How do preimplantation embryos sense and respond to maternal nutrition affecting fetal development and adult health?
Lead Research Organisation:
University of Southampton
Department Name: Centre for Biological Sciences
Abstract
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.
Technical Summary
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
Publications
Aljahdali A
(2020)
The duration of embryo culture after mouse IVF differentially affects cardiovascular and metabolic health in male offspring.
in Human reproduction (Oxford, England)
Barker D
(2013)
Developmental biology: Support mothers to secure future public health.
in Nature
Caetano L
(2021)
Blastocyst trophectoderm endocytic activation, a marker of adverse developmental programming.
in Reproduction (Cambridge, England)
Denisenko O
(2016)
Regulation of ribosomal RNA expression across the lifespan is fine-tuned by maternal diet before implantation.
in Biochimica et biophysica acta
Eckert J
(2011)
The effect of nutrition and environment on the preimplantation embryo
in The Obstetrician & Gynaecologist
Eckert JJ
(2015)
Cell signalling during blastocyst morphogenesis.
in Advances in experimental medicine and biology
Fleming T
(2011)
The Placenta and Human Developmental Programming
Fleming T
(2018)
Origins of Lifetime Health Around the Time of Conception: Causes and Consequences
in Obstetrical & Gynecological Survey
Fleming T
(2018)
Encyclopedia of Reproduction
Fleming T
(2009)
Early Life Origins of Human Health and Disease
Fleming TP
(2018)
Origins of lifetime health around the time of conception: causes and consequences.
in Lancet (London, England)
Fleming TP
(2021)
Environmental Exposures around Conception: Developmental Pathways Leading to Lifetime Disease Risk.
in International journal of environmental research and public health
Fleming TP
(2011)
Adaptive responses of the embryo to maternal diet and consequences for post-implantation development.
in Reproduction, fertility, and development
Fleming TP
(2012)
Nutrition of females during the peri-conceptional period and effects on foetal programming and health of offspring.
in Animal reproduction science
Fleming TP
(2015)
Do little embryos make big decisions? How maternal dietary protein restriction can permanently change an embryo's potential, affecting adult health.
in Reproduction, fertility, and development
Fleming TP
(2015)
Embryos, DOHaD and David Barker.
in Journal of developmental origins of health and disease
Fleming TP
(2018)
The remarkable legacy of a father's diet on the health of his offspring.
in Proceedings of the National Academy of Sciences of the United States of America
Fleming TP
(2017)
The Role of Maternal Nutrition During the Periconceptional Period and Its Effect on Offspring Phenotype.
in Advances in experimental medicine and biology
Gould J
(2018)
Mouse maternal protein restriction during preimplantation alone permanently alters brain neuron proportion and adult short-term memory
in Proceedings of the National Academy of Sciences
Gürke J
(2016)
Maternal diabetes promotes mTORC1 downstream signalling in rabbit preimplantation embryos.
in Reproduction (Cambridge, England)
Igosheva N
(2010)
Maternal Diet-Induced Obesity Alters Mitochondrial Activity and Redox Status in Mouse Oocytes and Zygotes
in PLoS ONE
Khurana P
(2022)
Advanced maternal age perturbs mouse embryo development and alters the phenotype of derived embryonic stem cells.
in Journal of developmental origins of health and disease
Khurana P
(2023)
Maternal Undernutrition Induces Cell Signalling and Metabolic Dysfunction in Undifferentiated Mouse Embryonic Stem Cells.
in Stem cell reviews and reports
Kimura TE
(2012)
Desmosomal adhesiveness is developmentally regulated in the mouse embryo and modulated during trophectoderm migration.
in Developmental biology
Lanham SA
(2021)
Periconception maternal low-protein diet adversely affects male mouse fetal bone growth and mineral density quality in late gestation.
in Journal of developmental origins of health and disease
Lucas ES
(2009)
Article
in Cell &Tissue Biology Research
Lucas ES
(2011)
Tissue-specific selection of reference genes is required for expression studies in the mouse model of maternal protein undernutrition.
in Theriogenology
Ojeda DA
(2023)
Preimplantation or gestation/lactation high-fat diet alters adult offspring metabolism and neurogenesis.
in Brain communications
Sellayah D
(2014)
Effect of maternal protein restriction during pregnancy and postweaning high-fat feeding on diet-induced thermogenesis in adult mouse offspring.
in European journal of nutrition
Sellayah D
(2008)
Appetite regulatory mechanisms and food intake in mice are sensitive to mismatch in diets between pregnancy and postnatal periods.
in Brain research
Shevchuk A
(2013)
Combined ion conductance and fluorescence confocal microscopy for biological cell membrane transport studies
in Journal of Optics
Sun C
(2014)
Mouse early extra-embryonic lineages activate compensatory endocytosis in response to poor maternal nutrition.
in Development (Cambridge, England)
Sun C
(2015)
Epigenetic regulation of histone modifications and Gata6 gene expression induced by maternal diet in mouse embryoid bodies in a model of developmental programming.
in BMC developmental biology
Velazquez M
(2016)
The Epigenome and Developmental Origins of Health and Disease
Velazquez M
(2013)
Oogenesis
Velazquez MA
(2019)
Periconceptional environment and the developmental origins of disease.
in The Journal of endocrinology
Velazquez MA
(2018)
Insulin and branched-chain amino acid depletion during mouse preimplantation embryo culture programmes body weight gain and raised blood pressure during early postnatal life.
in Biochimica et biophysica acta. Molecular basis of disease
Velazquez MA
(2015)
The Epigenome and Developmental Origins of Health and Disease
Velazquez MA
(2016)
Advanced maternal age causes adverse programming of mouse blastocysts leading to altered growth and impaired cardiometabolic health in post-natal life.
in Human reproduction (Oxford, England)
Watkins A
(2008)
Low protein diet fed exclusively during mouse oocyte maturation leads to behavioural and cardiovascular abnormalities in offspring
in The Journal of Physiology
Watkins A
(2008)
Adaptive Responses by Mouse Early Embryos to Maternal Diet Protect Fetal Growth but Predispose to Adult Onset Disease1
in Biology of Reproduction
Watkins AJ
(2008)
The preimplantation embryo: handle with care.
in Seminars in reproductive medicine
Watkins AJ
(2010)
Maternal low-protein diet during mouse pre-implantation development induces vascular dysfunction and altered renin-angiotensin-system homeostasis in the offspring.
in The British journal of nutrition
Watkins AJ
(2009)
Blastocyst environment and its influence on offspring cardiovascular health: the heart of the matter.
in Journal of anatomy
Watkins AJ
(2010)
Impact of the periconceptional environment on the programming of adult disease.
in Journal of developmental origins of health and disease
Description | Through our publications, conference presentations and public engagement practices, we have shown that the extra-embryonic lineages of early embryos are sensitive to environmental conditions that can change how they develop and function and associate with later postnatal disease risk |
Exploitation Route | Through forming a foundation for future research to understand the mechanisms of adverse periconceptional developmental programming and through clinical embryology practice and importance of nutrition around the time of conception on adult offspring health |
Sectors | Education Healthcare |
Description | They have been used by other researchers to further understand the importance of environmental conditions in embryo developmental potential. Also, through interaction with educational and social groups to inform on important factors influencing health. |
First Year Of Impact | 2011 |
Sector | Education,Healthcare |
Impact Types | Societal |
Description | Bernd Fischer |
Organisation | Martin Luther University of Halle-Wittenberg |
Department | Department of Anatomy and Cell Biology |
Country | Germany |
Sector | Academic/University |
PI Contribution | Contribution of research expertise |
Collaborator Contribution | Contribution of research material and facilities |
Impact | Maternal diabetes promotes mTORC1 downstream signalling in rabbit preimplantation embryos. Gürke J, Schindler M, Pendzialek SM, Thieme R, Grybel KJ, Heller R, Spengler K, Fleming TP, Fischer B, Navarrete Santos A. Reproduction. 2016 May;151(5):465-76. doi: 10.1530/REP-15-0523. PMID: 26836250 |
Start Year | 2010 |
Description | Henry Leese |
Organisation | University of York |
Department | Department of Psychology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Research material, facilities and expertise |
Collaborator Contribution | Research facilities and expertise |
Impact | Metabolic induction and early responses of mouse blastocyst developmental programming following maternal low protein diet affecting life-long health. Eckert JJ, Porter R, Watkins AJ, Burt E, Brooks S, Leese HJ, Humpherson PG, Cameron IT, Fleming TP. PLoS One. 2012;7(12):e52791. doi: 10.1371/journal.pone.0052791. PMID: 23300778 |
Start Year | 2008 |
Description | Oleg Denisenko |
Organisation | University of Washington |
Department | Department of Biology |
Country | United States |
Sector | Academic/University |
PI Contribution | Collaboration with Dr Oleg Denisenko from University of Washington, Seattle, USA. We provided stored tissue samples, facilities and expertise in developmental programming. |
Collaborator Contribution | Technical and research contribution of ribosome biogenesis mechanism to regulate fetal and offspring tissue growth throughout the lifespan following maternal protein restriction during preimplantation development. |
Impact | Regulation of ribosomal RNA expression across the lifespan is fine-tuned by maternal diet before implantation. Denisenko O, Lucas ES, Sun C, Watkins AJ, Mar D, Bomsztyk K, Fleming TP. Biochim Biophys Acta. 2016 Jul;1859(7):906-13. doi: 10.1016/j.bbagrm.2016.04.001. PMID: 27060415 Epigenetic regulation of histone modifications and Gata6 gene expression induced by maternal diet in mouse embryoid bodies in a model of developmental programming. Sun C, Denisenko O, Sheth B, Cox A, Lucas ES, Smyth NR, Fleming TP. BMC Dev Biol. 2015 Jan 21;15:3. doi: 10.1186/s12861-015-0053-1. PMID: 25609498 |
Start Year | 2012 |
Description | Sue Kimber |
Organisation | University of Manchester |
Department | School of Earth and Environmental Sciences |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Research materials, facilities and expertise |
Collaborator Contribution | Research materials and expertise |
Impact | Maternal nutrition modifies trophoblast giant cell phenotype and fetal growth in mice. Watkins AJ, Lucas ES, Marfy-Smith S, Bates N, Kimber SJ, Fleming TP. Reproduction. 2015 Jun;149(6):563-75. doi: 10.1530/REP-14-0667. PMID: 25755287 |
Start Year | 2012 |