Award details

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

Reference	BB/F007450/1
Principal Investigator / Supervisor	Professor Thomas Fleming
Co-Investigators / Co-Supervisors	Dr Judith Eckert, Professor Mark Hanson, Professor Susan Kimber, Professor Rohan Lewis, Professor Karen Lillycrop, Professor Terry Mayhew, Dr Thomas Papenbrock
Institution	University of Southampton
Department	Centre for Biological Sciences
Funding type	Research
Value (£)	814,870
Status	Completed
Type	Research Grant
Start date	01/04/2008
End date	30/04/2011
Duration	37 months

Abstract

The proposal investigates mechanisms of developmental plasticity induced within the mouse preimplantation embryo, responding to maternal dietary protein level in vivo. From our past work using this model, we have found maternal low protein diet fed exclusively during this period (Emb-LPD) leads to enhanced perinatal growth and onset of adult disease in offspring, including overweight, hypertension and abnormal behaviour especially in females. Our data show that the rise in perinatal growth is (i) induced by the blastocyst stage as a compensatory response to poor maternal diet, (ii) is mediated at least in part by increased histiotrophic endocytic activity of the extra-embryonic visceral yolk sac later in development, and (iii) is predictive of adult overweight and hypertension. Embryo responses to maternal diet may protect fetal growth and likely confer competitive fitness but also lead to adult diseases. Here, we propose three new research directions to identify the contributory mechanisms to embryo developmental plasticity: (a) to determine how dietary signals mediate embryonic growth control via the mTOR signalling complex; (b) to determine the relative contributions of placental and yolk sac lineages in the compensatory responses made by embryos to maternal diet, and (c) to determine whether these physiological mechanisms derive from epigenetic changes to key gene families; notably, (i) DNA methyltransferases which we find are significantly upregulated in transcription by dietary-induced embryo responses from the blastocyst stage onwards, and (ii) imprinted genes which, through mechanisms of genomic conflict, may coordinate extra-embryonic responses to maternal Emb-LPD. Throughout, our research plan comprises multidisciplinary approaches to understand the integrated nature of mechanisms regulating embryo developmental plasticity in vivo, reflecting the specific expertise of the individual applicants

Summary

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 toprotect 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.

Committee	Closed Committee - Agri-food (AF)
Research Topics	Diet and Health
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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