Developmental Toxicity of Cannabidiol and Δ9-Tetrahydrocannabinol

大麻二酚和α9-四氢大麻酚的发育毒性

• 批准号: 9371725
• 负责人: KRISTINE L WILLETT
• 金额: $ 20.54万
• 依托单位: UNIVERSITY OF MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9371725
• 关键词: Address; Adolescent; Adult; Adverse effects; Barker Hypothesis; Behavioral; Brain; Cannabidiol; Cannabinoids; Cannabis; Centers of Research Excellence; Chemicals; Child; Collaborations; Data; Defect; Deformity; Dependence; Development; Developmental Biology; Disease; Dose; Drug resistance; Early treatment; Embryo; Epilepsy; Etiology; Exposure to; Female; Fertility; Fertilization; Fishes; Formulation; Frequencies; Future; Gene Expression; Genes; Genomics; Germ Cells; Goals; Impairment; In Situ Hybridization; Knowledge; Larva; Legal; Life; Link; Measures; Mediating; Microscopy; Mississippi; Modeling; Molecular; Morphology; National Institute of Drug Abuse; Neurosecretory Systems; Organogenesis; Parents; Partner in relationship; Pathway interactions; Pharmaceutical Preparations; Phenotype; Physiology; Pregnancy loss; Quantitative Reverse Transcriptase PCR; Research; Research Support; Resistance; Seizures; THC exposure; Testing; Tetrahydrocannabinol; Therapeutic; Time; Tissue-Specific Gene Expression; Tissues; Toxic effect; Toxicology; Treatment Efficacy; United States National Institutes of Health; Universities; Work; Zebrafish; adverse outcome; clinically relevant; cost; design; developmental toxicity; drug development; early onset; exposed human population; insight; male; malformation; marijuana use; offspring; reproductive; reproductive success; reproductive toxicity; screening; sex; small molecule; social; sperm cell; toxicant; transcriptome sequencing; transcriptomics

Developmental Toxicity of Cannabidiol and Δ9-Tetrahydrocannabinol The University of Mississippi ABSTRACT The goal of this project is to compare the relative morphological, behavioral, reproductive and multigenerational phenotypes that result after developmental exposures to cannabidiol (CBD) and Δ9- tetrahydrocannabinol (THC). Due to relaxed prohibitions on marijuana use and therapeutic potential of cannabis constituents in the treatment of early-onset pharmaco-resistant epilepsy, exposure of children to these chemicals is increasing. CBD and/or mixtures containing it is now legal in 23 states for drug-resistant epilepsy. While CBD shows anecdotal efficacy in reducing seizure frequency, little is known about the potential adverse side-effects of cannabinoids on child physiology, brain development, adult disease, and/or F1 offspring. In this study we will leverage the advantages of the zebrafish model including high fecundity, low culture costs, transparent and conserved developmental biology and genomics. We will comprehensively assess phenotypic alterations caused by two developmental exposures (either during organogenesis or sexual differentiation) and mechanistically link the adverse outcomes with targeted and global transcriptomic analyses. This research will address the significant knowledge gap that exists related to adult and multigenerational behavioral and reproductive consequences of early life cannabinoid exposure. Using an adverse outcome pathway paradigm will allow us to rigorously differentiate the unique dose-, tissue-, sex- and developmental stage-dependent effects of CBD and THC and will provide insight into the molecular pathways underlying the morphological, behavioral and neuroendocrine/reproductive toxicities of cannabinoids. Importantly, this proposed project addresses the NIH emphasis on understanding the functional consequences of cannabis and cannabinoid exposures on the developing brain as outlined in PA-14-162.

大麻二酚和Δ 9-四氢大麻酚的发育毒性 密西西比大学 摘要 本项目的目标是比较相对形态，行为，生殖和 发育暴露于大麻二酚（CBD）和Δ 9- 四氢大麻酚（THC）。由于放松了对大麻使用和治疗潜力的禁令， 大麻成分在治疗早发性耐药性癫痫中的作用， 这些化学品的危害越来越大。CBD和/或含有它的混合物现在在23个州是法律的 治疗抗药性癫痫虽然CBD在减少癫痫发作频率方面显示出轶事般的功效， 已知大麻素对儿童生理、大脑、 发育、成年疾病和/或F1后代。在这项研究中，我们将利用 斑马鱼模型具有繁殖力高、养殖成本低、发育过程透明和保守等优点 生物学和基因组学。我们将全面评估由两种原因引起的表型改变， 发育暴露（无论是在器官发生或性别分化）和机制 将不良结果与目标和全球转录组学分析联系起来。这项研究将 解决与成人和多代人行为有关的重大知识差距 以及早期接触大麻素对生殖的影响。利用不利的结果 途径范例将使我们能够严格区分独特的剂量，组织，性别和 CBD和THC的发育阶段依赖性影响，并将提供对分子生物学的深入了解。 形态学、行为学和神经内分泌/生殖毒性的潜在途径 大麻素重要的是，这个拟议的项目解决了NIH对理解 大麻和大麻素暴露对发育中的大脑的功能性影响 在PA-14 - 162中。