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

背景：超重和肥胖人群的数量在全世界和英国都在上升。肥胖现在影响着儿童、青少年和成年人。年轻人尤其容易受到肥胖伴随2型糖尿病和高血压的终生影响。一旦患上肥胖症，减肥就很难实现，尤其难以维持。因此，首先预防超重和肥胖是改善公众健康的诱人目标。肥胖的起源可以追溯到我们在母亲的子宫里，甚至在怀孕之前。在怀孕期间，发育中的婴儿根据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。一个超重或肥胖的母亲更容易生一个大孩子，而一个超重或肥胖的男人更容易生一个小孩子。婴儿在子宫里的发育状况很重要，因为它会影响婴儿成年后的健康。在子宫里发育不良的婴儿出生体重低，患2型糖尿病、高血压和肥胖的风险也会增加。体型过大的婴儿未来也有患2型糖尿病的风险。目的：我们希望发现人类的行为是否与动物一样，通过将获得的特征（如肥胖）从父亲传递给未出生的婴儿。我们设计了一项多阶段的综合研究，以发现肥胖父亲如何抑制未出生婴儿的生长，以及父亲减肥是否有可能改善胎儿生长，并为下一代提供终身疾病的最终一级预防。方法：我们将发现肥胖、2型糖尿病和低出生体重是否与基因周围化学物质的一致变化有关，即表观遗传变化。我们联系了一个挪威小组，他们收集了11,000多个家庭（母亲，父亲，婴儿）的DNA。与1000名体重正常的父亲相比，我们计划调查1000名肥胖父亲的DNA是否显示出一致的肥胖相关表观遗传变化。我们将确定其他人在已发表的报告中发现的与肥胖相关的表观遗传标记是否在1000名肥胖父亲中也很明显。这将产生一个有效的“肥胖相关”表观遗传变化列表。接下来，我们将在一项针对新孕妇的研究中，确定来自肥胖父亲的与肥胖相关的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个由肥胖男性生育的孕妇，以及250个由正常体重男性生育的孕妇。我们将确定肥胖的父亲是否更有可能生出低出生体重的婴儿。我们将考虑母亲体型和父母双方基因的影响。我们将确定肥胖男性所生胎儿的胎盘（基因上一半为父系）与正常体重男性所生胎儿的胎盘功能是否不同。最后，在另一项针对15名肥胖男性的研究中，我们将确定通过减肥手术（胃旁路手术）大幅减肥是否与他们血液和精子中与肥胖相关的DNA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利益。如果肥胖父亲及其低出生体重婴儿的精子中存在与肥胖相关的表观遗传标记，那么我们就发现了一种潜在的机制，通过这种机制，获得性父亲肥胖使后代对肥胖的脆弱性持续存在。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科学依据，以调查孕前父亲体重减轻是否能促进胎儿生长，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.