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

了解中度与重度慢性母体大麻暴露对非人类灵长类动物模型的影响

• 批准号: 10000192
• 负责人: Jamie Lo
• 金额: $ 8.75万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-22 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10000192
• 关键词: Abuse Reporting; Amniocentesis; Amniotic Fluid; Animal Model; Animals; Autopsy; Behavior; Biological Availability; Blood flow; Brain; Chorionic Villi Sampling; Chronic; Collection; Conflict (Psychology); Counseling; Data; Development; Dose; Drug Kinetics; Ethics; Excretory function; Exposure to; Fetal Development; Fetal Growth Retardation; Fetal Tissues; Frequencies; Functional disorder; Future; Growth; Hair; High Prevalence; Histologic; Human; Human Milk; Imaging Techniques; Impairment; In Vitro; Infrastructure; Ingestion; Legal; Link; Literature; Longitudinal Studies; Magnetic Resonance Imaging; Maintenance; Marijuana; Measures; Metabolism; Modeling; Neonatal; Nicotine; Observational Study; Oryctolagus cuniculus; Outcome; Oxygen; Pathology; Patient Self-Report; Perfusion; Pharmaceutical Preparations; Physiology; Placenta; Plasma; Pregnancy; Recommendation; Research; Research Design; Rodent; Role; Safety; Sample Size; Sampling; Serum; Standardization; Structure; Suggestion; THC concentration; THC exposure; Techniques; Testing; Tetrahydrocannabinol; Time; Tissue Sample; Tissues; Ultrasonography; Umbilical Cord Blood; Urine; Villous; Woman; Work; absorption; antenatal; cannabinoid receptor; design; early childhood; early pregnancy; electric impedance; experience; fetal; fetal marijuana exposure; healthy pregnancy; hemodynamics; human model; illicit drug use; imaging modality; in utero; in vivo; in vivo imaging; indexing; insight; marijuana use; marijuana use in pregnancy; maternal marijuana exposure; maternal marijuana use; neurodevelopment; non-invasive imaging; nonhuman primate; novel; placental transfer; polysubstance abuse; prenatal; response; stillbirth; translational model

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.

项目摘要 玛丽琳是怀孕期间最常用的非法药物，它与死胎有关， 异常的胎盘血流动力学和胎儿神经发育后果。然而， 人类是有限的和相互矛盾的;大多数研究是观察性的或回顾性的，并且严重混淆 滥用多种药物和自我报告偏见。然而，动物模型可以允许实验性的 标准化、混淆因素最小化和受试者变异性。先前的啮齿动物和家兔研究 在20世纪60 - 80年代进行的研究提供了一些关于吸收、分布、胎盘转移 代谢和排泄的较低的历史剂量的活性成分的大麻（δ-9- 四氢大麻酚，THC）。鉴于产前大麻的使用越来越普遍， 效力显着增加，了解产前大麻使用对胎盘的纵向影响 和胎儿体内药代动力学和结果对于建立关于 怀孕期间使用安全。我们的团队拥有建立非人灵长类动物（NHP）的丰富经验。 孕妇不良行为的怀孕模型，并有基础设施和专业知识，以建立一个国家卫生保健计划 标准化的产前大麻暴露模型。由于NHP有妊娠期，大麻血浆 性格，发育个体发生类似于人类，包括他们的胎盘结构和时间， 在胎儿发育中，NHP是人类状况的合适的转化模型。我们建议研究 使用相关的， 现代NHP模式这种拟议的NHP模型将允许对母体、胎儿和 子宫内胎盘组织，在人类中不可行或不符合伦理，尤其是在妊娠早期，直接测量 THC及其主要代谢物的水平。组织浓度将与 母亲THC暴露的已知量和时间，以确定生物利用度和代谢， 孕三个月，因为母体，胎儿和胎盘的生理变化在整个怀孕期间。此外，我们将 使用先进的、非侵入性的体内成像模式，结合超声和MRI技术， 大麻对胎盘灌注和氧可用性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，以将不良胎盘灌注的程度与 氧合与胎盘组织损伤程度的关系。纵向采样将允许 组织药物浓度与体内成像和术后检测到的胎盘功能改变的相关性 在匹配的妊娠时间点的纳塔尔病理学。最终，我们预计这项工作将产生高- 高质量的母体-胎盘-胎儿药代动力学数据，在人类中无法实现，这对于 产科医生为妇女提供有关怀孕期间吸食大麻的适当咨询，并促进 未来更大规模的产前大麻研究的设计，以研究对儿童早期发育的影响。