Maternal mechanisms induced by diet regulating embryo developmental plasticity affecting life-long health
Lead Research Organisation:
University of Southampton
Department Name: Centre for Biological Sciences
Abstract
The prevalence of adult cardiovascular and metabolic diseases continues to increase worldwide at an epidemic rate. Studies on patients have shown that risk factors for such diseases relate more strongly to conditions of prenatal life, such as the quality of maternal nutrition, that contemporary lifestyle factors. Our work, using rodent models, has demonstrated that the earliest stage of embryo development, before implantation has occurred, is highly sensitive to maternal nutrient levels. Poor maternal protein nutrition at this time can change how the embryo develops, an attempt to heighten its survival chances and called 'developmental plasticity', but which ultimately leads to increased risk of cardiovascular and metabolic disease in later adult life. New data on IVF children who would also have experienced relatively poor nutrient conditions as embryos in culture, show increased risk of elevated blood pressure and metabolic disorders. More recently, our research has focused on many of the mechanisms of embryo responses to poor maternal diet and how these change the subsequent developmental programme and adult health, however, we still do not know how the responses are activated in the first place. If we could discover what precisely induces developmental plasticity in embryos, this information would allow us to devise preventative strategies against adverse health outcomes. We have a substantial body of preliminary data that indicates that the mother utilises the composition of amino acids and possibly insulin within the uterine lumen to communicate to the embryo that nutrient levels are poor which then provokes developmental plasticity in the embryo to enhance survival but leads to adult disease. We will use an embryo in vitro culture model we have developed to mimic conditions within the uterine lumen to modulate this communication pathway and determine precisely the molecular configuration of amino acids and insulin that provoke embryo responses. These responses and impact on later development and adult disease risk will be closely monitored using embryo transfer to foster mothers.This information will allow us to suplement maternal diet in precise ways in an attempt to block adverse developmental programming affecting adult health. A second part of our study concerns a further mechanism mediated by the mother in response to poor maternal diet. Our preliminary data has shown that the uterine wall is induced to generate an increased supply of blood vessels in response to poor diet around the time of implantation. This discovery raises a new concept that the mother can enhance nutient delivery in response to poor diet in early gestation, supplementing the activities mediated by the embryo responses. This maternal response will be characterised fully and assessed whether it is a direct response to dietary signals within the mother or represents the outcome of a signal mediated by the embryo. We will also assess, in quantitative terms, the contribution made by enhanced uterine vascularisation on embryo and fetal survival and growth relative to other aspects of embryo developmental plasticity. These studies on maternal mechanisms associated with developmental programming will provide a powerful resource for developing further dietary/pharmacological strategies to combat adverse gestational induction of disease.
Technical Summary
The worldwide increase in cardiovascular and metabolic diseases has been shown in epidemiological studies to derive mainly from prenatal causes associated with poor maternal nutrition and adverse developmental programming. Our past work using rodent models has shown that maternal low protein diet exclusively during preimplantation development (Emb-LPD) is sufficient to induce adult cardiovascular, metabolic and behavioural disease. Thus, embryos make compensatory responses to poor diet (developmental plasticity) that act to stimulate nutrient retrieval during later gestation to promote survival and growth but which associate with adult disease. An increased risk of cardiovascular and metabolic disorders has recently been shown in IVF children. This proposal will investigate two mechanisms induced by maternal Emb-LPD within the mother that contribute to embryo responses. The first concerns the molecular nature of the communication pathway within the maternal tract that induces embryo responses. Our substantial preliminary data implicate specific amino acid composition potentially coupled with insulin signalling as the inductive components. We will use an in vitro culture model to modulate this communication pathway and monitor outcomes at embryo, fetal and adult stages following embryo transfer as necessary. This will provide precise molecular information on the induction mechanism for adverse developmental plasticity leading to adult disease and will allow us to modulate diet in a precise way in an attempt to prevent adult disease. The second mechanism concerns our recent discovery of maternal upregulation of uterine angiogenesis at the time of implantation induced by Emb-LPD. This mechanism will be characterised in molecular terms, how it is induced, and its relative contribution to developmental programming determined in quantitative terms.
Planned Impact
Beneficiaries of this research and how its outcomes will be exploited: Apart from academic beneficiaries, this work will benefit the commercial private sector because it will lead to new information on the molecular identity of maternal factors that induce changes in the pattern of embryo development and which can associate with postnatal cardiovascular and metabolic adult disease. This will be of particular relevance to commercial interests in assisted embryology technologies (ART) in the provision of safer culture conditions for human embryos to suppress potential poor health outcomes via adverse developmental programming. This phenomenon of adverse cardiovascular and metabolic health has already been identified in IVF children. This research will also benefit the commercial private sector in the provision of potential factors and supplements, of a dietary or pharmacological nature, that may prevent adverse developmental programming in mothers at the time of conception. Policy makers, at government level or their agencies, at international or national levels, may benefit from this research as it will provide molecular information on the conditions that can activate adverse developmental programming in early gestation leading to cardiovascular and metabolic disease in adulthood. The impact of this information on, for example, the regulation of ART practices by the Human Fertilisation and Embryology Authority would be one governmental agency that would benefit. Also, those policy-makers concerned with safety in maternal periconceptional nutritional supplements would benefit from this work. The timescale for commercial and policy-making benefits would likely be within five years of completion of the project. The wider public will also benefit from this research. The opportunities presented by safer use of ART, strategies for improved nutrition at the time of conception, and causes and ways to prevent the alarming rise in cardiovascular and metabolic disease afflicting world populations are all issues of intense interest to the wider public at schools, public lectures, museums and other educational venues and events. The impact of our research will also benefit the research community itself by provision of a postdoctoral scientist with skills and training in relevant disciplines within the reproductive, cell biological, molecular and physiological fields associated with this project. Further generic skills appropriate for exploitation within the scientific profession include data management, image analysis, multivariate and random effects statistics, bioinformatics. The project will be managed to ensure appropriate exploitation and impact of our research is maximised. Research data will be communicated at national and international scientific meetings and published within peer-reviewed high impact journals. Direct commercial exploitation of relevant data will be achieved through the University of Southampton's Research and Enterprise Services to maximise potential. Dialogue with the wider public will be achieved, as now, from regular outreach activities including school and college visits, university Open Days, and more specialist Public Lecture events.
Publications
Eckert J
(2011)
The effect of nutrition and environment on the preimplantation embryo
in The Obstetrician & Gynaecologist
Lucas ES
(2011)
Tissue-specific selection of reference genes is required for expression studies in the mouse model of maternal protein undernutrition.
in Theriogenology
Fleming TP
(2011)
Adaptive responses of the embryo to maternal diet and consequences for post-implantation development.
in Reproduction, fertility, and development
Kimura TE
(2012)
Desmosomal adhesiveness is developmentally regulated in the mouse embryo and modulated during trophectoderm migration.
in Developmental biology
Fleming TP
(2012)
Nutrition of females during the peri-conceptional period and effects on foetal programming and health of offspring.
in Animal reproduction science
Barker D
(2013)
Developmental biology: Support mothers to secure future public health.
in Nature
Velazquez M
(2013)
Oogenesis
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)
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
Fleming TP
(2015)
Embryos, DOHaD and David Barker.
in Journal of developmental origins of health and disease
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
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
Watkins AJ
(2015)
Maternal nutrition modifies trophoblast giant cell phenotype and fetal growth in mice.
in Reproduction (Cambridge, England)
Eckert JJ
(2015)
Cell signalling during blastocyst morphogenesis.
in Advances in experimental medicine and biology
Velazquez MA
(2015)
The Epigenome and Developmental Origins of Health and Disease
Denisenko O
(2016)
Regulation of ribosomal RNA expression across the lifespan is fine-tuned by maternal diet before implantation.
in Biochimica et biophysica acta
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)
Gürke J
(2016)
Maternal diabetes promotes mTORC1 downstream signalling in rabbit preimplantation embryos.
in Reproduction (Cambridge, England)
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
Description | We have discovered key mechanisms inducing early developmental programming of embryos based upon poor maternal nutrition, mediated through embryo sensing of maternal select amino acids and insulin and that this can induce long-term programming of adult disease using a mouse model. |
Exploitation Route | To form a basis for future research in both basic science and clinical areas concerning the importance of early embryo environment on long-term health of offspring |
Sectors | Education,Healthcare |
Description | To further understand how maternal nutrition may affect the developmental potential of early embryos and to define which nutrients are responsible for this interaction. To inform the clinical embryology community on mechanisms of adverse developmental programming mediated through poor maternal diet |
First Year Of Impact | 2008 |
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 |