The major objective is to investigate the mechanisms by which mouse eggs and preimplantation embryos become susceptible to maternal low protein diet (LPD), and to determine how this condition may """"""""programme"""""""" long-term abnormality in fetal and postnatal growth and development. The concept of egg/embryo sensitivity to environmental conditions has far-reaching healthcare implications (a) in relation to in vitro treatment for human infertility and (b) in the wider context of the established link between poor maternal nutrition and increased risk of adult onset disease, such as coronary heart disease, stroke and hypertension (fetal origin of adult disease hypothesis, FOAD). This hypothesis originated at our institution (University of Southampton), which has a faculty-wide, multidisciplinary, research strategy to identify FOAD mechanisms. Our past studies with rodents have demonstrated that maternal LPD during preimplantation development programmes low birth weight, abnormal growth and hypertension; current work, with our collaborators at the University of York, indicates that the balance of amino acids within the uterine lumen is altered by maternal LPD and may initiate the programming response. We have also developed an in vitro culture and embryo transfer model, which replicates the programming effects of the in vivo LPD diet model, to support investigation of mechanisms. We will use these models to determine the impact of maternal LPD on embryo amino acid content, turnover and selected transporter expression, and address the role of amino acid signaling in fetal programming. The in vitro model will allow for rescue and interventional experimental strategies to be tested. To investigate downstream pathways leading from egg/embryo manipulation and induction of programming using our models to impaired postnatal physiological status, we will conduct (a) fetal gene microarray analysis; (b) fetal/neonatal endocrine analysis using selected components of stress signaling, HPA axis and renin-angiotensin system, shown previously by our FOAD researchers to contribute to programming from sustained maternal LPD throughout gestation; (c) postnatal arterial vasoconstriction and dilation responsiveness for evidence of vascular dysfunction, and (d) behavioural analyses in offspring designed to identify early signs of neurological disease. Our multidisciplinary approach has been designed to provide the first integrative assessment of dietary programming mechanisms, from embryo to adult.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01HD044635-03S1
Application #
7282776
Study Section
Special Emphasis Panel (ZHD1)
Program Officer
Rankin, Tracy L
Project Start
2003-09-11
Project End
2007-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
3
Fiscal Year
2006
Total Cost
$107,572
Indirect Cost
Name
University of Southampton
Department
Type
DUNS #
225595503
City
Southampton
State
Country
United Kingdom
Zip Code
SO17 -1BJ
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Lucas, E S; Watkins, A J; Cox, A L et al. (2011) Tissue-specific selection of reference genes is required for expression studies in the mouse model of maternal protein undernutrition. Theriogenology 76:558-69
Watkins, Adam J; Fleming, Tom P (2009) Blastocyst environment and its influence on offspring cardiovascular health: the heart of the matter. J Anat 215:52-9
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Watkins, Adam J; Papenbrock, Tom; Fleming, Tom P (2008) The preimplantation embryo: handle with care. Semin Reprod Med 26:175-85
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