Maternal mechanisms induced by diet regulating embryo developmental plasticity affecting life-long health

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.

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.

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.