PBPK prediction and verification of maternal-fetal exposure to cannabinoids

美国孕妇使用大麻的比例正在上升，高达14%。 12-18岁的孕妇。美国妇产科学院建议 孕妇避免吸食大麻，因为有证据表明大麻会影响胎儿， 发展动物研究似乎支持这一建议。虽然其他成员 大麻不能打折扣，一般的科学共识是，109-四氢大麻酚（THC）， 大麻中最丰富和精神活性的成分，是发展的可能肇事者 大麻的神经毒性THC可以在怀孕期间失调大麻素受体1信号传导， 可能导致不良后果，如胎儿大脑发育受损，出生体重降低， 胎儿吸收甚至子宫内死亡THC可以影响发育中的小鼠胎脑中的轴突生长。 长期暴露于THC会导致雄性青春期小鼠的长期行为缺陷，类似于那些 在精神分裂症中观察到。然而，这些啮齿动物和体外研究是在高THC剂量下进行的。 或浓度，因此它们对人类的适用性，其中THC血浆浓度低于 微摩尔，未知。由于许多原因，在使用避孕药的孕妇中进行的观察性临床研究 大麻并不能说明怀孕期间使用大麻是否安全。由于 鉴于上述所有方法的局限性，我们在此提出一种系统药理学方法，开始 解决这个重大的公共卫生问题。通过本项目和项目1和项目2获得的数据， 将预测并验证母亲-胎盘-胎儿暴露于THC及其精神活性的程度 代谢物，11-OH-THC，在整个怀孕期间，口服和吸入（吸烟）使用大麻后。 为此，我们将完善和扩展一种新的基于母体-胎儿生理学的药代动力学（m-f-PBPK） 我们开发的模型。此外，我们将以探索性的方式确定这些 大麻素产生任何指示短期或长期发育神经毒性的分子特征， 人类我们的方法使用新颖和创新的工具（例如，m-f-PBPK模型， 吸入m-f-PBPK模型，定量靶向蛋白质组学，转录组学，蛋白质组学和 代谢组学）来解决一个引人注目的公共卫生问题。 1

Use of marijuana (cannabis) among pregnant women in the US is increasing with prevalence as high as 14% among 12–18 year old pregnant women. The American College of Obstetrics and Gynecology recommends that pregnant women avoid marijuana due to evidence that it affects the fetus and may interfere with brain development. Studies in animals appear to support this recommendation. Although other constituents of marijuana cannot be discounted, the general scientific consensus is that ∆9-tetrahydrocannabinol (THC), the most abundant and psychoactive component in marijuana, is the likely perpetrator of the developmental neurotoxicity of marijuana. THC can dysregulate cannabinoid receptor 1 signaling during pregnancy and can result in adverse outcomes such as impaired fetal brain development, lower birth weight, increased fetal resorption, and even in utero deaths. THC can impact axon growth in the developing mouse fetal brain. Chronic exposure to THC leads to long-term behavioral deficits in male adolescent mice, akin to those observed in schizophrenia. However, these rodent and in vitro studies were conducted at high THC doses or concentrations and therefore their applicability to humans, where THC plasma concentrations are sub- micromolar, is unknown. For many reasons, observational clinical studies in pregnant women who use marijuana are not informative as to whether marijuana is safe when used during pregnancy. Due to the limitations of all the above approaches, we propose here a systems pharmacology approach to begin to address this significant public health question. Through data obtained by this project and Projects 1 & 2, we will predict and then verify the magnitude of maternal-placental-fetal exposure to THC and its psychoactive metabolite, 11-OH-THC, throughout pregnancy, after both oral and inhalational (smoking) use of marijuana. To do so, we will refine and extend a novel maternal-fetal Physiologically Based PharmacoKinetic (m-f-PBPK) model we have developed. In addition, in an exploratory manner, we will determine whether these cannabinoids produce any molecular signatures indicative of short or long-term developmental neurotoxicity in humans. Our approach uses novel and innovative tools (e.g. m-f-PBPK model, development of an inhalational m-f-PBPK model, quantitative targeted proteomics, transcriptomics, proteomics and metabolomics) to address a compelling public health question. 1