Transgenerational effects of nicotine in F1 generation of exposed fathers in mice

尼古丁对小鼠 F1 代暴露父亲的跨代影响

基本信息

批准号：
8609485
负责人：
Markus Parzival Vallaster
金额：
$ 5.75万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-22 至 2016-01-21
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8609485
关键词：
Accounting Addictive Behavior Address Adolescent Adult Affect Behavior Behavioral Brain Brain region Cardiovascular system Cessation of life Characteristics Child Chronic DNA Sequence Data Data Analyses Dependence Detection Diet Disease Drug Addiction Embryo Environment Environmental Risk Factor Epidemic Epidemiology Epigenetic Process Exposure to Fathers Female Fertilization in Vitro Fostering Gene Expression Gene Expression Profile Gene Mutation Generations Genes Genetic Genome Genotype Goals Health Heritability Histones Human Immunohistochemistry Inherited Knowledge Lead Link Liver Lung Malignant Neoplasms Malignant neoplasm of lung Maps Measures Mediating Memory Metabolism Methylation Midbrain structure Modification Molecular Profiling Mus Neuraxis Neuropeptides Nicotine Nicotine Dependence Nicotinic Receptors Nucleosomes Nucleus Accumbens Parents Partner in relationship Paternal Exposure Pattern Peripheral Phenotype Play Population Positioning Attribute Predisposition Prefrontal Cortex Prevention Prevention approach Preventive Intervention Psychological reinforcement RNA Sequences Recording of previous events Reproduction Rewards Risk Role Seminal fluid Series Signal Pathway Signal Transduction Single Nucleotide Polymorphism Small RNA Smoker Smoking Smoking History Symptoms Tail Testing Testis Tissues Tobacco Tobacco use Twin Studies Ventral Tegmental Area Western World Withdrawal Work base behavior change blastocyst cardiovascular disorder risk cardiovascular injury dopaminergic neuron drinking water epigenome genetic variant high risk improved innovation killings male mortality mouse model neurotransmitter release new therapeutic target next generation novel strategies novel therapeutics offspring preference pregnant public health relevance research study response reward circuitry sperm cell transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Smoking kills almost 6 million people per year worldwide. The addictive component of tobacco, nicotine, represents a major cause of diseases such as cardiovascular injuries and cancer. There is strong indication that a genetic component exists underlying nicotine-related behaviors and dependence. However, changes in the genome as determined in twin studies or detection of single nucleotide polymorphisms (SNPs) explain only part of the human heritability of nicotine usage. Recent studies suggest that the proclivity t become nicotine dependent can be inherited from fathers and that changes in the environmental conditions of one generation affect and influence the health (or likelihood of acquiring disease states) of subsequent generations. In fact, information contained in the epigenome such as methylation patterns, nucleosome positioning, and small RNA populations, might be influenced by altering environmental conditions and can be transferred to the offspring during reproduction. Reviving Charles Darwin's and Jean-Baptiste Lamarck's idea that the inheritance of certain characteristics from one generation to the next can be influenced by changes in the environment, I have performed transcriptome analysis of offspring from nicotine-treated and control fathers, using microarray and RNA-seq to identify key genes whose expression levels change in progeny. The identified genes are involved in neurotransmitter release, neuropeptide signaling pathways and behavioral responses to nicotine. I hypothesize that in mouse progeny, changes in the expression levels of these genes are a consequence of epigenetic reprogramming resulting from exposure to nicotine in mouse fathers. I will investigate the gene expression profiles in different progeny groups and determine the effects of paternal exposure to nicotine on behavioral responses in offspring, eventually connecting the observed (epi)genotype with a phenotype. Furthermore, I will examine epigenetic regulatory mechanisms in sperm from nicotine- treated mice and controls performing in-vitro fertilization to exclude confounding effects such as mating preferences. Epigenome mapping studies, including RRBS, nucleosome retention mapping, and RNA- sequencing, in sperm from fathers will elucidate underlying mechanisms of transgenerational inheritance. The results of my study will contribute to a deeper understanding of how the epigenome regulates gene expression and how environmental factors can influence these mechanisms. This will lead to new approaches in prevention and treatment of nicotine dependence and diseases linked to chronic nicotine exposure and its transgenerational inheritance.

描述（由申请人提供）：全世界每年有近 600 万人因吸烟而死亡。烟草中的成瘾成分尼古丁是导致心血管损伤和癌症等疾病的主要原因。有强有力的迹象表明，尼古丁相关行为和依赖背后存在遗传成分。然而，双胞胎研究或单核苷酸多态性 (SNP) 检测中确定的基因组变化只能解释人类尼古丁使用遗传性的部分原因。最近的研究表明，尼古丁依赖的倾向可以从父亲那里遗传，一代人环境条件的变化会影响后代的健康（或患上疾病的可能性）。事实上，表观基因组中包含的信息，如甲基化模式、核小体定位和小 RNA 群体，可能会受到环境条件改变的影响，并可以在繁殖过程中传递给后代。恢复了查尔斯·达尔文和让·巴蒂斯特·拉马克的观点，即某些特征从一代到下一代的遗传可能会受到环境变化的影响，我使用微阵列和 RNA 对尼古丁治疗和对照父亲的后代进行了转录组分析。 seq 来识别其表达水平在后代中发生变化的关键基因。已鉴定的基因涉及神经递质释放、神经肽信号通路和对尼古丁的行为反应。我假设，在小鼠后代中，这些基因表达水平的变化是小鼠父亲暴露于尼古丁导致的表观遗传重编程的结果。我将研究不同后代群体的基因表达谱，并确定父亲接触尼古丁对后代行为反应的影响，最终将观察到的（表观）基因型与表型联系起来。此外，我将检查尼古丁处理小鼠和进行体外受精的对照组精子的表观遗传调节机制，以排除交配偏好等混杂效应。对父亲精子的表观基因组图谱研究，包括 RRBS、核小体保留图谱和 RNA 测序，将阐明跨代遗传的潜在机制。我的研究结果将有助于更深入地了解表观基因组如何调节基因表达以及环境因素如何影响这些机制。这将带来预防和治疗尼古丁依赖以及与慢性尼古丁暴露及其跨代遗传相关的疾病的新方法。