How do preimplantation embryos sense and respond to maternal nutrition affecting fetal development and adult health?

研究表明，一些成人疾病，包括冠心病、中风、二型糖尿病、高血压、骨质疏松症和某些神经系统疾病，更多地源于怀孕期间的“早期生活”经历，而不是成人生活方式因素。从动物和临床研究中，“发育起源”假说已经出现，并提出母体营养的质量将引起发育中的胎儿生长和生理状态的变化，以匹配对出生后生活的营养可用性预测。然而，如果产前和产后的营养供应不一致，适应性反应就会不适当，成人患病的风险就会增加。我们已经开发了一个小鼠模型，在这个模型中，我们特别评估了母体营养在胚胎发育初期，即胚胎包含约50个细胞和植入子宫之前的重要性。这是胚胎产生和分离未来胎儿的创始细胞系与未来胎盘和卵黄囊的细胞系（所谓的胚胎外细胞系涉及母胎营养转移）的时候。我们发现，在母亲的早期发育阶段只喂低蛋白质的饮食，然后在怀孕的其余时间和后代中给予正常饮食，会导致出生体重增加，导致成年疾病，包括超重、高血压和与焦虑有关的异常行为，尤其是在雌性中。我们还发现，怀孕期间体重的增加预示着以后会患上成人疾病，而且似乎至少部分源于胚胎外卵黄囊谱系的变化，卵黄囊谱系在母体向胎儿输送营养物质的细胞过程中变得更有效。根据我们的数据，我们认为胚胎能够感知并对母体营养的质量做出反应，从而确定其未来的生长速度。这些反应是为了保护胎儿发育而设计的，例如，通过控制母胎营养交换的速率。然而，尽管这样的反应可能会为后代提供竞争适应性，以繁殖和传递他们的基因，但它们在以后的生活中具有增加慢性疾病风险的缺点。在目前的拨款申请中，鉴于我们工作的医疗保健意义，我们的目标是确定胚胎对母体饮食的反应是如何产生的。首先，我们将研究胚胎与其环境之间的信号活动，这决定了蛋白质合成和细胞生长的速度，饮食如何改变这一途径以及哪些信号成分易受饮食的影响。其次，我们将研究胚胎外谱系，以了解它们在母胎营养传递中的效率如何被母体饮食所改变。胎盘和卵黄囊是否参与了这一机制？哪些基因和生理过程参与了这一机制？最后，我们将确定母体饮食如何影响胚胎基因组的结构组织，即所谓的表观遗传状态，它决定了基因表达的时间和地点，并可能是已确定的生理反应的基础。我们目前的数据表明，控制表观遗传状态的关键酶在胚胎发育过程中受到母体饮食的影响。我们的研究涉及一个申请人联盟，每个申请人都有特定的研究专长，以支持项目的多学科领域。除了确定机制外，我们还将研究通过包括膳食补充剂来控制胚胎对母体营养反应的不利影响的方法，我们的数据表明，膳食补充剂可能与成人疾病结局有关。

It has been shown that the origin of several adult diseases, including coronary heart disease, stroke, type II diabetes, hypertension, osteoporosis, and certain neurological disorders, derives more from 'early life' experiences during pregnancy that from adult lifestyle factors. From animal and clinical studies, the 'Developmental Origins' hypothesis has emerged and proposes that the quality of maternal nutrition will evoke changes in the growth and physiological status of the developing fetus to match the nutrient availability predicted for postnatal life. However, if pre- and post-natal nutrient availability are inconsistent, adaptive responses become inappropriate and the risk of adult disease increases. We have developed a mouse model in which we have specifically evaluated the importance of maternal nutrition at the beginning of development, when the embryo comprises some 50 cells and before it implants into the uterus. This is when the embryo generates and separates the founder cell lineages for the future fetus from those of the future placenta and yolk sac (so-called extra-embryonic lineages involved in maternal-fetal nutient transfer). We have found that a diet low in protein fed to mothers exclusively during this early developmental period, before giving normal diet for the rest of pregnancy and to the offspring, causes increased birth weight leading to adult disease including overweight, hypertension and abnormal anxiety-related behaviour, especially in females. We have also found that the increased weight during pregnancy was predictive of later acquisition of adult disease and appeared to derive at least in part from changes in the extra-embryonic yolk sac lineage which became more efficient in cellular processes involved in nutrient delivery from mother to fetus. From our data, we propose that the embryo is able to sense and respond to the quality of maternal nutrition available to set its rate of future growth. The responses are designed to protect fetal development by, for example, controlling the rate of maternal-fetal nutrient exchange. However, whilst such responses may confer competitive fitness for offspring to reproduce and pass on their genes, they have the disadvantage in later life of increasing the risk of chronic disease. In the current grant application, given the healthcare implications of our work, we aim to identify how embryo responses to maternal diet are brought about. Firstly, we will investigate the signalling activity between the embryo and its environment which sets the rate of protein synthesis and cell growth, how diet alters this pathway and which signalling components are susceptible to diet. Secondly, we will investigate the extra-embryonic lineages to understand how their efficiency in maternal-fetal nutrient delivery might be altered by maternal diet. Does the placenta contribute to this mechanism as well as the yolk sac, and which genes and what physiological processes are involved? Lastly, we will determine how maternal diet affects the structural organisation of the embryo's genome, the so-called epigenetic status, which governs when and where genes are expressed and may underlie the physiological responses identified. Our current data indicate key enzymes controlling epigenetic status are affected by maternal diet during embryo development. Our studies involve a consortium of applicants, each with specific research expertise to underpin the multidisciplinary areas of the project. In addition to identifying mechanisms, we will also investigate ways to control the adverse effects of embryo response to maternal nutrition by including dietary supplements which our data indicate may be centrally involved in adult disease outcomes.