Diet and Exercise Modulate the Sperm Epigenome in Men

项目1.饮食和运动对男性精子表观基因组的调节 众所周知，年轻男女不健康的饮食和缺乏体育活动是导致 代谢综合征、糖尿病和高脂血症的晚期发展，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，只有 解释这些代谢性疾病约20%的遗传性。临床前模型提供了明确的证据 受孕前饮食或运动的改变会导致后代的代谢和表型变化 通过代际扰乱正常的表观遗传基因表达调控。这通过以下方式发生 动物中i)DNA甲基化、ii)组蛋白修饰和iii)非编码RNA(NcRNAs)的变化 研究和在男人身上。我们的中心假设是，超重和不活跃的生活方式会导致 精瘦和活跃男性的精子表观基因组相对于正常表观遗传程序，以及饮食和 运动调节导致这些表观突变的逆转，从而产生更健康的“表型”和 在停止干预后可能持续存在的“表观类型”。我们提出了三个目标：目标1.确定 精子表观基因组差异(DNA甲基化、组蛋白修饰和非编码RNA) 肥胖、不活跃与健康活跃的西班牙裔男性的横断面研究。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，年龄在18岁到40岁之间。只有西班牙裔男性会被研究 由于西班牙裔年轻男性肥胖和缺乏运动的高发，并减少了基因 影响表观基因组的可变性。目的2.表征精子表观基因组的可塑性 对肥胖和不活跃的西班牙裔男性进行12周饮食和/或运动训练干预。80个肥胖和不活跃的人 男性将被随机分为4组，每组20人：1)不干预(对照组)；2)低脂肪、低热量饮食；3) 有监督的、分期的耐力和抵抗力训练，无需改变饮食；以及4)运动和 饮食调整。对每组干预前后的精子表型进行比较，并 在小组之间。目标3.在12周和36周后确定饮食和运动训练的持续影响 停止干预后停止对精子表观基因组的干预。项目无缝对接 以男性生殖表观遗传学中心的目标和项目2和3中的小鼠研究为目标 将揭示不健康的生活方式导致精子上突变形成的机制 随后传播给雄性后代，在内部传播，并对雄性后代有害-基于 不能在人类身上完成的机械学研究。

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.