Developmental programming of the metabolic syndrome by maternal nutritional imbalance: how strong is the evidence from experimental models in mammals?

The incidence of the metabolic syndrome, a cluster of abnormalities focusing on insulin resistance and associated with high risk for cardiovascular disease and diabetes, is reaching epidemic proportions. Prevalent in both developed and developing countries, the metabolic syndrome has largely been attributed to altered dietary and lifestyle factors that favour the development of central obesity. However, population‐based studies have suggested that predisposition to the metabolic syndrome may be acquired very early in development through inappropriate fetal or neonatal nutrition. Further evidence for developmental programming of the metabolic syndrome has now been suggested by animal studies in which the fetal environment has been manipulated through altered maternal dietary intake or modification of uterine artery blood flow. This review examines these studies and assesses whether the metabolic syndrome can be reliably induced by the interventions made. The validity of the different species, diets, feeding regimes and end‐point measures used is also discussed.

[1]  P Trayhurn,et al.  Leptin resistance in obese humans: does it exist and what does it mean? , 1998, International Journal of Obesity.

[2]  C. Yajnik,et al.  Interactions of perturbations in intrauterine growth and growth during childhood on the risk of adult-onset disease , 2000, Proceedings of the Nutrition Society.

[3]  T. G. Butler,et al.  Differential effects of the early and late intrauterine environment on corticotrophic cell development. , 2002, The Journal of clinical investigation.

[4]  A. Jackson,et al.  Increased systolic blood pressure in adult rats induced by fetal exposure to maternal low protein diets. , 1994, Clinical science.

[5]  J. Owens,et al.  Changes to metabolite concentration in fetal sheep subjected to prolonged hypobaric hypoxia. , 1988, Journal of developmental physiology.

[6]  S. Oparil,et al.  Sex difference in blood pressure of spontaneously hypertensive rats influenced by perinatal NaCl exposure , 1992, Physiology & Behavior.

[7]  D. Pawlak,et al.  Diabetes in Old Male Offspring of Rat Dams Fed a Reduced Protein Diet , 2001, International journal of experimental diabetes research.

[8]  P. Gluckman,et al.  A model of intrauterine growth retardation caused by chronic maternal undernutrition in the rat: effects on the somatotrophic axis and postnatal growth. , 1996, The Journal of endocrinology.

[9]  P. Czernichow,et al.  Beta-cell mass and proliferation following late fetal and early postnatal malnutrition in the rat , 1998, Diabetologia.

[10]  E. Wintour,et al.  Programmed hypertension: kidney, brain or both? , 2002, Trends in Endocrinology & Metabolism.

[11]  Alan A Jackson,et al.  Increased systolic blood pressure in rats induced by a maternal low-protein diet is reversed by dietary supplementation with glycine. , 2002, Clinical science.

[12]  C. Remacle,et al.  Islet Function in Offspring of Mothers on Low-Protein Diet During Gestation , 1991, Diabetes.

[13]  Simon J. M. Welham,et al.  Weanling rats exposed to maternal low-protein diets during discrete periods of gestation exhibit differing severity of hypertension. , 1996, Clinical science.

[14]  Z. Fortes,et al.  Severe Nutritional Restriction in Pregnant Rats Aggravates Hypertension, Altered Vascular Reactivity, and Renal Development in Spontaneously Hypertensive Rats Offspring , 2002, Journal of cardiovascular pharmacology.

[15]  C. Osmond,et al.  Coronary heart disease after prenatal exposure to the Dutch famine, 1944–45 , 2000, Heart.

[16]  B. Richardson,et al.  Cerebral circulatory responses of near-term ovine fetuses during sustained fetal placental embolization. , 1997, American journal of physiology. Heart and circulatory physiology.

[17]  S. Grundy,et al.  The metabolic syndrome: a practical guide to origins and treatment: Part II. , 2003, Circulation.

[18]  R. Collins,et al.  Unravelling the fetal origins hypothesis: is there really an inverse association between birthweight and subsequent blood pressure? , 2002, The Lancet.

[19]  L. Aerts,et al.  Long-term consequences for offspring of diabetes during pregnancy. , 2001, British medical bulletin.

[20]  E. Lakatta Age-related alterations in the cardiovascular response to adrenergic mediated stress. , 1980, Federation proceedings.

[21]  B. Breier,et al.  IGF-I treatment reduces hyperphagia, obesity, and hypertension in metabolic disorders induced by fetal programming. , 2001, Endocrinology.

[22]  D. Gardner,et al.  Peri-Implantation Undernutrition Programs Blunted Angiotensin II Evoked Baroreflex Responses in Young Adult Sheep , 2004, Hypertension.

[23]  A. Piersma,et al.  Dietary fatty acid composition during pregnancy and lactation in the rat programs growth and glucose metabolism in the offspring , 2002, Diabetologia.

[24]  P. D. de Leeuw,et al.  Reduced Uteroplacental Blood Flow Alters Renal Arterial Reactivity and Glomerular Properties in the Rat Offspring , 2004, Hypertension.

[25]  P. Gluckman,et al.  Fetal origins of hyperphagia, obesity, and hypertension and postnatal amplification by hypercaloric nutrition. , 2000, American journal of physiology. Endocrinology and metabolism.

[26]  F. Hu,et al.  Dietary modulation of endothelial function: implications for cardiovascular disease. , 2001, The American journal of clinical nutrition.

[27]  B. Reusens,et al.  Nutrient metabolism in pancreatic islets from protein malnourished rats. , 1996, Biochemical and molecular medicine.

[28]  A. Harris,et al.  Carboplatin/cisplatin , 2012, Reactions Weekly.

[29]  Rohan M. Lewis,et al.  Long-term programming of blood pressure by maternal dietary iron restriction in the rat , 2002, British Journal of Nutrition.

[30]  P. Primatesta,et al.  Birthweight and blood pressure in children: does the association exist? Annual Scientific Meeting of the British Hypertension Society , 2003 .

[31]  J. Parer,et al.  Regional brain blood flow and cerebral hemispheric oxygen consumption during acute hypoxaemia in the llama fetus , 2002, The Journal of physiology.

[32]  S. Grundy,et al.  The metabolic syndrome: practical guide to origins and treatment: Part I. , 2003, Circulation.

[33]  ImranKhan,et al.  Predictive Adaptive Responses to Maternal High-Fat Diet Prevent Endothelial Dysfunction but Not Hypertension in Adult Rat Offspring , 2004 .

[34]  K. Jen,et al.  High-fat feeding during pregnancy and lactation affects offspring metabolism in rats , 1995, Physiology & Behavior.

[35]  P. Clifton,et al.  Effect of maternal feed restriction on blood pressure in the adult guinea pig , 2002, Experimental physiology.

[36]  S E Ozanne,et al.  Effect of maternal iron restriction during pregnancy on renal morphology in the adult rat offspring , 2003, British Journal of Nutrition.

[37]  B. Reusens,et al.  Effect of a low protein diet during pregnancy on the fetal rat endocrine pancreas. , 1990, Biology of the neonate.

[38]  M. Susser,et al.  Obesity in young men after famine exposure in utero and early infancy. , 1976, The New England journal of medicine.

[39]  L. Poston,et al.  Maternal food restriction in the second half of pregnancy affects vascular function but not blood pressure of rat female offspring , 1999, British Journal of Nutrition.

[40]  R. Grimble,et al.  Influence of dietary fats upon systolic blood pressure in the rat. , 1996, International journal of food sciences and nutrition.

[41]  C. Cooper,et al.  Prenatal Exposure to a Maternal Low Protein Diet Shortens Life Span in Rats , 2001, Gerontology.

[42]  S. Ozanne,et al.  Early protein restriction and obesity independently induce hypertension in 1-year-old rats. , 1997, Clinical science.

[43]  D. Keisler,et al.  Programming of adult cardiovascular function after early maternal undernutrition in sheep. , 2004, American journal of physiology. Regulatory, integrative and comparative physiology.

[44]  J. Preston,et al.  Effects of maternal dietary protein restriction on body weight and organ growth in rat offspring , 2004 .

[45]  V. Herrera,et al.  Prenatal malnutrition-induced changes in blood pressure: dissociation of stress and nonstress responses using radiotelemetry. , 1998, Hypertension.

[46]  A. Nuyt,et al.  Altered Vascular Function in Fetal Programming of Hypertension , 2002, Stroke.

[47]  P. Taylor,et al.  Exposure to a high fat diet during gestation & weaning results in reduced elasticity & endothelial function as well as altered gene expression & fatty acid content of rat aorta. , 2004 .

[48]  I. McMillen,et al.  Maternal undernutrition increases arterial blood pressure in the sheep fetus during late gestation , 2001, The Journal of physiology.

[49]  C. Osmond,et al.  Plasma lipid profiles in adults after prenatal exposure to the Dutch famine. , 2000, The American journal of clinical nutrition.

[50]  R. Lewis,et al.  Effects of maternal iron restriction in the rat on blood pressure, glucose tolerance, and serum lipids in the 3-month-old offspring. , 2001, Metabolism: clinical and experimental.

[51]  L. Poston,et al.  Maternal protein restriction in the rat impairs resistance artery but not conduit artery function in pregnant offspring , 2003, The Journal of physiology.

[52]  E. Kraegen,et al.  Influence of Dietary Fat Composition on Development of Insulin Resistance in Rats: Relationship to Muscle Triglyceride and ω-3 Fatty Acids in Muscle Phospholipid , 1991, Diabetes.

[53]  N. Solanky,et al.  Iron deficiency during pregnancy affects postnatal blood pressure in the rat , 2003, The Journal of physiology.

[54]  C. Osmond,et al.  Adult survival after prenatal exposure to the Dutch famine 1944--45. , 2001, Paediatric and perinatal epidemiology.

[55]  S. Picard,et al.  Induction of intrauterine growth restriction with a low-sodium diet fed to pregnant rats. , 1999, American journal of obstetrics and gynecology.

[56]  Imran Y. Khan,et al.  Predictive Adaptive Responses to Maternal High-Fat Diet Prevent Endothelial Dysfunction but Not Hypertension in Adult Rat Offspring , 2004, Circulation.

[57]  Imran Y. Khan,et al.  Impaired glucose homeostasis and mitochondrial abnormalities in offspring of rats fed a fat-rich diet in pregnancy. , 2005, American journal of physiology. Regulatory, integrative and comparative physiology.

[58]  A. Fowden,et al.  Low Doses of Dexamethasone Suppress Pituitary-Adrenal Function but Augment the Glycemic Response to Acute Hypoxemia in Fetal Sheep during Late Gestation , 2000, Pediatric Research.

[59]  S. Rees,et al.  Fetal brain injury following prolonged hypoxemia and placental insufficiency: a review. , 1998, Comparative biochemistry and physiology. Part A, Molecular & integrative physiology.

[60]  C. Martyn,et al.  Growth in utero, adult blood pressure, and arterial compliance. , 1995, British heart journal.

[61]  Mark Hanson,et al.  Dietary Protein Restriction in Pregnancy Induces Hypertension and Vascular Defects in Rat Male Offspring , 2003, Pediatric Research.

[62]  Clive Osmond,et al.  Effects of prenatal exposure to the Dutch famine on adult disease in later life: an overview , 2001, Molecular and Cellular Endocrinology.

[63]  P. V. van Zijl,et al.  Effects of Intrauterine Growth Restriction and Intraamniotic Insulin-like Growth Factor-I Treatment on Blood and Amniotic Fluid Concentrations and on Fetal Gut Uptake of Amino Acids in Late-Gestation Ovine Fetuses , 2002, Journal of pediatric gastroenterology and nutrition.

[64]  D. Barker,et al.  The thrifty phenotype hypothesis. , 2001, British medical bulletin.

[65]  S. Ozanne,et al.  Altered muscle insulin sensitivity in the male offspring of protein-malnourished rats. , 1996, The American journal of physiology.

[66]  S. Ozanne,et al.  Early growth restriction leads to down regulation of protein kinase C zeta and insulin resistance in skeletal muscle. , 2003, The Journal of endocrinology.

[67]  C. Scavone,et al.  Enhanced Oxidative Stress As a Potential Mechanism Underlying the Programming of Hypertension In Utero , 2002, Journal of cardiovascular pharmacology.

[68]  Mark A. Hanson,et al.  The developmental origins of the metabolic syndrome , 2004, Trends in Endocrinology & Metabolism.

[69]  P. Calder,et al.  Effect of reduced maternal protein intake in pregnancy in the rat on the fatty acid composition of brain, liver, plasma, heart and lung phospholipids of the offspring after weaning , 2003, British Journal of Nutrition.

[70]  P. Clifton,et al.  Effect of maternal feed restriction during pregnancy on glucose tolerance in the adult guinea pig. , 2003, American journal of physiology. Regulatory, integrative and comparative physiology.

[71]  P. Czernichow,et al.  In utero undernutrition impairs rat beta-cell development , 1997, Diabetologia.

[72]  H. K. Lee Evidence that the mitochondrial genome is the thrifty genome. , 1999, Diabetes research and clinical practice.

[73]  C Osmond,et al.  Obesity at the age of 50 y in men and women exposed to famine prenatally. , 1999, The American journal of clinical nutrition.

[74]  M. Hanson,et al.  Effect of maternal nutrient restriction in early gestation on development of the hypothalamic-pituitary-adrenal axis in fetal sheep at 0.8-0.9 of gestation. , 1999, The Journal of endocrinology.

[75]  Lubo Zhang,et al.  Effects of chronic hypoxia on maternal vasodilation and vascular reactivity in guinea pig and ovine pregnancy. , 2003, High altitude medicine & biology.

[76]  C. Osmond,et al.  Blood pressure in adults after prenatal exposure to famine. , 1999, Journal of hypertension.

[77]  M. Runge,et al.  Mitochondrial Integrity and Function in Atherogenesis , 2002, Circulation.

[78]  R. J. Contreras High NaCl intake of rat dams alters maternal behavior and elevates blood pressure of adult offspring. , 1993, The American journal of physiology.

[79]  R. J. Contreras,et al.  Perinatal exposure to a high NaCl diet increases the NaCl intake of adult rats , 1990, Physiology & Behavior.

[80]  M A Hanson,et al.  Dietary restriction in pregnant rats causes gender‐related hypertension and vascular dysfunction in offspring , 2001, The Journal of physiology.

[81]  Y. Pak,et al.  Fetal and early postnatal protein malnutrition cause long-term changes in rat liver and muscle mitochondria. , 2003, The Journal of nutrition.

[82]  Michael J Meaney,et al.  Epigenetic programming by maternal behavior , 2004, Nature Neuroscience.

[83]  James C. Smith,et al.  High dietary NaCl early in development enhances mean arterial pressure of adult rats , 2000, Physiology & Behavior.

[84]  M. Holness,et al.  Antecedent protein restriction exacerbates development of impaired insulin action after high-fat feeding. , 1999, American journal of physiology. Endocrinology and metabolism.

[85]  P. Clifton,et al.  Restricted fetal growth and the response to dietary cholesterol in the guinea pig. , 1999, American journal of physiology. Regulatory, integrative and comparative physiology.

[86]  A. Vingrys,et al.  Perinatal omega-3 fatty acid deficiency affects blood pressure later in life , 2001, Nature Medicine.

[87]  S. Ozanne,et al.  Altered adipocyte properties in the offspring of protein malnourished rats , 1997, British Journal of Nutrition.

[88]  J. Dobbing,et al.  Fetal nutrition and cardiovascular disease in adult life , 1993, The Lancet.

[89]  K. Bergmann,et al.  Iron deficiency is prevalent in a sample of pregnant women at delivery in Germany. , 2002, European journal of obstetrics, gynecology, and reproductive biology.

[90]  J. Caldwell,et al.  Effects of aging on cardiovascular responses to parasympathetic withdrawal. , 2003, Journal of the American College of Cardiology.

[91]  D J Barker,et al.  Fetal origins of coronary heart disease , 1995, BMJ.

[92]  C Osmond,et al.  Size at birth, maternal weight, and Type 2 diabetes in South India , 1998, Diabetic medicine : a journal of the British Diabetic Association.

[93]  J. Cooke,et al.  Phytoestrogens and cardiovascular health. , 2000, Journal of the American College of Cardiology.

[94]  W. Connor The beneficial effects of omega-3 fatty acids: cardiovascular disease and neurodevelopment. , 1997, Current opinion in lipidology.

[95]  M. Srinivasan,et al.  Lifespan: Catch-up growth and obesity in male mice , 2004, Nature.

[96]  E. Grossman,et al.  Rosiglitazone reduces blood pressure and urinary albumin excretion in type 2 diabetes: G Bakris et al , 2003, Journal of Human Hypertension.

[97]  C. Popp-Snijders,et al.  Endocrine regulation and extended follow up of longitudinal growth in intrauterine growth-retarded rats. , 2000, The Journal of endocrinology.

[98]  L. Poston,et al.  Glycine rectifies vascular dysfunction induced by dietary protein imbalance during pregnancy , 2004, The Journal of physiology.

[99]  D. Barker,et al.  WEIGHT IN INFANCY AND DEATH FROM ISCHAEMIC HEART DISEASE , 1989, The Lancet.

[100]  C. Hales,et al.  Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis , 1992, Diabetologia.

[101]  M. Jamieson,et al.  Evaluation of the IITC tail cuff blood pressure recorder in the rat against intraarterial pressure according to criteria for human devices. , 1997, American journal of hypertension.

[102]  S. Langley-Evans,et al.  Captopril normalises systolic blood pressure in rats with hypertension induced by fetal exposure to maternal low protein diets. , 1995, Comparative biochemistry and physiology. Part A, Physiology.

[103]  A. Fowden,et al.  Hindlimb glucose and lactate metabolism during umbilical cord compression and acute hypoxemia in the late-gestation ovine fetus. , 2003, American journal of physiology. Regulatory, integrative and comparative physiology.

[104]  C. Martyn,et al.  Growth in utero and serum cholesterol concentrations in adult life. , 1993, BMJ.

[105]  N Cameron,et al.  An inverse relation between blood pressure and birth weight among 5 year old children from Soweto, South Africa. , 1999, Journal of epidemiology and community health.

[106]  B. Gusterson,et al.  The maternal endocrine environment in the low-protein model of intra-uterine growth restriction , 2003, British Journal of Nutrition.

[107]  C Osmond,et al.  Catch-up growth in childhood and death from coronary heart disease: longitudinal study , 1999, BMJ.

[108]  L. Poston,et al.  Effects of undernutrition in early pregnancy on systemic small artery function in late-gestation fetal sheep. , 2000, American journal of obstetrics and gynecology.

[109]  J. McConnell,et al.  Serum concentrations of homocysteine are elevated during early pregnancy in rodent models of fetal programming. , 2002, The British journal of nutrition.

[110]  P. Gluckman,et al.  Glucose tolerance in adults after prenatal exposure to famine , 2001, The Lancet.

[111]  J. Galler,et al.  Prenatal protein malnutrition and maternal behavior in Sprague-Dawley rats. , 1991, The Journal of nutrition.

[112]  Y. Pak,et al.  Peripheral blood mitochondrial DNA content is related to insulin sensitivity in offspring of type 2 diabetic patients. , 2001, Diabetes care.

[113]  S. Kiechl,et al.  Metabolic Syndrome: epidemiology and more extensive phenotypic description. Cross-sectional data from the Bruneck Study , 2003, International Journal of Obesity.

[114]  J. Hsu,et al.  Uteroplacental insufficiency increases apoptosis and alters p53 gene methylation in the full-term IUGR rat kidney. , 2003, American journal of physiology. Regulatory, integrative and comparative physiology.

[115]  J. Seckl,et al.  Glucocorticoids, 11β-hydroxysteroid dehydrogenase, and fetal programming , 2000 .

[116]  J. Mathews,et al.  A new dimension to the Barker hypothesis: low birthweight and susceptibility to renal disease. , 1999, Kidney international.

[117]  Wentworth Ra,et al.  Regional blood flow distribution in fetal sheep with intrauterine growth retardation produced by decreased umbilical placental perfusion. , 1990 .

[118]  T. R. Hansen,et al.  Maternal Undernutrition from Early- to Mid-Gestation Leads to Growth Retardation, Cardiac Ventricular Hypertrophy, and Increased Liver Weight in the Fetal Sheep , 2003, Biology of reproduction.

[119]  S. Carlson,et al.  Essentiality of omega 3 fatty acids in growth and development of infants. , 1991, World review of nutrition and dietetics.

[120]  R. J. Contreras,et al.  Maternal dietary NaCl intake influences weanling rats' salt preferences without affecting taste nerve responsiveness. , 1987, Developmental psychobiology.

[121]  T. Meinertz,et al.  Endothelial Dysfunction, Oxidative Stress, and Risk of Cardiovascular Events in Patients With Coronary Artery Disease , 2001, Circulation.

[122]  Trefor Owen Morgan,et al.  Perinatal Salt Intake Alters Blood Pressure and Salt Balance in Hypertensive Rats , 1990, Hypertension.

[123]  S. Langley-Evans,et al.  Antihypertensive treatment in early postnatal life modulates prenatal dietary influences upon blood pressure in the rat. , 2000, Clinical science.

[124]  Z. Fortes,et al.  NADPH oxidase and enhanced superoxide generation in intrauterine undernourished rats: involvement of the renin-angiotensin system. , 2003, Cardiovascular research.

[125]  A. Jackson,et al.  Altered glucose tolerance in rats exposed to maternal low protein diets in utero. , 1994, Comparative biochemistry and physiology. Physiology.

[126]  L. Poston,et al.  Abnormal aortic fatty acid composition and small artery function in offspring of rats fed a high fat diet in pregnancy , 2001, The Journal of physiology.

[127]  L. Poston,et al.  Cholesterol‐independent endothelial dysfunction in virgin and pregnant rats fed a diet high in saturated fat , 1999, The Journal of physiology.

[128]  M. Weisfeldt Aging, changes in the cardiovascular system, and responses to stress. , 1996, American journal of hypertension.

[129]  L. Poston,et al.  Offspring of normal and diabetic rats fed saturated fat in pregnancy demonstrate vascular dysfunction. , 1998, Circulation.

[130]  A Lucas,et al.  Programming by early nutrition in man. , 2007, Ciba Foundation symposium.

[131]  H. Bolt,et al.  Estrogenic isoflavones in rodent diets. , 2002, Toxicology letters.

[132]  J. White,et al.  The influence of restraint on blood pressure in the rat. , 1997, Journal of pharmacological and toxicological methods.

[133]  C. Napoli,et al.  Maternal Hypercholesterolemia and Treatment During Pregnancy Influence the Long-Term Progression of Atherosclerosis in Offspring of Rabbits , 2001, Circulation research.

[134]  A. Fowden,et al.  Neuropeptide Y in the Sheep Fetus: Effects of Acute Hypoxemia and Dexamethasone During Late Gestation* * This work was funded by the Tommy's Campaign and the British Heart Foundation, UK. , 2000, Endocrinology.

[135]  Rohan M. Lewis,et al.  Early programming of weight gain in mice prevents the induction of obesity by a highly palatable diet. , 2004, Clinical science.

[136]  B. Reusens,et al.  Effect of maternal low-protein diet and taurine on the vulnerability of adult Wistar rat islets to cytokines , 2004, Diabetologia.

[137]  M. Hanson,et al.  Effect of maternal undernutrition in early gestation on ovine fetal blood pressure and cardiovascular reflexes. , 2000, American journal of physiology. Regulatory, integrative and comparative physiology.

[138]  J. Nyengaard,et al.  Maternal Protein Restriction Suppresses the Newborn Renin-Angiotensin System and Programs Adult Hypertension in Rats , 2001, Pediatric Research.

[139]  P. Nilsson,et al.  Frequency of the WHO metabolic syndrome in European cohorts, and an alternative definition of an insulin resistance syndrome. , 2002, Diabetes & metabolism.

[140]  C. Blanco,et al.  Prenatal stress changes rat arterial adrenergic reactivity in a regionally selective manner. , 2004, European journal of pharmacology.

[141]  B. Reusens,et al.  A Low Protein Diet Alters the Balance of Islet Cell Replication and Apoptosis in the Fetal and Neonatal Rat and Is Associated with a Reduced Pancreatic Expression of Insulin-Like Growth Factor-II1. , 1999, Endocrinology.

[142]  J S Yudkin,et al.  Does malnutrition in utero determine diabetes and coronary heart disease in adulthood? Results from the Leningrad siege study, a cross sectional study , 1997, BMJ.

[143]  J. Ärnlöv,et al.  Supplementation With Conjugated Linoleic Acid Causes Isomer-Dependent Oxidative Stress and Elevated C-Reactive Protein: A Potential Link to Fatty Acid-Induced Insulin Resistance , 2002, Circulation.

[144]  J. D. Brown,et al.  Cerebral oxidative metabolism during intrauterine growth retardation. , 1978, Biology of the neonate.

[145]  T. Iguchi,et al.  Evaluation of estrogenic activity in diets for experimental animals using in vitro assay. , 2004, Journal of agricultural and food chemistry.

[146]  C. Byrne,et al.  Regulation of hepatic enzymes and insulin levels in offspring of rat dams fed a reduced-protein diet. , 1997, American journal of physiology. Gastrointestinal and liver physiology.

[147]  Imran Y. Khan,et al.  Gender-Linked Hypertension in Offspring of Lard-Fed Pregnant Rats , 2003, Hypertension.

[148]  T. Forrester,et al.  Blood pressure is related to placental volume and birth weight. , 2000, Hypertension.

[149]  D. Giussani,et al.  Plasma Adrenocorticotropin and Cortisol Concentrations during Acute Hypoxemia after a Reversible Period of Adverse Intrauterine Conditions in the Ovine Fetus During Late Gestation**This work was supported by the British Heart Foundation. , 2001, Endocrinology.

[150]  Clive Osmond,et al.  Fetal and placental size and risk of hypertension in adult life. , 1990, BMJ.

[151]  C. Scavone,et al.  Intrauterine undernutrition: expression and activity of the endothelial nitric oxide synthase in male and female adult offspring. , 2002, Cardiovascular research.

[152]  P. Czernichow,et al.  Effect of ageing on beta-cell mass and function in rats malnourished during the perinatal period , 1999, Diabetologia.

[153]  S. Langley-Evans Intrauterine programming of hypertension in the rat: nutrient interactions. , 1996, Comparative biochemistry and physiology. Part A, Physiology.

[154]  A. Vingrys,et al.  Increased blood pressure later in life may be associated with perinatal n−3 fatty acid deficiency , 2003, Lipids.

[155]  M. Brochu,et al.  Intrauterine growth restriction in rats is associated with hypertension and renal dysfunction in adulthood. , 2002, American journal of physiology. Endocrinology and metabolism.

[156]  W. Rees,et al.  Maternal protein deficiency causes hypermethylation of DNA in the livers of rat fetuses. , 2000, The Journal of nutrition.

[157]  A. E. Caballero,et al.  Endothelial dysfunction in obesity and insulin resistance: a road to diabetes and heart disease. , 2003, Obesity research.

[158]  J. Manning,et al.  Prenatal programming of adult hypertension in the rat. , 2001, Kidney international.

[159]  A. Fowden,et al.  Effects of prevailing hypoxaemia, acidaemia or hypoglycaemia upon the cardiovascular, endocrine and metabolic responses to acute hypoxaemia in the ovine fetus , 2002, The Journal of physiology.

[160]  C. Napoli,et al.  Maternal Hypercholesterolemia Enhances Atherogenesis in Normocholesterolemic Rabbits, Which Is Inhibited by Antioxidant or Lipid-Lowering Intervention During Pregnancy: An Experimental Model of Atherogenic Mechanisms in Human Fetuses , 2000, Circulation research.

[161]  S. Langley-Evans,et al.  Critical differences between two low protein diet protocols in the programming of hypertension in the rat , 2000, International journal of food sciences and nutrition.

[162]  B. Breier,et al.  Dysregulation of the adipoinsular axis -- a mechanism for the pathogenesis of hyperleptinemia and adipogenic diabetes induced by fetal programming. , 2001, The Journal of endocrinology.

[163]  Fetal nutrition and cardiovascular disease in later life. , 1997, British medical bulletin.

[164]  P. Hahn,et al.  Effect of litter size on plasma cholesterol and insulin and some liver and adipose tissue enzymes in adult rodents. , 1984, The Journal of nutrition.

[165]  D. Giussani,et al.  Plasma adrenocorticotropin and cortisol concentrations during acute hypoxemia after a reversible period of adverse intrauterine conditions in the ovine fetus during late gestation. , 2001, Endocrinology.

[166]  R. Harding,et al.  Postnatal Development of Arterial Pressure: Influence of the Intrauterine Environment , 2003, Archives of physiology and biochemistry.

[167]  P. Czernichow,et al.  Postnatal Somatic Growth and Insulin Contents in Moderate or Severe Intrauterine Growth Retardation in the Rat , 1998, Neonatology.

[168]  B. Reusens,et al.  Intrauterine programming of fetal islet gene expression in rats—effects of maternal protein restriction during gestation revealed by proteome analysis , 2003, Diabetologia.

[169]  J. Meulen Glucose tolerance in adults after prenatal exposure to famine , 2001, The Lancet.

[170]  M. Reilly,et al.  The Metabolic Syndrome: More Than the Sum of Its Parts? , 2003, Circulation.

[171]  A. Lucas,et al.  Nutrition in pregnant or lactating rats programs lipid metabolism in the offspring , 1996, British Journal of Nutrition.

[172]  S. Langley-Evans,et al.  Rats with hypertension induced by in utero exposure to maternal low-protein diets fail to increase blood pressure in response to a high salt intake. , 1996, Annals of nutrition & metabolism.

[173]  K. Park,et al.  Decreased mitochondrial DNA content in peripheral blood precedes the development of non-insulin-dependent diabetes mellitus. , 1998, Diabetes research and clinical practice.

[174]  K. Godfrey,et al.  Maternal birthweight and diet in pregnancy in relation to the infant's thinness at birth , 1997, British journal of obstetrics and gynaecology.

[175]  J. Manson,et al.  Biomarkers of endothelial dysfunction and risk of type 2 diabetes mellitus. , 2004, JAMA.

[176]  B. Block,et al.  Regional blood flow distribution in fetal sheep with intrauterine growth retardation produced by decreased umbilical placental perfusion. , 1990, Journal of developmental physiology.

[177]  J. Parer,et al.  Studies on the growth of the fetal sheep. Effects of surgical reduction in placental size, or experimental manipulation of uterine blood flow on plasma sulphation promoting activity and on the concentration of insulin-like growth factors I and II. , 1988, Journal of developmental physiology.

[178]  S. Min,et al.  Power spectral analysis of heart rate variability during acute hypoxia in fetal lambs , 2002, Acta obstetricia et gynecologica Scandinavica.

[179]  D. Barker,et al.  Effects of Altitude versus Economic Status on Birth Weight and Body Shape at Birth , 2001, Pediatric Research.

[180]  T. Kosten,et al.  Prenatal and early postnatal sodium chloride intake modifies the solution preferences of adult rats. , 1983, The Journal of nutrition.

[181]  W Rohde,et al.  Obesity and enhanced diabetes and cardiovascular risk in adult rats due to early postnatal overfeeding. , 2009, Experimental and clinical endocrinology.