Epigenetic mechanisms linking maternal pre-conceptional micronutrient supplementation with offspring health in India and The Gambia

由于饮食质量差而缺乏必需维生素和矿物质（微量营养素）是低收入和中等收入国家的一个主要公共卫生问题。在孕妇中，它们会损害胎儿发育并导致儿童发育迟缓。最近在英国率先进行的研究表明，它们会给后代带来长期问题，包括大脑和肌肉发育不良、体脂增加、成年后患心脏病和糖尿病。这些慢性疾病在中低收入国家迅速增加，使工作年龄的人致残，需要昂贵的治疗。目前预防这些疾病的工作重点是促进更健康的成人生活方式。对健康和疾病的发育起源的研究，通过优化产妇营养，开辟了改善儿童发育和预防成人疾病的潜力。直到最近，关于产妇营养不良的长期影响的证据都是基于观察性研究。本应用程序的研究小组通过在印度和冈比亚营养不良的母亲中进行孕前和孕产期随机对照营养试验，取得了阶段性的改变。这些试验为研究表观遗传机制提供了理想的载体，通过这种机制，个体在子宫内的营养环境的“记忆”可以保留到以后的生活中，并影响健康。其中一种机制是DNA甲基化，在这种机制中，DNA中的基因序列被化学（甲基）基团覆盖，甲基控制基因的开启或关闭。甲基化模式（“表观遗传特征”）在胎儿早期形成，并受到母亲营养状况的影响。在实验动物中，改变母体孕期饮食会永久改变后代的DNA甲基化、基因表达和成年代谢。越来越多的间接证据表明，在人类中也有类似的效果，但目前还没有具体的孕产期营养干预的可比研究。英国、印度和冈比亚的研究小组已经在观察工作中建立了强有力的证据，证明母亲缺乏“甲基供体”营养物质，如维生素B2、B6、B12和叶酸，会损害胎儿的生长和儿童的大脑功能，增加心脏病和糖尿病的风险标记，并破坏特定基因的甲基化。拟议的工作将以这些观察结果为基础，使用金标准研究设计。我们将从两个互补的随机对照试验中分析儿童的DNA甲基化，在这两个试验中，母亲在怀孕前和怀孕早期补充微量营养素。这两个项目是：1)孟买孕产妇营养项目，让孟买贫民窟的妇女每天获得由富含微量营养素的食物制成的零食；2)在冈比亚农村开展的围产期多种微量营养素补充试验，为妇女补充多种微量营养素胶囊。他们记录了胎儿的生长和新生儿的大小，并对这些孩子进行了跟踪。英国-印度小组由MRC资助，为期3年，研究孟买5-6岁儿童的身体组成、后来心脏病和糖尿病的风险因素以及大脑功能。正在从血液样本和脸颊拭子中收集DNA。冈比亚试验中的儿童在7-8岁时被重新追踪，我们将收集相同的结果数据。该提案寻求资金来研究两组儿童的DNA甲基化（孟买N=1100，冈比亚N=350）。全基因组甲基化模式将在干预组之间和队列之间进行比较，并与儿童的体脂、肌肉和骨骼、疾病风险因素、脑功能以及出生结局和发育迟缓相关。一个首要目标是在印度和冈比亚建立表观遗传学研究的能力。该项目将使人们更好地了解产妇营养对儿童的影响，并最终为准备怀孕的母亲设计更好的营养干预措施。

Deficiencies of essential vitamins and minerals (micronutrients) due to poor quality diets are a major public health problem in low-and-middle-income countries (LMICs). In pregnant women they impair fetal development and cause childhood stunting. Recent research pioneered in the UK suggests that they cause long-term problems in the offspring including poor brain and muscle development, increased body fat, and adult heart disease and diabetes. These chronic diseases are rising rapidly in LMICs, where they disable working-age people and require costly treatment. Efforts to prevent them currently focus on promoting healthier adult lifestyles. Research into the developmental origins of health and disease (DOHaD) opens up the potential to both improve child development and prevent adult disease by optimising maternal nutrition. Until recently, evidence for long-term effects of maternal undernutrition was based on observational studies. The research groups in this application have made a step-change by conducting pre- and peri-conceptional randomised controlled nutrition trials among undernourished mothers in India and The Gambia. These trials provide ideal vehicles to study epigenetic mechanisms by which the 'memory' of an individual's nutritional environment in utero could be retained into later life and influence health. One such mechanism is DNA methylation in which the sequence of genes in DNA is overlaid with chemical (methyl) groups which control whether genes are switched on or off. Methylation patterns ('epigenetic signatures') are laid down in early fetal life and are influenced by the mother's nutritional state. In experimental animals, altering maternal diet peri-conceptionally permanently changes offspring DNA methylation, gene expression and adult metabolism. There is growing indirect evidence of similar effects in humans but there are as yet no comparable studies from specific peri-conceptional nutritional interventions.The UK, Indian and Gambian groups have already built strong evidence in observational work that maternal deficiencies of 'methyl donor' nutrients such as vitamins B2, B6, B12 and folate impair fetal growth and the child's brain function, increase heart disease and diabetes risk markers, and disrupt the methylation of specific genes. The proposed work will build on these observations using a gold-standard study design. We will analyse DNA methylation in children from two complementary randomised controlled trials in which mothers were supplemented with micronutrients before conception and into early pregnancy. These are: 1) the Mumbai Maternal Nutrition Project, in which women living in Mumbai slums received a daily snack made from micronutrient-rich foods and 2) the Peri-conceptional Multiple Micronutrient Supplementation Trial in rural Gambia, which supplemented women with multiple micronutrient capsules. Fetal growth and newborn size were recorded and the children are being tracked. The UK-India group is funded by MRC for 3 years to study body composition, risk factors for later heart disease and diabetes, and brain function in the Mumbai children at the age of 5-6 years. DNA is being collected from blood samples and cheek swabs. Children from the Gambian trial have been re-traced at the age of 7-8 years and we will collect the same outcome data. This proposal seeks funds to study DNA methylation in both cohorts of children (Mumbai N=1100, The Gambia N=350). Genome-wide methylation patterns will be compared between intervention groups and between cohorts, and related to the children's body fat, muscle and bone, disease risk factors, and brain function, as well as birth outcomes and stunting. An over-arching objective is to build capacity for epigenetic studies in India and The Gambia. The project will lead to a better understanding of the effects of maternal nutrition on the child, and ultimately to the design of improved nutritional interventions for mothers preparing for pregnancy.