Understanding Fetal Exposure to Cannabinoids Through In Vitro and In Vivo Studies

通过体外和体内研究了解胎儿接触大麻素的情况

• 批准号: 10688223
• 负责人: QINGCHENG MAO
• 金额: $ 45.27万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10688223
• 关键词: ABCB1 gene; ABCG2 gene; Address; Alcohols; Animals; Brain; CYP1A1 gene; Cannabinoids; Cannabis; Catheterization; Cells; Cessation of life; Data; Development; Dose; Drug Kinetics; Engineering; Enzymes; Ethics; Exposure to; Fetal Liver; Fetal Resorption; Fetal Tissues; Fetal safety; Fetus; Future; Goals; Health; Human; In Vitro; Inhalation; Intestines; Literature; Liver; Low Birth Weight Infant; Macaca; Marijuana; Maternal Exposure; Measurement; Medicine; Metabolic; Metabolism; Microsomes; Modeling; Mus; Organ; Outcome; Patient Self-Report; Perfusion; Perinatal; Pharmaceutical Preparations; Pharmacology; Placenta; Plasma; Pregnancy; Pregnant Women; Proliferating; Public Health; Randomized, Controlled Trials; Recreation; Review Literature; Risk; Rodent; Substance of Abuse; System; THC concentration; THC exposure; Testing; Tetrahydrocannabinol; Tissues; Tobacco; Toxic effect; Transfection; Umbilical vein; United States National Academy of Sciences; Weight; Work; developmental toxicity; dosage; drug of abuse; fetal; human data; in utero; in vivo; innovation; long-term sequelae; male; marijuana use; marijuana use in pregnancy; maternal marijuana use; models and simulation; mouse model; neonatal outcome; neurotoxicity; physiologically based pharmacokinetics; placental transfer; pregnant; prenatal; prenatal exposure; pup; randomized, clinical trials; substance use; trophoblast

Marijuana (cannabis) use by pregnant women in the US is increasing. Yet, we do not know if this use is safe for the fetus. A recent comprehensive literature review by the National Academy of Sciences, Engineering and Medicine found substantial evidence of an association between marijuana use during pregnancy and lower birth weight, but only limited evidence of other health problems related to prenatal, perinatal or neonatal outcomes of marijuana use during pregnancy. However, they noted a number of limitations of the reviewed studies such as reliance on self-reporting to ascertain marijuana exposure, the varying potency, dosage and timing of marijuana exposure, limited statistical power to detect many outcomes, and marijuana exposure confounded by the use of other substances namely tobacco and alcohol. To understand fetal safety of marijuana use during pregnancy, animal studies were conducted and showed that fetal exposure to Δ9-tetrahydrocannabinol (THC), the most abundant and psychoactive cannabinoid, caused lower birth weight, increased fetal resorption and even in utero deaths in animals. THC also inhibits human placental trophoblast proliferation and differentiation. However, most of the animal and in vitro studies were conducted with high THC doses or concentrations that cannot be used or observed in humans and therefore the data obtained cannot be used to predict human toxicity. Also, fetal plasma/tissue THC concentrations, after maternal marijuana use, are unknown. Given the limitations of human observational, animal and in vitro studies, alternative approaches to determine fetal exposure and risks of marijuana use during pregnancy need to be explored. The overall goals of this P01 are to predict maternal-fetal exposure to THC and its psychoactive metabolite 11-OH-THC through innovative in vitro and in vivo studies integrated through maternal-fetal-Physiologically Based Pharmacokinetic (m-f-PBPK) modeling and simulations (M & S) and conduct exploratory studies that will inform fetal neurotoxicity of THC/11- OH-THC that could result in long-term sequelae. To achieve these goals, it is imperative that we first understand factors that determine fetal exposure to THC/11-OH-THC, the focus of this project (Project 1). Based on literature data and our preliminary studies, we hypothesize that placental P-gp, BCRP and CYP1A1 work in tandem to modulate fetal exposure to THC/11-OH-THC. To test this hypothesis, Project 1 will characterize THC/11-OH- THC metabolism and transport in relevant maternal organs (intestine and liver), placenta and fetal tissues. To verify if efflux transporters in the placenta are involved in trans-placental transfer of THC/11-OH-THC, we will also perform ex vivo human placental perfusion and in vivo maternal/fetal pharmacokinetic studies in mouse models. These studies address a critical gap in our understanding of THC/11-OH-THC metabolism and transport clearances in humans and will provide data to Projects 2 & 3 to allow prediction of maternal-fetal exposure to THC/11-OH-THC through PBPK M & S. Data generated by this project will also inform future relevant animal and in vitro toxicity studies to assess fetal and long-term developmental toxicity of THC/11-OH-THC.

美国孕妇使用大麻的情况正在增加。然而，我们不知道这种使用是否安全 为了胎儿美国国家科学院、工程院和 医学发现大量证据表明怀孕期间使用大麻与低出生率之间存在关联 体重，但只有有限的证据表明，其他健康问题有关的产前，围产期或新生儿的结果， 怀孕期间使用大麻然而，他们注意到审查研究的一些局限性， 依靠自我报告来确定大麻的暴露，大麻的不同效力，剂量和时间 暴露，有限的统计能力，以检测许多结果，大麻暴露混淆使用 其他物质，即烟草和酒精。为了了解怀孕期间使用大麻对胎儿的安全性， 进行了动物研究，结果表明，胎儿暴露于Δ9-四氢大麻酚（THC）， 丰富的和精神活性的大麻素，导致出生体重较低，增加胎儿吸收，甚至在子宫内 动物死亡。THC还抑制人胎盘滋养层细胞增殖和分化。但大多数 的动物和体外研究用不能使用的高THC剂量或浓度进行， 在人体中观察到，因此获得的数据不能用于预测人体毒性。此外，胎儿 母亲使用大麻后的血浆/组织THC浓度是未知的。 考虑到人类观察、动物和体外研究的局限性， 需要探讨胎儿接触大麻的情况和怀孕期间使用大麻的风险。本P01的总体目标是 通过创新的体外实验预测母胎对THC及其精神活性代谢物11-OH-THC的暴露 和通过基于母体-胎儿生理学的药代动力学（m-f-PBPK）整合的体内研究 建模和模拟（M & S），并进行探索性研究，将告知THC/11的胎儿神经毒性- OH-THC可能导致长期后遗症。为了实现这些目标，我们必须首先了解 决定胎儿接触THC/11-OH-THC的因素，这是该项目的重点（项目1）。基于文献 数据和我们的初步研究，我们假设胎盘P-gp、BCRP和CYP 1A 1协同工作， 调节胎儿暴露于THC/11-OH-THC。为了验证这一假设，项目1将表征THC/11-OH- THC在母体相关器官（肠和肝脏）、胎盘和胎儿组织中的代谢和转运。到 验证胎盘中的外排转运蛋白是否参与THC/11-OH-THC的经胎盘转移，我们还将 在小鼠模型中进行离体人胎盘灌注和体内母体/胎儿药代动力学研究。 这些研究解决了我们对THC/11-OH-THC代谢和运输的理解中的一个关键空白 并将为项目2和3提供数据，以预测母胎接触 THC/11-OH-THC通过PBPK M & S。该项目产生的数据也将为未来的相关动物和 体外毒性研究，以评估THC/11-OH-THC的胎儿和长期发育毒性。