regarding marijuana use in pregnancy and facilitate the design for future larger prenatal marijuana studies to research the effects on early childhood development.