Diet and Exercise Modulate the Sperm Epigenome 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，青年男女的不健康饮食和缺乏体育锻炼是导致 代谢综合征、糖尿病和高脂血症的晚年发展，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， 可以解释这些代谢性疾病20%的遗传性。临床前模型提供了明确的证据， 怀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节的代际破坏。这是通过 在动物中i）DNA甲基化，ii）组蛋白修饰，和iii）非编码RNA（ncRNA）的改变， 研究和男人。我们的中心假设是超重和不活动的生活方式导致表型突变， 精子表观基因组相对于瘦男性和活跃男性的正常表观遗传编程， 运动调节导致这些表型突变的逆转，从而产生更健康的“表型”， “表观基因型”，这可能会持续停止干预后。我们提出三个目标：目标1。确定 精子表观基因组的差异（DNA甲基化，组蛋白修饰和非编码RNA）在一个交叉- 在肥胖不活跃与健康活跃的西班牙裔男性中进行的横断面研究。我们将招募20名健康活跃的男性和80名 肥胖和不活跃的西班牙裔男性之间的18和40岁的这一目标。只有西班牙裔男性将被研究 因为西班牙裔年轻男性肥胖和缺乏运动的患病率很高， 影响表观基因组的变异性。目标2.表征精子表观基因组响应于 12-一周的饮食和/或运动训练干预肥胖和不活跃的西班牙裔男子。80肥胖和不活动 将男性随机分为4组，每组20人：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，进行有监督的、周期性的耐力和阻力训练;以及4） 饮食调整将比较各组干预前后的精子表型突变， 在群体之间。目标3。确定饮食和运动训练在12周和36周后的持续影响， 停止干预后，停止对精子表观基因组的干预。项目无缝对接 与男性生殖表观遗传学中心的目标和项目2和3中的小鼠研究， 将揭示不健康的生活方式导致精子表型突变形成的机制 随后传播给男性后代、在男性后代中繁殖并对男性后代有害--基于 无法在男性身上进行的机制研究。

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.