THC effects on human implantation: role of trophoblast CB1

THC 对人体着床的影响：滋养层 CB1 的作用

• 批准号: 9224975
• 负责人: SUSAN J. FISHER
• 金额: $ 23.78万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9224975
• 关键词: 2-arachidonylglycerol; Admission activity; Agonist; Alcoholic Beverages; Amino Acids; Animal Model; Basic Science; Binding; Biological; Birth Rate; Blood; Blood Vessels; Blood flow; CNR1 gene; Cannabinoids; Cannabis; Cells; Chorionic villi; Congenital Abnormality; Consumption; Data; Decidua; District of Columbia; Dose; Drug usage; Economically Deprived Population; Endocannabinoids; Epithelium; Functional disorder; Genetic Transcription; Goals; Habitual Abortion; Health; Hormones; Human; Hypoxia; Immunoblotting; Impairment; In Vitro; Invaded; Knowledge; Label; Ligands; Low Birth Weight Infant; Marijuana; Maternal-Fetal Exchange; Medical; Messenger RNA; Molecular Target; Mothers; Mus; Natural Products; Neonatal Intensive Care; Outcome; Pathway interactions; Pharmaceutical Preparations; Physiological; Placenta; Placentation; Plasma; Play; Population; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnancy loss; Pregnant Women; Premature Birth; Production; Proteins; Psychotropic Drugs; Publishing; Reporting; Reproduction; Research Project Grants; Role; Sampling; Signal Transduction; Slice; Smoke; Spices; Surface; Surveys; Syncytiotrophoblast; System; THC receptor; Testing; Tetrahydrocannabinol; Tissues; Uterus; Woman; Work; anandamide; cell type; cytotrophoblast; endocannabinoid signaling; evidence base; experimental study; human data; implantation; insight; laser capture microdissection; marijuana legalization; marijuana use; organ growth; pregnancy disorder; premature; receptor; receptor binding; social; trophoblast; uptake

Abstract The goal of the proposed experiments is to test the hypothesis that Δ (9)-tetrahydrocannabinol (THC), the psychoactive compound in cannabis, impairs human cytotrophoblast (CTB) functions and that the negative consequences on trophoblast function are evident beginning at implantation. Nearly half the States and the District of Columbia have legalized marijuana for recreational or medical use. As a result, over 20 million people in the US report using this drug and the number is rapidly rising. In addition, synthetic THC derivatives with enhanced receptor binding profiles are widely available and gaining in popularity. Substantial numbers of pregnant women also use marijuana—2-30% of mothers depending on the subpopulation. Why are these numbers so high? Many women believe that marijuana, a natural product, is inherently safer than other drugs. Given the magnitude of marijuana use during pregnancy, relatively little is known about the impact on pregnancy. The strongest data are from studies of the endogenous signaling system in animal models. In the mouse, endocannabinoid levels, primarily via interactions with cannabinoid receptor 1 (CB1), govern outcomes, leading to the concept that anandamide (CB1 ligand) “tone” is an important component of the dialogue between the trophoblast and the uterus. In humans, dysregulated levels of endocannabinoid ligands and their receptors in plasma, trophoblast or decidua have been reported in the setting of spontaneous pregnancy loss and recurrent miscarriage. In line with these data, THC administration to mice impairs many aspects of pregnancy. In humans, the data suggest that marijuana use leads to higher rates of sillbirth, low birth weight, neonatal intensive care admissions and (variably) preterm birth. Recent data from our group might help explain this relationship. Global transcriptional profiling, confirmed by protein level data, showed that invasive cytotrophoblasts (CTBs) expressed CB1. As to function, we made the unexpected discovery that a CB1 agonist significantly increased CTB invasion, an unusual effect. In this context, we propose two Specific Aims. The goal of the first is to establish biologically effective doses of THC in early gestation CTBs. The goal of the second is to identify the molecular targets of CB1 ligands, including THC, in these cells. The proposed work will yield several important results. To date, only 3 published studies have investigated THC effects on the human placenta. Term samples were dosed in vitro and targeted analyses evaluated a limited number of endpoints. To fill this knowledge gap, we propose global transcriptional profiling of THC effects on early gestation CTBs, which will reveal effects on implantation and the formative early stages of pregnancy in which CTBs attach to, invade and remodel the uterus. Finally, this basic science research project has translational potential in terms of yielding information that enables evidence-based decisions regarding the use of marijuana (and synthetic THCs) during pregnancy. Additionally, CB1 agonists that increase CTB invasion could be useful for treating pregnancy disorders, such as preeclampsia, which are associated with shallow placentation.

摘要 所提出的实验的目标是检验Δ（9）-四氢大麻酚（THC）， 大麻中的精神活性化合物损害人类细胞滋养层（CTB）功能， 对滋养层功能的影响在植入时就开始显现。几乎一半的州和 哥伦比亚特区已经将娱乐或医疗用途的大麻合法化。结果，超过两千万的 在美国，人们报告使用这种药物，而且这个数字正在迅速上升。此外，合成THC衍生物 具有增强的受体结合特征的药物广泛可用并且越来越流行。相当数量的 孕妇也吸食大麻-根据不同的人群，占母亲的2-30%。为什么这些 数字如此之高？许多女性认为大麻是一种天然产品，本质上比其他药物更安全。 考虑到怀孕期间大麻使用的规模，对怀孕的影响知之甚少。 怀孕最有力的数据来自动物模型中内源性信号系统的研究。在 小鼠内源性大麻素水平，主要通过与大麻素受体1（CB 1）的相互作用，控制结果， 导致anandamide（CB 1配体）“音调”是对话的重要组成部分的概念 滋养层和子宫之间的联系在人类中，内源性大麻素配体及其代谢产物的水平失调， 据报道，在自然流产的情况下，血浆、滋养层或蜕膜中的受体 和反复流产与这些数据一致，对小鼠施用THC损害了小鼠的许多方面。 怀孕在人类中，数据表明，大麻的使用会导致更高的死胎率，低出生体重， 新生儿重症监护入院和早产。我们小组最近的数据可能有助于解释 这种关系通过蛋白质水平数据证实的全局转录谱显示， 细胞滋养层细胞（CTB）表达CB 1。至于功能，我们意外地发现CB 1 激动剂显著增加CTB侵袭，这是一种不寻常的作用。在这方面，我们提出两个具体目标。 第一个目标是在妊娠早期CTB中建立THC的生物有效剂量。的目标 第二是鉴定这些细胞中CB 1配体（包括THC）的分子靶点。拟议工作 将产生几个重要的结果。到目前为止，只有3项已发表的研究调查了THC对 人胎盘在体外对足月样本给药，并对有限数量的 端点。为了填补这一知识空白，我们提出了THC对早期乳腺癌的影响的全球转录谱， 妊娠CTB，这将揭示对着床和妊娠早期形成阶段的影响， CTB附着、侵入和重塑子宫。最后，本基础科学研究项目具有转化性 在产生信息方面的潜力，使有关大麻使用的循证决策成为可能 (and合成THC）。此外，增加CTB侵袭的CB 1激动剂可能是有用的。 用于治疗与浅胎盘有关的妊娠障碍，例如先兆子痫。