Functional and epigenetic consequences of maternal folate deficiency, supplementation and fetal growth restriction

出生前发育缓慢或早产是很常见的。这两种情况都大大增加了出生时患病或死亡的风险，以及婴儿在以后的生活中患上糖尿病和心血管疾病等主要疾病的风险。尽管它们很重要，但我们对导致胎儿生长衰竭或早产的原因知之甚少，也不知道它们为什么会影响个体的一生健康。最近的研究结果表明，由于饮食或遗传因素，母亲体内叶酸水平低可能与它们的起源和长期后果有关。叶酸是生长和维持健康所需的一种营养物质。目前建议妇女在怀孕前和怀孕早期补充叶酸，但可能在整个怀孕期间都有促进婴儿生长和健康的作用。通过实验模型，该项目将确定母亲叶酸过少或过多是否会改变婴儿的遗传密码（称为表观遗传变化），从而导致后来的代谢性疾病和高血压。这些表观遗传变化是DNA的轻微和微妙的化学修饰，持续存在于婴儿的细胞中，改变了它们的功能。母亲补充叶酸对改善小婴儿这些结果的功效也将在模型中进行测试。最后，将测试正常婴儿和小婴儿叶酸状态对其胎盘、脐带血白细胞和口腔粘膜细胞表观遗传状态的影响。这些结果将有助于设计和测试在母亲体内添加叶酸和相关营养素的干预措施，从而在婴儿出生前和随后的一生中改善其健康。由于这些由早产或早产引起的妊娠并发症很常见，并且是晚年发生的糖尿病的主要原因，因此开发有效的干预措施对健康的益处可能很大。

Growing slowly before birth or being born early and premature are very common. Both conditions greatly increase the risk of illness or death around birth and of the infant developing major conditions such as diabetes and cardiovascular disease in later life. Despite their importance, we understand little of what causes fetal growth failure or prematurity or why they influence an individual's health throughout life. Recent findings suggest that low levels of folate in the mother, due to either dietary or genetic factors, may be involved in their origins and their long-term outcomes. Folate is a nutrient required regularly in small amounts for growth and maintenance of health. Folate supplementation in women is currently recommended before and in early pregnancy, but may have a role throughout the whole of pregnancy in promoting growth and health of the infant. Using experimental models, this project will determine if too little or too much maternal folate modifies the genetic code of the infant (called epigenetic changes), which leads to later metabolic disease and high blood pressure. These epigenetic changes are mild and subtle chemical modifications of DNA that persist in the cells of the infant altering their function. The efficacy of maternal folate supplementation in improving these outcomes for the small baby will also be tested in the models. Finally, the effect of folate status in the normal and small human infant on the epigenetic state of their placenta, cord blood white blood cells and mucous cells of the mouth will be tested. These outcomes will enable the design and testing of interventions with folate and related nutrients in the mother to improve the health of their babies before birth and subsequently throughout their lives. Because these pregnancy complications of being born small or early are common and account for much of the diabetes that occurs in later life, the health benefits from development of effective interventions may be large.