Heritable epigenetic mechanisms of paternal THC exposure

父亲 THC 暴露的遗传表观遗传机制

• 批准号: 9908523
• 负责人: Gregory Ronald Rompala
• 金额: $ 6.49万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-07 至 2023-02-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9908523
• 关键词: Adolescence; Adolescent; Adult; Adult Children; Affect; Bioinformatics; Biological Assay; Brain; Brain region; Cannabis; Cell Nucleus; Child Development; Chromatin; Chronic stress; Cohort Effect; Collection; Corpus striatum structure; Data; Data Analyses; Development; Diet; Dose; Drug usage; Embryo; Embryonic Development; Epigenetic Process; Exposure to; Fathers; Fatty acid glycerol esters; Female; Fertilization; Fluorescence; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Glutamates; Habits; Health; Heritability; Heterogeneity; Hour; Ingestion; Laboratories; Lead; Legal; Life; Male Adolescents; Mental disorders; Messenger RNA; MicroRNAs; Modeling; Mothers; Neurons; Partner in relationship; Paternal Exposure; Pathway interactions; Phenotype; Play; Post-Transcriptional Regulation; Pregnancy; Prevalence; RNA analysis; Rattus; Rewards; Risk; Role; Shapes; Small RNA; Sorting - Cell Movement; Sperm Motility; Stress; Synaptic plasticity; THC exposure; Teenagers; Testing; Tetrahydrocannabinol; Time; Transposase; United States; Untranslated RNA; Work; base; brain cell; drug seeking behavior; epigenome; experimental study; father role; fetal; follow-up; genome-wide; inhibitor/antagonist; insight; intergenerational; mRNA Transcript Degradation; male; marijuana use; neurobehavioral; neurodevelopment; next generation; novel; offspring; prenatal; reproductive; sperm cell; transcriptome sequencing; young adult

PROJECT SUMMARY There is a growing appreciation that a father’s preconception stress, diet, or drug use can directly affect the development of his children via epigenetic mechanisms in the germline. Accordingly, recent findings from our lab revealed that parental (mother and father) exposure to 9-tetrahydrocannabinol (THC) increased drug- seeking behavior in male offspring. Suggesting a significant role for the father, I found that THC significantly alters an epigenetic mechanism in sperm known to play a causal role in heritable neurobehavioral phenotypes. Given the progressive legalization of recreational cannabis use, it is imperative that the associated reproductive and intergenerational health risks become better defined. Therefore, I will examine the heritable epigenetic effects of paternal THC exposure on the sperm, developing embryo, and fetal brain. In Aim 1, I will examine the effects of THC on sperm small noncoding RNAs across three translationally- relevant doses. Subsequently, in Aim 2a, I will characterize the effects of paternal THC exposure on gene expression in the early embryo. Moreover, Aim 2b will follow-up on preliminary experiments showing that a low dose THC exposure reduces sperm-borne microRNA-34c by examining the effects of microRNA-34c inhibition on early embryonic gene expression programming. Finally, in Aim 3, I will determine the heritable epigenetic effects of paternal THC exposure on prenatal neurodevelopment by examining genome-wide chromatin accessibility in embryonic striatal neurons. This project represents an important advancement in our understanding of the intergenerational effects of THC exposure, aiming to identify novel mechanisms of epigenetic inheritance through the male germline. The findings will help determine potential health risks associated with the cannabis use of fathers-to-be.

项目总结 越来越多的人认识到，父亲的先入为主的压力、饮食或药物使用可以直接影响 他的孩子通过胚系中的表观遗传机制发育。因此，我们的最新发现 实验室显示，父母(母亲和父亲)接触9-四氢大麻酚(THC)会增加药物- 在雄性后代中寻找行为。暗示了父亲的重要作用，我发现THC显著 改变精子中已知在可遗传神经行为表型中起因果作用的表观遗传机制。 鉴于娱乐性大麻使用逐渐合法化，当务之急是 生殖和代际健康风险得到了更好的界定。因此，我将研究可遗传的 父亲THC暴露对精子、发育中的胚胎和胎儿大脑的表观遗传学影响。 在目标1中，我将研究THC对三个翻译上的精子小非编码RNA的影响- 相关剂量。随后，在目标2a中，我将描述父亲接触THC对基因的影响 在早期胚胎中的表达。此外，目标2b将跟进初步实验表明，低 剂量暴露通过检测microRNA-34c抑制效应来减少精子携带的microRNA-34c 关于早期胚胎基因表达编程。最后，在目标3中，我将确定可遗传的表观遗传学 通过检测全基因组染色质研究父亲THC暴露对产前神经发育的影响 胚胎纹状体神经元的可及性。 这个项目代表着我们在理解THC的代际影响方面取得的重要进展。 暴露，旨在通过男性生殖系确定表观遗传的新机制。这个 研究结果将有助于确定与使用大麻有关的潜在健康风险。