DOHaD

The epidemiological studies by Prof David Barker (1938 - 2013) (Barker et al., 1993) at the University of Southampton (USH) have demonstrated that susceptibility to adult diseases such as coronary heart disease, stroke, hypertension, type II diabetes, obesity and osteoporosis, whilst having adult lifestyle risk factors, correlate independently and more strongly with early life factors such as low weight, small size and thinness at birth.

The concept of postnatal phenotype and health being strongly related to developmental programming in utero has fundamental implications for preventative healthcare policy. The concept of Developmental Origins of Health and Disease (DOHaD) has radically altered the fields of reproductive and developmental biology. The DOHaD concept has been consolidated and confirmed in many epidemiological studies on diverse global populations, and the underlying mechanisms explored across many animal models. However, very recently, DOHaD has advanced into a new, and potentially the most critical, window in which developmental plasticity is vulnerable to environmental challenge – the periconception period. It is at this early stage that epigenetic restructuring of the genome is most intense and also where clinical and biotechnological interventions, i.e. IVF and related reproductive interventions, are at their peak. This combination of biological vulnerability and technological opportunity makes it imperative to advance our understanding of periconception programming and to train new scientists in this challenging area. The expertise of our consortium is focused on this critical window, and we have state-of-the-art technologies and models to transmit this knowledge to new, young investigators. While the DOHaD concept is not novel, its major implications for human and animal health have only been fully recognised relatively recently; this was reflected by the 2010/11 FP7 collaborative calls in Health and KBBE specifically requesting projects on this topic. Most of the partners of current EpiHealthNet application successfully applied within the FP7 call and are collaboratively working on periconceptional developmental programming within the EpiHealth project (FP7-EpiHealth N°278418) - however, there is a lack of training networks to provide ESRs for the expected rapid growth of this multidisciplinary field and the current proposal is focusing to complement and go far beyond the collaborative project scene with novel scientific and training elements, including “omics” trainings and 4 additional non-rodent animal models. There is now an appreciation that extrinsic factors interact with the core developmental process, providing ‘plasticity’ in phenotype during development, which allows an organism to ‘select’ the phenotype best suited to its future environment from a given genotype, mediated through factors associated with nutrient availability (Gluckman and Hanson, 2004). If nutrient availability changes from that ‘predicted’ during the period of developmental plasticity, the mismatch can lead to an increased risk of adult disease. Mechanisms contributing to DOHaD are complex and involve interactions across epigenetic, endocrine and physiological processes. Recent work by USH using rat and mouse models has shown that early embryos perform a central role in detecting the quality of maternal nutrition and making compensatory responses by the blastocyst stage, which modify how they develop and underlies the subsequent change in growth, postnatal phenotype and disease risk (notably hypertension, anxiety-related behaviour, and abnormal organ allometry, especially in females (Kwong et al, 2000, Watkins et al, 2008, 2010). Very recently USH preliminary data has shown that immunological challenges to the mother during the pre-implantation period influences the immune response of the progeny. (Williams et al, 2011). It is clear that major long term health effects in adults are expected from this biological variability originating from the first few days of embryonic development.