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

植入前胚胎如何感知和应对影响胎儿发育和成人健康的母体营养？

• 批准号: BB/F007450/1
• 负责人: Thomas Fleming
• 金额: $ 103.83万
• 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: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FF007450%2F1
• 关键词: How; do; preimplantation; embryos; sense

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.

研究表明，包括冠心病、中风、II型糖尿病、高血压、骨质疏松症和某些神经系统疾病在内的几种成人疾病的起源更多地来自怀孕期间的“早期生活”经历，而不是成人的生活方式因素。从动物和临床研究中，已经出现了“发育起源”假说，并提出母体营养的质量将引起发育中胎儿的生长和生理状态的变化，以匹配出生后生命的营养供应预测。然而，如果产前和产后营养供应不一致，适应性反应变得不适当，成人疾病的风险增加。我们开发了一种小鼠模型，在该模型中，我们专门评估了在胚胎发育开始时，即胚胎包含约50个细胞时以及植入子宫之前母体营养的重要性。这是胚胎产生未来胎儿的创始细胞谱系并将其与未来胎盘和卵黄囊的创始细胞谱系（所谓的参与母胎营养转移的胚外谱系）分离的时候。我们已经发现，在妊娠期的剩余时间和后代给予正常饮食之前，仅在这一早期发育期喂养母亲的低蛋白饮食会导致出生体重增加，导致成年疾病，包括超重、高血压和异常焦虑相关行为，特别是在女性中。我们还发现，怀孕期间体重增加是后期获得成人疾病的预测，并且似乎至少部分来自胚胎外卵黄囊谱系的变化，该谱系在参与母亲向胎儿输送营养的细胞过程中变得更有效。从我们的数据中，我们提出胚胎能够感知和响应母体营养的质量，以确定其未来的生长速度。这些反应旨在通过例如控制母胎营养交换的速率来保护胎儿发育。然而，虽然这种反应可能会赋予后代繁殖和传递基因的竞争适应性，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，考虑到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，我们将研究胚胎及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率，饮食如何改变这一途径，以及哪些信号成分对饮食敏感。其次，我们将研究胚胎外谱系，以了解它们在母胎营养输送中的效率如何被母体饮食改变。胎盘是否与卵黄囊一样参与了这一机制，哪些基因和哪些生理过程参与其中？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，并可能成为确定的生理反应的基础。我们目前的数据表明，在胚胎发育过程中，控制表观遗传状态的关键酶受到母体饮食的影响。我们的研究涉及一个申请人财团，每个人都有具体的研究专业知识，以支持该项目的多学科领域。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良影响的方法，我们的数据表明膳食补充剂可能与成人疾病结局密切相关。

项目成果

Early Life Origins of Human Health and Disease

人类健康和疾病的早期生命起源

• DOI: 10.1159/000221154
• 发表时间: 2009
• 作者: Fleming T

Metabolic induction and early responses of mouse blastocyst developmental programming following maternal low protein diet affecting life-long health.

• DOI: 10.1371/journal.pone.0052791
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Eckert JJ;Porter R;Watkins AJ;Burt E;Brooks S;Leese HJ;Humpherson PG;Cameron IT;Fleming TP
• 通讯作者: Fleming TP

Regulation of ribosomal RNA expression across the lifespan is fine-tuned by maternal diet before implantation.

• DOI: 10.1016/j.bbagrm.2016.04.001
• 发表时间: 2016-07
• 期刊: Biochimica et biophysica acta
• 作者: Denisenko O;Lucas ES;Sun C;Watkins AJ;Mar D;Bomsztyk K;Fleming TP
• 通讯作者: Fleming TP

The duration of embryo culture after mouse IVF differentially affects cardiovascular and metabolic health in male offspring.

• DOI: 10.1093/humrep/deaa205
• 发表时间: 2020-11-01
• 期刊: Human reproduction (Oxford, England)
• 作者: Aljahdali A;Airina RKRI;Velazquez MA;Sheth B;Wallen K;Osmond C;Watkins AJ;Eckert JJ;Smyth NR;Fleming TP
• 通讯作者: Fleming TP

Encyclopedia of Reproduction

繁殖百科全书

• DOI: 10.1016/b978-0-12-801238-3.64515-4
• 发表时间: 2018
• 作者: Fleming T