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
基本信息
- 批准号:10231039
- 负责人:
- 金额:$ 49.69万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:ABCB1 geneABCG2 geneAddressAlcoholsAnimalsBrainCYP1A1 geneCannabinoidsCannabisCathetersCellsCessation of lifeDataDevelopmentDoseDrug KineticsEngineeringEnzymesEthicsExposure toFetal LiverFetal ResorptionFetal TissuesFetal safetyFetusFutureGoalsHealthHumanIn VitroInhalationIntestinesLiteratureLiverLow Birth Weight InfantMacacaMarijuanaMaternal ExposureMeasurementMedicineMetabolicMetabolismModelingMusOrganOutcomePatient Self-ReportPerfusionPharmaceutical PreparationsPharmacologyPlacentaPlasmaPregnancyPregnant WomenPublic HealthRandomized Clinical TrialsRandomized Controlled TrialsReview LiteratureRiskRodentSubstance of AbuseSystemTHC concentrationTHC exposureTestingTetrahydrocannabinolTissuesTobaccoToxic effectUmbilical veinUnited States National Academy of SciencesWeightWeight GainWorkbasedevelopmental toxicitydosagedrug of abusefetalhuman datain uteroin vivoinnovationmalemarijuana usemarijuana use in pregnancymaternal marijuana usemodels and simulationmouse modelneonatal outcomeneurotoxicityperinatal outcomesphysiologically based pharmacokineticspregnantprenatalprenatal exposurepupsubstance usetrophoblast
项目摘要
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.
美国孕妇的大麻使用量正在增加。然而,我们还不知道这种使用是否安全
对胎儿来说。美国国家科学、工程和科学研究院最近的一篇综合文献综述
医学发现大量证据表明怀孕期间吸食大麻与低出生有关
体重,但与产前、围产期或新生儿结局有关的其他健康问题的证据有限
怀孕期间吸食大麻。然而,他们指出了审查研究的一些局限性,如
依靠自我报告来确定大麻的接触情况、大麻的不同效力、剂量和时机
暴露,检测许多结果的统计能力有限,以及大麻暴露因使用
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,
动物研究表明,胎儿暴露于Δ-9-四氢大麻酚(THC)中,
丰富的具有精神活性的大麻素,导致出生体重降低,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的增殖和分化。然而,大多数
在高剂量或不能使用或不能使用的浓度下进行体外研究。
在人类身上观察到的,因此获得的数据不能用于预测人类毒性。还有,胎儿
母体使用大麻后的血浆/组织THC浓度尚不清楚。
考虑到人类观察、动物和体外研究的局限性,确定
需要探讨胎儿在怀孕期间接触大麻和使用大麻的风险。这个P01的总体目标是
通过体外创新预测母婴暴露于THC及其精神活性代谢物11-OH-THC
以及通过基于母体-胎儿-生理的药代动力学(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,以告知THC/11的胎儿神经毒性-
哦,这可能会导致长期的后遗症。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,这是本项目(项目1)的重点。以文学为基础
数据和我们的初步研究,我们假设胎盘P-gp、BCRP和CyP1A1协同作用
调节胎儿对THC/11-OH-THC的暴露。为了验证这一假设,项目1将表征THC/11-OH-
THC在相关的母体器官(肠和肝脏)、胎盘和胎儿组织中的代谢和运输。至
验证胎盘中的外排转运体是否参与THC/11-OH-THC的胎盘转运,我们还将
在小鼠模型上进行体外人胎盘灌流和体内母体/胎儿药代动力学研究。
这些研究解决了我们在了解THC/11-OH-THC代谢和运输方面的一个关键差距
并将向项目2和项目3提供数据,以预测母婴暴露于
THC/11-OH-THC通过PBPK M&S生成的数据也将通知未来相关动物和
体外毒性研究以评估THC/11-OH-THC的胎儿毒性和长期发育毒性。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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QINGCHENG MAO其他文献
QINGCHENG MAO的其他文献
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{{ truncateString('QINGCHENG MAO', 18)}}的其他基金
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 - 财政年份:2013
- 资助金额:
$ 49.69万 - 项目类别:
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:
10463603 - 财政年份:2013
- 资助金额:
$ 49.69万 - 项目类别:
Placental P-gp/BCRP in fetal drug exposure and regulation by hormones/xenobiotic
胎盘 P-gp/BCRP 在胎儿药物暴露和激素/异生素调节中的作用
- 批准号:
9277440 - 财政年份:
- 资助金额:
$ 49.69万 - 项目类别:
Placental P-gp/BCRP in fetal drug exposure and regulation by hormones/xenobiotic
胎盘 P-gp/BCRP 在胎儿药物暴露和激素/异生素调节中的作用
- 批准号:
9069784 - 财政年份:
- 资助金额:
$ 49.69万 - 项目类别:
Placental P-gp/BCRP in fetal drug exposure and regulation by hormones/xenobiotic
胎盘 P-gp/BCRP 在胎儿药物暴露和激素/异生素调节中的作用
- 批准号:
8470410 - 财政年份:
- 资助金额:
$ 49.69万 - 项目类别: