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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：
10018076
负责人：
RONALD Sherwin SWERDLOFF
金额：
$ 30.8万
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/10018076
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 Hispanics 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 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精子表观基因组众所周知，年轻男性和女性不健康的饮食和缺乏身体活动是导致晚年出现代谢综合征、糖尿病和高脂血症，导致心血管疾病增加疾病风险。全基因组关联研究已经确定了单核苷酸多态性，这些多态性只能解释了这些代谢性疾病约20%的遗传性。临床前模型提供了明确的证据表明受孕前饮食或运动的改变会导致后代的代谢和表型变化通过基因表达的正常表观遗传调控的代际破坏。这是通过以下方式发生的动物体内 i) DNA 甲基化、ii) 组蛋白修饰和 iii) 非编码 RNA (ncRNA) 的改变研究和男性。我们的中心假设是，超重和不活跃的生活方式会导致表观突变精子表观基因组相对于精瘦和活跃男性的正常表观遗传编程以及饮食和运动调节会导致这些表观突变的逆转，从而产生更健康的“表型”和 “表观基因型”在停止干预后可能会持续存在。我们提出三个目标：目标 1. 确定交叉精子表观基因组（DNA 甲基化、组蛋白修饰和非编码 RNA）的差异针对肥胖、不活动的西班牙裔男性与健康、活跃的西班牙裔男性的截面研究。我们将招募20名健康、活跃的男性和80名 18 至 40 岁之间肥胖且缺乏运动的西班牙裔男性为这一目标。仅对西班牙裔男性进行研究因为西班牙裔年轻男性肥胖和缺乏运动的患病率很高，并且为了减少遗传因素影响表观基因组的变异性。目标 2. 描述精子表观基因组响应的可塑性对肥胖和缺乏运动的西班牙裔男性进行 12 周饮食和/或运动训练干预。 80 肥胖且缺乏运动男性将被随机分为 4 组，每组 20 名男性：1) 无干预（对照）； 2）低脂肪、低热量饮食； 3）在不改变饮食的情况下进行监督、定期的耐力和阻力训练； 4) 锻炼和饮食调整。将比较每组干预前后的精子表突变组之间。目标 3. 确定饮食和运动训练在术后 12 周和 36 周的持续影响停止干预后停止对精子表观基因组的干预。项目无缝衔接为了实现男性生殖表观遗传学中心的目标以及项目 2 和 3 中对小鼠的研究将揭示不健康的生活方式导致精子表观突变形成的机制随后被传播给雄性后代、在雄性后代中传播并对雄性后代有害——基于无法在男性中进行的机制研究。