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

印度和冈比亚孕产前微量营养素补充与后代健康之间的表观遗传机制

• 批准号: MR/N006208/1
• 负责人: Caroline Fall
• 金额: $ 61.94万
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN006208%2F1
• 关键词: Epigenetic; mechanisms; linking; maternal; pre

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.

由于饮食质量差而导致的必需维生素和矿物质（微量营养素）缺乏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，它们会导致后代的长期问题，包括大脑和肌肉发育不良，身体脂肪增加，成年心脏病和糖尿病。这些慢性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，预防这些疾病的努力集中在促进更健康的成人生活方式上。对健康和疾病的发展起源（DOHaD）的研究开辟了通过优化孕产妇营养来改善儿童发育和预防成人疾病的潜力。直到最近，产妇营养不良的长期影响的证据是基于观察研究。本申请中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围产期随机对照营养试验，做出了一个步骤性的改变。这些试验为研究表观遗传机制提供了理想的工具，通过表观遗传机制，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，其中DNA中的基因序列被化学（甲基）基团覆盖，这些基团控制基因的开启或关闭。甲基化模式（“表观遗传特征”）在胎儿早期就已确定，并受到母亲营养状况的影响。在实验动物中，改变母亲的饮食围概念永久改变后代DNA甲基化，基因表达和成人代谢。越来越多的间接证据表明人类存在类似的影响，但目前还没有针对特定围产期营养干预措施的可比研究。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，表明母亲缺乏“甲基供体”营养素，如维生素B2、B6、B12和叶酸会损害胎儿生长和儿童的大脑功能，增加心脏病和糖尿病风险标志物，并破坏特定基因的甲基化。拟议的工作将建立在这些观察使用金标准的研究设计。我们将分析来自两个互补的随机对照试验的儿童的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。这些是：1）孟买产妇营养项目，在该项目中，生活在孟买贫民窟的妇女每天得到一份由富含微量营养素的食物制成的零食; 2）冈比亚农村围孕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。记录了胎儿生长和新生儿大小，并对儿童进行了跟踪。英国-印度小组由MRC资助，为期3年，研究孟买5-6岁儿童的身体成分、日后心脏病和糖尿病的危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岁时重新追踪，我们将收集相同的结局数据。该提案寻求资金以研究两组儿童的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，疾病风险因素和脑功能以及出生结果和发育迟缓有关。一个重要的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。

项目成果

Effect of maternal preconceptional and pregnancy micronutrient interventions on children's DNA methylation: Findings from the EMPHASIS study.

• DOI: 10.1093/ajcn/nqaa193
• 发表时间: 2020-10-01
• 期刊: The American journal of clinical nutrition
• 作者: Saffari A;Shrestha S;Issarapu P;Sajjadi S;Betts M;Sahariah SA;Tomar AS;James P;Dedaniya A;Yadav DK;Kumaran K;Prentice AM;Lillycrop KA;Fall CHD;Chandak GR;Silver MJ;EMPHASIS Study Group
• 通讯作者: EMPHASIS Study Group

Periconceptional environment predicts leukocyte telomere length in a cross-sectional study of 7–9 year old rural Gambian children

• DOI: 10.1038/s41598-020-66729-9
• 发表时间: 2020-06
• 期刊: Scientific Reports
• 影响因子: 4.6
• 作者: Kim Maasen;P. James;A. Prentice;S. Moore;C. Fall;G. Chandak;Modupeh Betts;M. Silver;J. Buxton

Protocol for the EMPHASIS study; epigenetic mechanisms linking maternal pre-conceptional nutrition and children's health in India and Sub-Saharan Africa.

• DOI: 10.1186/s40795-017-0200-0
• 发表时间: 2017-10-30
• 期刊: BMC nutrition
• 影响因子: 2
• 作者: Chandak, Giriraj R;Silver, Matt J;Fall, Caroline Hd
• 通讯作者: Fall, Caroline Hd

Candidate genes linking maternal nutrient exposure to offspring health via DNA methylation: a review of existing evidence in humans with specific focus on one-carbon metabolism.

• DOI: 10.1093/ije/dyy153
• 发表时间: 2018-12-01
• 期刊: International journal of epidemiology
• 影响因子: 7.7
• 作者: James P;Sajjadi S;Tomar AS;Saffari A;Fall CHD;Prentice AM;Shrestha S;Issarapu P;Yadav DK;Kaur L;Lillycrop K;Silver M;Chandak GR;EMPHASIS study group
• 通讯作者: EMPHASIS study group

Tissue- and ethnicity-independent hypervariable DNA methylation states show evidence of establishment in the early human embryo.

• DOI: 10.1093/nar/gkac503
• 发表时间: 2022-07-08
• 期刊: NUCLEIC ACIDS RESEARCH
• 影响因子: 14.9
• 作者: Derakhshan, Maria;Kessler, Noah J.;Ishida, Miho;Demetriou, Charalambos;Brucato, Nicolas;Moore, Gudrun E.;Fall, Caroline H. D.;Chandak, Giriraj R.;Ricaut, Francois-Xavier;Prentice, Andrew M.;Hellenthal, Garrett;Silver, Matt J.
• 通讯作者: Silver, Matt J.