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

• 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
• 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

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）：每年吸烟​​在全球范围内杀死近600万人。烟草的成瘾成分是尼古丁，代表了心血管损伤和癌症等疾病的主要原因。有很大的迹象表明，遗传成分存在与尼古丁相关的行为和依赖性。但是，在双研究或检测单核苷酸多态性（SNP）中确定的基因组的变化仅解释了尼古丁使用的人类遗传力的一部分。最近的研究表明，可以从父亲那里遗传而来的倾向，并且一代人的环境条件的变化会影响和影响随后世代的健康（或获得疾病状态的可能性）。实际上，表观基因组中包含的信息，例如甲基化模式，核小体定位和少量RNA种群，可能会受到环境条件改变的影响，并且可以在繁殖过程中转移到后代。 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.确定的基因参与神经递质释放，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，这些基因的表达水平的变化是小鼠父亲中暴露于尼古丁引起的表观遗传重编程的结果。我将研究不同后代组的基因表达谱，并确定父亲对尼古丁对后代行为反应的影响，最终将观察到的（EPI）基因型与表型联系起来。此外，我将研究来自尼古丁处理的小鼠的精子的表观遗传调节机制，以及进行体外受精的对照，以排除混杂作用，例如交配偏好。在父亲的精子中，包括RRB，核小体保留映射和RNA测序在内的表观基因组映射研究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。这将导致在预防和治疗尼古丁依赖性和与慢性尼古丁暴露及其跨代遗传有关的疾病方面采用新的方法。