Diet and Exercise Modulate the Sperm Epigenome in Men

饮食和运动调节男性精子表观基因组

基本信息

批准号：
10260434
负责人：
RONALD Sherwin SWERDLOFF
金额：
$ 30.82万
依托单位：
LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-13 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10260434
关键词：
Adult Animals Cells Clinical Trials Complex Conceptions Coupled Cross-Sectional Studies DNA Methylation Development Diabetes Mellitus Diet Diet Modification Disease Outcome Educational Intervention Elderly Environment Environmental Exposure Environmental Risk Factor Epidemic Epigenetic Process Exercise Fatty acid glycerol esters Gene Expression Gene Expression Regulation Genetic Genetic Programming Genome Germ Cells Goals Health Heritability High Fat Diet High Prevalence Hispanic Human Hyperlipidemia Intervention Life Life Style Link Metabolic Metabolic Diseases Metabolic syndrome Modification Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Nutritional Obesity Outcome Overweight Pathogenesis Pattern Phenotype Plague Population Pre-Clinical Model Prevalence Randomized Reporting Research Design Research Personnel Risk Single Nucleotide Polymorphism Supervision Thinness Translating Translations Unhealthy Diet United States Untranslated RNA base cardiovascular disorder risk design diet and exercise dietary epigenetic regulation epigenome epigenomics exercise training experience genome wide association study histone modification human study in utero intergenerational lifestyle intervention male men metabolic phenotype next generation obesity development offspring physical inactivity prevent programs recruit reproductive response sperm cell strength training transmission process unhealthy lifestyle young man young woman

项目摘要

Project 1. Diet and Exercise Modulate the Sperm Epigenome in Men It is well known that unhealthy diet and physical inactivity in young men and women are major contributors to later-life development of metabolic syndrome, diabetes and hyperlipidemia, leading to increased cardiovascular disease risk. Genome wide association studies have identified single nucleotide polymorphisms that can only explain about 20% of the heritability of these metabolic diseases. Preclinical models provide clear evidence that dietary or exercise modifications before conception result in metabolic and phenotypic changes in the offspring through intergenerational disruption of normal epigenetic regulations of gene expression. This occurs via alterations in i) DNA methylation, ii) histone modifications, and iii) non-coding RNAs (ncRNAs) both in animal studies and in men. Our central hypotheses are that overweight and inactive lifestyle results in epimutations in the sperm epigenome relative to the normal epigenetic programming in lean and active men and that diet and exercise modulation leads to reversal of these epimutations resulting in both a healthier “phenotype” and “epigenotype” which may persist after stopping the interventions. We propose three aims: Aim 1. Determines the differences in sperm epigenome (DNA methylation, histone modifications and non-coding RNAs) in a cross- sectional study in obese inactive vs. healthy active Hispanic men. We will recruit 20 healthy, active men and 80 obese and inactive Hispanic men between 18 and 40 years for this Aim. Only Hispanic men will be studied because of the high prevalence of obesity and inactivity in Hispanic younger men and to reduce the genetic variability influencing the epigenome. Aim 2. Characterize the plasticity of the sperm epigenome in response to 12-week diet and/or exercise training interventions in obese and inactive Hispanic men. 80 obese and inactive men will be randomized to 4 groups of 20 men: 1) No intervention (control); 2) Low fat, low caloric diet; 3) Supervised, periodized endurance and resistance training without modification of diet; and 4) Both exercise and diet modification. Sperm epimutations will be compared before and after intervention within each group and between groups. Aim 3. Identify the persistent effects of diet and exercise training at 12 and 36 weeks after cessation of interventions on the sperm epigenome after stopping the interventions. Project aligns seamlessly with the goals of the Center of Male Reproductive Epigenetics and with studies in mice in Project 2 and 3 that will reveal the mechanisms by which an unhealthy lifestyle leads to formation of epimutations in spermatozoa that are subsequently transmitted to, propagated within, and deleterious to male offspring – based on mechanistic studies that cannot be done in men.

项目1。饮食和运动调节男性的精子表观体众所周知，年轻男女的不健康饮食和身体不活动是主要贡献者代谢综合征，糖尿病和高脂血症的后期发展，导致心血管增加疾病风险。基因组广泛的关联研究已经确定了只能解释这些代谢疾病的遗传力中约有20％。临床前模型提供了明确的证据表明概念之前的饮食或运动修改会导致后代的代谢和表型变化通过代基因表达的正常表观遗传调节的代际破坏。这是通过 I）DNA甲基化的改变，II）组蛋白修饰和III）在动物中的非编码RNA（NCRNA）研究和男性。我们的核心假设是，超重和不活跃的生活方式会导致表达精子表观基因组相对于精益和活跃男人的正常表观遗传编程以及饮食和运动调节会导致这些表述的逆转，从而导致更健康的“表型”和停止干预措施后可能会持续存在的“表观遗传型”。我们提出三个目标：目标1。确定精子表观基因组（DNA甲基化，组蛋白修饰和非编码RNA）的差异肥胖不活动与健康活跃的西班牙裔男子的分区研究。我们将招募20名健康，活跃的男人和80名肥胖和不活跃的西班牙裔男子在18至40年之间以这个目标。只有西班牙裔男人才会研究由于西班牙裔年轻人的肥胖症和不活动率很高，并减少了通用影响表观基因组的变异性。 AIM 2。表征精子表观基因组的可塑性 12周的饮食和/或肥胖和不活跃的西班牙裔男性运动训练干预措施。 80肥胖和不活跃男人将被随机分为4组20人：1）不干预（对照）； 2）低脂肪，低热量饮食； 3）监督，周期性的耐力和抵抗训练，而无需改变饮食； 4）运动和饮食修改。将在每个组内干预之前和之后比较精子的表述，两组之间。目标3。确定饮食和运动训练在12和36周后的持续效果停止干预措施后，停止精子表观基因组的干预措施。项目无缝对齐以男性生殖表观遗传学中心的目标以及项目2和3的小鼠研究将揭示不健康的生活方式导致精子中表现形成的机制随后将其传输到，在内部传播并删除给男性后代 - 基于男性无法进行的机械研究。