Tom Fleming BBSRC Maternal Mechanisms 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.