Paternal obesity-associated DNA methylation: an investigation into its reproducibility, reversibility and association with fetal growth restriction

摘要背景：超重和肥胖的人数在世界各地和英国都在上升。肥胖现在影响儿童、青少年和成人。年轻人特别容易患上肥胖症、2型糖尿病和高血压的终身后果。一旦获得肥胖，体重减轻就难以实现，特别是难以维持。因此，首先预防超重和肥胖，是改善公众健康的一个有吸引力的目标。肥胖的起源可以追溯到我们在母亲子宫里的时间，甚至在怀孕之前。在怀孕期间，发育中的婴儿随着母亲的健康和体重而生长。然而，父亲在受孕时的体重也有影响，但与母亲的影响相反。而超重或肥胖的母亲倾向于有一个大的婴儿，超重或肥胖的男人倾向于父亲一个小婴儿。婴儿在子宫中的生长情况很重要，因为它影响着婴儿成年后的健康。在子宫内生长不良的婴儿出生体重低，患2型糖尿病、高血压和肥胖症的风险增加。非常大的婴儿将来也有患2型糖尿病的风险。目的：我们希望发现人类是否会像动物一样，通过将肥胖等后天特征从父亲遗传给未出生的婴儿。我们设计了一个多阶段的综合研究，以发现如何肥胖的父亲可能会抑制他未出生的婴儿的生长，以及是否父亲的体重减轻有可能改善胎儿的生长，并提供最终的一级预防终身疾病在下一代.METHODS：我们将发现是否肥胖，2型糖尿病和低出生体重与周围的基因，被称为表观遗传变化的化学变化的一致性。我们与一个挪威组织建立了联系，该组织收集了11，000多个家庭（母亲，父亲和婴儿）的DNA。我们计划调查1000名肥胖父亲的DNA是否显示出与1000名正常体重父亲相比较的与肥胖相关的表观遗传学变化。我们将确定是否肥胖相关的表观遗传标记，其他人在已发表的报告中确定，也明显在1000名肥胖的父亲。这将生成一个经过验证的“肥胖相关”表观遗传变化列表。接下来，我们将在一项新怀孕妇女的研究中确定来自肥胖父亲的经验证的肥胖相关表观遗传标记对其后代出生体重的相对贡献。我们将研究250例父亲为肥胖男性的孕妇，并与250例父亲为正常体重男性的孕妇进行比较。我们将确定是否肥胖的父亲更有可能父亲低出生体重婴儿。我们将考虑母亲的体型和父母双方的基因的影响。我们将确定是否胎盘（遗传上半父）从怀孕的父亲是肥胖的男性胎盘功能不同，从怀孕的父亲是正常体重的男性。最后，在一项针对15名肥胖男性的单独研究中，我们将确定通过减肥手术（绕过胃）的体重急剧减轻是否与血液和精子DNA中与肥胖相关的表观遗传标记的逆转有关。预期结果：该项目的结果具有科学和公共卫生意义。如果肥胖相关的表观遗传标记在肥胖父亲及其低出生体重婴儿的精子中很明显，我们就会发现一种潜在的机制，通过这种机制，获得性父亲肥胖使下一代对肥胖的脆弱性永久化。如果体重减轻消除了这些表观遗传标记，那么我们将为未来的研究建立一个科学的理论基础，以调查怀孕前父亲的体重减轻是否会改善胎儿的生长，并可能改善下一代的长期健康。

SUMMARYBACKGROUND:The number of overweight and obese people is rising all over the world and in the UK. Obesity now affects children, adolescents and adults. Younger people are particularly prone to the lifelong consequences of obesity with type-2 diabetes and high blood pressure. Once obesity is acquired, weight loss is difficult to achieve and in particular to maintain. Therefore, preventing overweight and obesity in the first place, is an attractive ambition to improve public health. The origins of obesity can be traced back to the time we spent in our mother's womb and even before conception. During pregnancy, the developing baby grows in response to the health and weight of its mother. However, the father's weight at the time of conception is also influential, but in the opposite way to the mother's influence. Whereas an overweight or obese mother is predisposed to have a large baby, an overweight or obese man is predisposed to father a small baby. How well a baby grows in the womb is important, as it influences the health of that baby in adult life. Babies that grow poorly in the womb have a low birth weight and are at increased risk of type-2 diabetes, high blood pressure and obesity. Very large babies are also at risk of future type-2 diabetes.AIMS:We wish to discover if humans behave in the same way as animals by passing on acquired characteristics such as obesity, from father to unborn baby. We have designed a multi-staged, integrated study to discover how an obese father might inhibit the growth of his unborn baby and whether paternal weight loss has the potential to improve fetal growth and provide the ultimate primary prevention of life-long disease in the next generation.METHODS:We will discover whether obesity, type-2 diabetes and low birth weight are associated with consistent changes in the chemistry around genes, known as epigenetic change. We have linked with a Norwegian group who have collected DNA from over 11,000 families (mother, father baby). We plan to investigate whether DNA from 1000 obese fathers shows consistent obesity-associated epigenetic changes, compared with 1000 normal-weight fathers. We will determine if obesity-associated epigenetic marks identified by others in published reports are also evident in the 1000 obese fathers. This will generate a validated list of 'obesity-associated' epigenetic changes. We will next determine the relative contribution of validated obesity-associated epigenetic marks from the obese father on the birth weight of their offspring in a study of newly pregnant women. We will study 250 pregnancies fathered by obese men compared with 250 pregnancies fathered by normal weight men. We will determine whether obese fathers are more likely to father low birth weight babies. We will take into account the influence of mothers' size and genes from both parents. We will determine whether placentae (genetically half paternal) from pregnancies fathered by obese men function differently to placentae from pregnancies fathered by normal weight men. Finally, in a separate study of 15 obese men, we will determine whether dramatic weight loss through bariatric surgery (by-pass of the stomach), is associated with reversal of obesity-associated epigenetic marks in DNA from their blood and sperm. EXPECTED RESULTS:The results of this project are of both scientific and public health interest. If obesity-associated epigenetic marks are evident in sperm of obese fathers and their low birth weight babies, we would have discovered a potential mechanism through which acquired paternal obesity perpetuates a vulnerability to obesity in a future generation. If weight loss eliminates these epigenetic marks, then we will have established a scientific rationale for a future study to investigate whether pre-conception paternal weight loss improves fetal growth and potentially improves the long-term health of the next generation.