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

父亲肥胖相关的 DNA 甲基化：对其再现性、可逆性及其与胎儿生长受限的关系的研究

• 批准号: MR/P011799/1
• 负责人: David Williams
• 金额: $ 115.06万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP011799%2F1
• 关键词: Paternal; obesity; associated; DNA; methylation

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.

摘要背景：超重和肥胖的人数在世界各地和英国都在增加。肥胖现在会影响儿童，青少年和成人。年轻人特别容易遭受2型糖尿病和高血压肥胖的终生后果。一旦获得肥胖，就很难实现体重减轻，尤其是维持。因此，首先防止超重和肥胖是改善公共卫生的有吸引力的野心。肥胖的起源可以追溯到我们在母亲的子宫中乃至受孕之前的时间。在怀孕期间，发育中的婴儿会因母亲的健康和体重而生长。但是，父亲在受孕时的体重也具有影响力，但与母亲的影响相反。尽管超重或肥胖的母亲倾向于生一个大婴儿，而超重或肥胖的男人则倾向于父亲一个小婴儿。婴儿在子宫中的生长程度很重要，因为它影响了成人生活中该婴儿的健康状况。在子宫中生长较差的婴儿出生体重低，患有2型糖尿病，高血压和肥胖的风险增加。非常大的婴儿也有未来2型糖尿病的风险。我们设计了一项多阶段，综合的研究，以发现肥胖父亲如何抑制他未出生的婴儿的成长，以及父亲的体重减轻是否有可能改善胎儿的生长并在下一届中提供最终的初级预防终身疾病Generation.Methods：我们将发现肥胖，2型糖尿病和低出生体重是否与化学周围化学的一致变化有关，称为表观遗传学变化。我们已经与一个从11,000多个家庭（母亲，宝贝父亲）那里收集了一个DNA的挪威团体有关。我们计划研究1000名肥胖父亲的DNA是否表现出与肥胖相关的表观遗传变化一致，而1000个正常体重的父亲。我们将确定1000名肥胖父亲在公开报告中其他人在公开报告中发现与肥胖相关的表观遗传标记是否也很明显。这将产生经过验证的“肥胖相关”表观遗传变化的列表。接下来，我们将在对新孕妇的研究中确定肥胖父亲对后代的出生体重的经过验证的肥胖相关表观遗传标记的相对贡献。我们将研究由肥胖男性父亲的250例怀孕，而正常体重男性则为250例怀孕。我们将确定肥胖的父亲是否更有可能父亲出生体重婴儿。我们将考虑到父母的大小和基因的影响。我们将确定肥胖男性父亲妊娠的胎盘（遗传性父亲）是否与正常体重男性父母的怀孕不同。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（胃部旁路）的显着体重减轻与DNA中与肥胖相关的表观遗传标记的逆转有关。预期结果：该项目的结果既具有科学和公共卫生的兴趣。如果在肥胖父亲的精子及其低出生体重婴儿中与肥胖相关的表观遗传标记是明显的，我们会发现一种潜在的机制，通过这种机制，获得的父亲肥胖使未来一代的肥胖症变得脆弱。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由，以研究概念前的父亲体重减轻是否可以改善胎儿的生长并有可能改善下一代的长期健康。

项目成果

The impact of paternal metabolic health on sperm DNA methylation and fetal growth

父亲代谢健康对精子DNA甲基化和胎儿生长的影响

• 发表时间: 2019
• 作者: Asenius Karin Ingrid Fredrika

DNA methylation in human sperm: a systematic review

• DOI: 10.1093/humupd/dmaa025
• 发表时间: 2020-11-01
• 期刊: HUMAN REPRODUCTION UPDATE
• 影响因子: 13.3
• 作者: Asenius, Fredrika;Danson, Amy F.;Marzi, Sarah J.
• 通讯作者: Marzi, Sarah J.

The DNA methylome of human sperm is distinct from blood with little evidence for tissue-consistent obesity associations.

• DOI: 10.1371/journal.pgen.1009035
• 发表时间: 2020-10
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Åsenius F;Gorrie-Stone TJ;Brew A;Panchbhaya Y;Williamson E;Schalkwyk LC;Rakyan VK;Holland ML;Marzi SJ;Williams DJ
• 通讯作者: Williams DJ