PBPK prediction and verification of maternal-fetal exposure to cannabinoids

美国孕妇对大麻(大麻)的使用正在增加，流行率高达14% 在12-18岁的孕妇中。美国妇产科学院建议 孕妇避免吸食大麻是因为有证据表明它会影响胎儿并可能干扰大脑 发展。对动物的研究似乎支持这一建议。虽然其他成分 大麻不能打折，普遍的科学共识是∆9-四氢大麻酚(Thc)， 大麻中最丰富和最具精神活性的成分，可能是发育的肇事者 大麻的神经毒性。THC可在妊娠和妊娠期间失调大麻素受体1信号转导 会导致不良后果，如胎儿大脑发育受损、出生体重降低、体重增加 胎儿吸收，甚至宫内死亡。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 在精神分裂症患者中观察到。然而，这些啮齿动物和体外研究是在高剂量下进行的。 或浓度，因此它们对人体的适用性，那里的血浆浓度低于 微摩尔，是未知的。由于许多原因，对使用 关于怀孕期间使用大麻是否安全，大麻并不能提供信息。由于 以上所有方法的局限性，我们在这里提出一种系统药理学的方法来开始 解决这一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，我们 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 在口服和吸入(吸烟)大麻后，代谢物11-OH-THC在整个怀孕期间。 为此，我们将改进和推广一种新的基于母胎生理的药代动力学(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 大麻类化合物产生的任何分子特征都表明对小鼠的发育神经毒性短期或长期 人类。我们的方法使用了新颖和创新的工具(例如m-f-PBPK模型、开发 吸入性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