Reproduction, Fertility and Development Reproduction, Fertility and Development Society
Vertebrate reproductive science and technology
RESEARCH ARTICLE

Long-term effects of nutritional programming of the embryo and fetus: mechanisms and critical windows

Michael E. Symonds A B , Terence Stephenson A , David S. Gardner A and Helen Budge A
+ Author Affiliations
- Author Affiliations

A Centre for Reproduction and Early Life, Institute of Clinical Research, University Hospital, Nottingham, NG7 2UH, UK.

B Corresponding author. Email: michael.symonds@nottingham.ac.uk

Reproduction, Fertility and Development 19(1) 53-63 https://doi.org/10.1071/RD06130
Published: 12 December 2006

Abstract

The maternal nutritional and metabolic environment is critical in determining not only reproduction, but also long-term health and viability. In the present review, the effects of maternal nutritional manipulation at defined stages of gestation coinciding with embryogenesis, maximal placental or fetal growth will be discussed. Long-term outcomes from these three developmental windows appear to be very different, with brain and cardiovascular function being most sensitive to influences in the embryonic period, the kidney during placental development and adipose tissue in the fetal phase. In view of the similarities in fetal development, number and maturity at birth, there are close similarities in these outcomes between findings from epidemiological studies in historical human cohorts and nutritional manipulation of large animals, such as sheep. One key nutrient that may modulate the long-term metabolic effects is the supply of glucose from the mother to the fetus, because this is sensitive to both global changes in food intake, maternal glucocorticoid status and an increase in the carbohydrate content of the diet. The extent to which these dietary-induced changes may reflect epigenetic changes remains to be established, especially when considering the very artificial diets used to induce these types of effects. In summary, the maintenance of a balanced and appropriate supply of glucose from the mother to the fetus may be pivotal in ensuring optimal embryonic, placental and fetal growth. Increased or decreased maternal plasma glucose alone, or in conjunction with other macro- or micronutrients, may result in offspring at increased risk of adult diseases.

Extra keywords: adipose tissue, blood pressure, cortisol, kidney.


Acknowledgments

The authors acknowledge the support of the British Heart Foundation and the European Union Sixth Framework Programme for Research and Technical Development of the European Community-The Early Nutrition Programming Project (FOOD-CT-2005-007036) in their research.


References

Armitage, J. A. , Khan, I. Y. , Taylor, P. D. , Nathanielsz, P. W. , and Poston, L. (2004). Developmental programming of the metabolic syndrome by maternal nutritional imbalance: how strong is the evidence from experimental models in mammals? J. Physiol. 561, 355–377.
CrossRef | PubMed |

Barker, D. J. P. , Bull, A. R. , Osmond, C. , and Simmonds, S. J. (1990). Fetal and placental size and risk of hypertension in adult life. BMJ 301, 259–262.
PubMed |

Bauer, M. K. , Breier, B. H. , Harding, J. , Veldhuis, J. D. , and Gluckman, P. D. (1995). The fetal somatotrophic axis during long term maternal undernutrition in sheep: evidence of nutritional regulation in utero. Endocrinology 136, 1250–1257.
CrossRef | PubMed |

Bertolini, M. , Moyer, A. L. , Mason, J. B. , Batchelder, C. A. , and Hoffert, K. A. , et al. (2004). Evidence of increased substrate availability to in vitro-derived bovine foetuses and association with accelerated conceptus growth. Reproduction 128, 341–354.
CrossRef | PubMed |

Bispham, J. , Gopalakrishnan, G. S. , Dandrea, J. , Wilson, V. , Budge, H. , Keisler, D. H. , Broughton Pipkin, F. , Stephenson, T. , and Symonds, M. E. (2003). Maternal endocrine adaptation throughout pregnancy to nutritional manipulation: consequences for maternal plasma leptin and cortisol and the programming of fetal adipose tissue development. Endocrinology 144, 3575–3585.
CrossRef | PubMed |

Bispham, J. , Gardner, D. S. , Gnanalingham, M. G. , Stephenson, T. , Symonds, M. E. , and Budge, H. (2005). Maternal nutritional programming of fetal adipose tissue development: differential effects on mRNA abundance for uncoupling proteins, peroxisome proliferator activated and prolactin receptors. Endocrinology 146, 3943–3949.
CrossRef | PubMed |

Bloomfield, F. H. , Oliver, M. H. , Hawkins, P. , Campbell, M. , Phillips, D. J. , Gluckman, P. D. , Challis, J. R. G. , and Harding, J. E. (2003). A periconceptional nutritional origin for noninfectious preterm birth. Science 300, 606.
CrossRef | PubMed |

Bouret, S. G. , Draper, S. J. , and Simerly, R. B. (2004). Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 304, 108–110.
CrossRef | PubMed |

Brachet, E. A. (1973). Presence of the complete sorbitol pathway in the human normal umbilical cord tissue. Biol. Neonate 23, 314–323.
PubMed |

Brameld, J. M. , Mostyn, A. , Dandrea, J. , Stephenson, T. J. , Dawson, J. , Buttery, P. J. , and Symonds, M. E. (2000). Maternal nutrition alters the expression of insulin-like growth factors in fetal sheep liver and skeletal muscle. J. Endocrinol. 167, 429–437.
CrossRef | PubMed |

Budge H., and Symonds M. E. (2006). Fetal and neonatal nutrition: lipid and carbohydrate requirements and adaptations to altered supply at birth. In ‘The Textbook of Perinatal Medicine’. (Eds H. N. Winn and P. D. Gluckman.) pp. 1007–1016. (Taylor & Francis: Great Yarmouth.)

Budge, H. , Bispham, J. , Dandrea, J. , Evans, E. , and Heasman, L. , et al. (2000). Effect of maternal nutrition on brown adipose tissue and prolactin receptor status in the fetal lamb. Pediatr. Res. 47, 781–786.
PubMed |

Budge, H. , Edwards, L. J. , McMillen, I. C. , Bryce, A. , Warnes, K. , Pearce, S. , Stephenson, T. , and Symonds, M. E. (2004). Nutritional manipulation of fetal adipose tissue deposition and uncoupling protein 1 abundance in the fetal sheep: differential effects of timing and duration. Biol. Reprod. 71, 359–365.
CrossRef | PubMed |

Cannon, B. , and Nedergaard, J. (2004). Brown adipose tissue: function and significance. Physiol. Rev. 84, 277–359.
CrossRef | PubMed |

Cannon B., Connoley E., Obregon M.-J., and Nedergaard J. (1988). Perinatal activation of brown adipose tissue. In ‘The Endocrine Control of the Fetus’. (Eds W. Kunzel and A. Jesen.) pp. 306–320. (Springer Verlag: Berlin.)

Carter, A. M. , and Mess, A. (2006). Evolution of the placenta in Eutherian mammals. Placenta ,in press.


Chappell, L. C. , Seed, P. T. , Briley, A. L. , Kelly, F. J. , and Lee, R. , et al. (1999). Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomised trial. Lancet 354, 810–816.
PubMed |

Clarke, L. , Bryant, M. J. , Lomax, M. A. , and Symonds, M. E. (1997). Maternal manipulation of brown adipose tissue and liver development in the ovine fetus during late gestation. Br. J. Nutr. 77, 871–883.
CrossRef | PubMed |

Clarke, L. , Heasman, L. , Juniper, D. T. , and Symonds, M. E. (1998a). Maternal nutrition in early–mid gestation and placental size in sheep. Br. J. Nutr. 79, 359–364.
CrossRef | PubMed |

Clarke, L. , Heasman, L. , and Symonds, M. E. (1998b). Influence of maternal dexamethasone administration on thermoregulation in lambs delivered by caesarean section. J. Endocrinol. 156, 307–314.
CrossRef | PubMed |

Dandrea, J. , Wilson, V. , Gopalakrishnan, G. , Heasman, L. , Budge, H. , Stephenson, T. , and Symonds, M. E. (2001). Maternal nutritional manipulation of placental growth and glucose transporter-1 abundance in sheep. Reproduction 122, 793–800.
CrossRef | PubMed |

Dandrea, J. , Cooper, S. , Ramsay, M. M. , Keller-Woods, M. , Broughton Pipkin, F. , Symonds, M. E. , and Stephenson, T. (2002). The effects of pregnancy and maternal nutrition on the maternal renin–angiotensin system in sheep. Exp. Physiol. 87, 353–359.
CrossRef | PubMed |

de Boo, H. A. , van Zijl, P. L. , Smith, D. E. , Kulik, W. , Lafeber, H. N. , and Harding, J. E. (2005). Arginine and mixed amino acids increase protein accretion in the growth-restricted and normal ovine fetus by different mechanisms. Pediatr. Res. 58, 270–277.
CrossRef | PubMed |

Dolinoy, D. C. , Weidman, J. R. , Waterland, R. A. , and Jirtle, R. L. (2006). Maternal genistein alters coat color and protects Avy mouse offspring from obesity by modifying the fetal epigenome. Environ. Health Perspect. 114, 567–572.
PubMed |

Durga, J. , and Verhoef, P. (2005). Let them eat cake. Current Nutr. Food Sci. 1, 35–40.
CrossRef |

Duvillie, B. , Currie, C. , Chrones, T. , Bucchini, D. , Jami, J. , Joshi, R. L. , and Hill, D. J. (2002). Increased islet cell proliferation, decreased apoptosis, and greater vascularization leading to beta-cell hyperplasia in mutant mice lacking insulin. Endocrinology 143, 1530–1537.
CrossRef | PubMed |

Eckberg, D. L. (1979). Carotid baroreflex function in young men with borderline blood pressure elevation. Circulation 59, 632–636.
PubMed |

Edwards, L. J. , and McMillen, I. C. (2001). Maternal undernutrition increases arterial blood pressure in the sheep fetus during late gestation. J. Physiol. 533, 561–570.
CrossRef | PubMed |

Edwards, L. J. , and McMillen, I. C. (2002). Impact of maternal undernutrition during the periconceptional period, fetal number, and fetal sex on the development of the hypothalamo–pituitary adrenal axis in sheep during late gestation. Biol. Reprod. 66, 1562–1569.
CrossRef | PubMed |

Edwards, L. J. , Symonds, M. E. , Warnes, K. , Owens, J. A. , Butler, T. G. , Jurisevic, A. , and McMillen, I. C. (2001). Responses of the fetal pituitary–adrenal axis to acute and chronic hypoglycaemia during late gestation in the sheep. Endocrinology 142, 1778–1785.
CrossRef | PubMed |

Edwards, L. J. , McFarlane, J. R. , Kauter, K. G. , and McMillen, I. C. (2005). Impact of periconceptional nutrition on maternal and fetal leptin and fetal adiposity in singleton and twin pregnancies. Am. J. Physiol. Regul. Intergr. Comp. Physiol. 288, R39–R45.


Erhard, H. W. , Boissy, A. , Rae, M. T. , and Rhind, S. M. (2004). Effects of prenatal undernutrition on emotional reactivity and cognitive flexibility in adult sheep. Behav. Brain Res. 151, 25–35.
CrossRef | PubMed |

Ehrhardt, R. A. , and Bell, A. W. (1995). Growth and metabolism of the ovine placenta during mid-gestation. Placenta 16, 727–741.
CrossRef | PubMed |

Fernandez-Twinn, D. S. , Ozanne, S. E. , Ekizoglou, S. , Doherty, C. , James, L. , Gusterson, B. , and Hales, C. N. (2003). The maternal endocrine environment in the low-protein model of intra-uterine growth restriction. Br. J. Nutr. 90, 815–822.
CrossRef | PubMed |

Festing, M. F. W. (2006). Design and statistical methods in studies using animal models of development. ILAR J. 47, 5–14.
PubMed |

Finn C. A. (1994). Implantation. In ‘Marshall’s Physiology of Reproduction, 4th edn, Volume 3, Pregnancy and Lactation, Part Two Fetal Physiology, Parturition and Lactation’. (Ed. G. E. Lamming.) pp. 159–234. (Chapman & Hall: London.)

Finn, D. , Lomax, M. A. , and Trayhurn, P. (1998). An immunohistochemical and in situ hybridisation study of the postnatal development of uncoupling protein-1 and uncoupling protein-1 mRNA in lamb perirenal adipose tissue. Cell Tissue Res. 294, 461–466.
CrossRef | PubMed |

Fowden, A. L. , Li, J. , and Forhead, A. J. (1998). Glucocorticoids and the preparation for life after birth: are there long-term consequences of the life insurance? Proc. Nutr. Soc. 57, 113–122.
CrossRef | PubMed |

Gardner, D. S. , Pearce, S. , Dandrea, J. , Walker, R. M. , Ramsey, M. M. , Stephenson, T. , and Symonds, M. E. (2004). Peri-implantation undernutrition programs blunted angiotensin II evoked baroreflex responses in young adult sheep. Hypertension 43, 1290–1296.
CrossRef | PubMed |

Gardner, D. S. , Tingey, K. , van Bon, B. W. M. , Ozanne, S. E. , Wilson, V. , Dandrea, J. , Keisler, D. H. , Stephenson, T. , and Symonds, M. E. (2005). Programming of glucose–insulin metabolism in adult sheep after maternal undernutrition. Am. J. Physiol. Regul. Intergr. Comp. Physiol. 289, R947–R954.


Gardner, D. S. , Buttery, P. J. , Daniel, Z. , and Symonds, M. E. (2006a). Factors affecting birth weight in sheep: maternal environment. Reproduction ,in press.


Gardner, D. S. , Von Bon, B. M. W. , Dandrea, J. , Goddard, P. J. , May, S. F. , Wilson, V. , Stephenson, T. , and Symonds, M. E. (2006b). Effect of periconceptual undernutrition and gender on hypothalamic–pituitary–adrenal axis function in young adult sheep. J. Endocrinol. 190, 203–212.
CrossRef | PubMed |

Girard, C. L. , Lapierre, H. , Desrochers, A. , Benchaar, C. , Matte, J. J. , and Remond, D. (2001). Net flux of folates and vitamin B12 through the gastrointestinal tract and the liver of lactating dairy cows. Br. J. Nutr. 86, 707–715.
PubMed |

Gnanalingham, M. G. , Mostyn, A. , Gardner, D. S. , Stephenson, T. , and Symonds, M. E. (2005). Developmental regulation of adipose tissue: nutritional manipulation of local glucocorticoid action and uncoupling protein 2. Adipocytes 1, 221–228.


Godfrey, K. , Robinson, S. , Barker, D. J. P. , Osmond, C. , and Cox, V. (1996). Maternal nutrition in early and late pregnancy in relation to placental and fetal growth. BMJ 312, 410–414.
PubMed |

Gopalakrishnan, G. , Gardner, D. S. , Dandrea, J. , Langley-Evans, S. C. , and Pearce, S. , et al. (2005). Influence of maternal pre-pregnancy body composition and diet during early–mid pregnancy on cardiovascular function and nephron number in juvenile sheep. Br. J. Nutr. 94, 938–947.
CrossRef | PubMed |

Harding, J. , Liu, L. , Evans, P. , Oliver, M. , and Gluckman, P. (1992). Intrauterine feeding of the growth retarded fetus: can we help? Early Hum. Dev. 29, 193–197.
CrossRef | PubMed |

Hay, W. W. (1995). Current topic: metabolic interrelationships of placenta and fetus. Placenta 16, 19–30.
CrossRef | PubMed |

Heasman, L. , Clarke, L. , Firth, K. , Stephenson, T. , and Symonds, M. E. (1998). Influence of restricted maternal nutrition in early to mid gestation on placental and fetal development at term in sheep. Pediatr. Res. 44, 546–551.
PubMed |

Hod, M. , Star, S. , Passonneau, J. , Unterman, T. G. , and Freinkel, N. (1990). Glucose-induced dysmorphogenesis in the cultured rat conceptus: prevention by supplementation with myo-inositol. Isr. J. Med. Sci. 26, 541–544.
PubMed |

Hod, M. , Star, S. , Passonneau, J. V. , Unterman, T. G. , and Freinkel, N. (1991). Effect of hyperglycemia on sorbitol and myo-inositol content of cultured rat conceptus: prevention of dysmorphogenesis with aldose reductase inhibitors and myo-inositol. J. Perinat. Med. 19(Suppl. 1), 370–375.
PubMed |

Hoy, W. E. , Hughson, M. D. , Bertram, J. F. , Douglas-Denton, R. , and Amann, K. (2005). Nephron number, hypertension, renal disease, and renal failure. J. Am. Soc. Nephrol. 16, 2557–2564.
CrossRef | PubMed |

Jaquiery, A. L. , Oliver, M. H. , Bloomfield, F. H. , Connor, K. L. , Challis, J. R. , and Harding, J. E. (2006). Fetal exposure to excess glucocorticoid is unlikely to explain the effects of periconceptional undernutrition in sheep. J. Physiol. 572, 109–118.
PubMed |

Jauniaux, E. , Watson, A. L. , Hempstock, J. , Bao, Y. P. , Skepper, J. N. , and Burton, G. J. (2000). Onset of maternal arterial blood flow and placental oxidative stress. A possible factor in human early pregnancy failure. Am. J. Pathol. 157, 2111–2122.
PubMed |

Jauniaux, E. , Cindrova-Davies, T. , Johns, J. , Dunster, C. , Hempstock, J. , Kelly, F. J. , and Burton, G. J. (2004). Distribution and transfer pathways of antioxidant molecules inside the first trimester human gestational sac. J. Clin. Endocrinol. Metab. 89, 1452–1458.
CrossRef | PubMed |

Jauniaux, E. , Hempstock, J. , Teng, C. , Battaglia, F. C. , and Burton, G. J. (2005). Polyol concentrations in the fluid compartments of the human conceptus during the first trimester of pregnancy: maintenance of redox potential in a low oxygen environment. J. Clin. Endocrinol. Metab. 90, 1171–1175.
CrossRef | PubMed |

Jellyman, J. K. , Gardner, D. S. , Edwards, C. M. , Fowden, A. L. , and Giussani, D. A. (2005). Fetal cardiovascular, metabolic and endocrine responses to acute hypoxaemia during and following maternal treatment with dexamethasone in sheep. J. Physiol. 567, 673–688.
CrossRef | PubMed |

Khan, I. Y. , Taylor, P. D. , Dekou, V. , Seed, P. T. , Lakasing, L. , Graham, D. , Dominiczak, A. F. , Hanson, M. A. , and Poston, L. (2003). Gender-linked hypertension in offspring of lard-fed pregnant rats. Hypertension 41, 168–175.
CrossRef | PubMed |

Klusmann, A. , Heinrich, B. , Stopler, H. , Gartner, J. , Mayatepek, E. , and Von Kries, R. (2005). A decreasing rate of neural tube defects following the recommendations for periconceptional folic acid supplementation. Acta Paediatr. 94, 1538–1542.
CrossRef | PubMed |

Krook, A. , Bjornholm, M. , Galuska, D. , Jiang, X. J. , Fahlman, R. , Myers, M. G. , Wallberg-Henriksson, H. , and Zierath, J. R. (2000). Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients. Diabetes 49, 284–292.
PubMed |

Kumar, P. , and Hanson, M. A. (1989). Re-setting of the hypoxic sensitivity of aortic chemoreceptors in the new-born lamb. J. Dev. Physiol. 11, 199–206.
PubMed |

Kwong, W. Y. , Wild, A. E. , Roberts, P. , Willis, A. C. , and Fleming, T. P. (2000). Maternal undernutrition during the preimplantation period of rat development causes blastocyst abnormalities and programming of postnatal hypertension. Development 127, 4195–4202.
PubMed |

Langley-Evans, S. C. , Hasse, A. , and Brewis, S. F. (2006). Programming effects of folic acid supplementation in rat pregancy on blood pressure and abdominal fat deposition. Proc. Nutr. Soc., ,in press.


Lean, M. E. J. (1989). Brown adipose tissue in humans. Proc. Nutr. Soc. 48, 243–256.
CrossRef | PubMed |

Liggins, G. C. (1979). Initiation of parturition. Br. Med. Bull. 35, 145–150.
PubMed |

Lillycrop, K. A. , Phillips, E. S. , Jackson, A. A. , Hanson, M. A. , and Burdge, G. C. (2005). Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J. Nutr. 135, 1382–1386.
PubMed |

Lowell, B. B. , S-Susulic, V. , Hamann, A. , Lawitts, J. A. , Himms-Hagen, J. , Boyer, B. B. , Kozak, L. P. , and Flier, J. S. (1993). Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature 366, 740–742.
CrossRef | PubMed |

Malcher-Lopes, R. , Di, S. , Marcheselli, V. S. , Weng, F. J. , Stuart, C. T. , Bazan, N. G. , and Tasker, J. G. (2006). Opposing crosstalk between leptin and glucocorticoids rapidly modulates synaptic excitation via endocannabinoid release. J. Neurosci. 26, 6643–6650.
CrossRef | PubMed |

Mathews, F. , Yudkin, P. , and Neil, A. (1999). Influence of maternal nutrition on outcome of pregnancy: prospective cohort study. BMJ 319, 339–343.
PubMed |

McMillen, I. C. , and Robinson, J. S. (2005). Developmental origins of the metabolic syndrome: prediction, plasticity, and programming. Physiol. Rev. 85, 571–633.
CrossRef | PubMed |

Mühlhäusler, B. S. , Roberts, C. T. , Yuen, B. S. , Marrocco, E. , and Budge, H. , et al. (2003). Determinants of fetal leptin synthesis, fat mass and circulating leptin concentrations in well nourished ewes in late pregnancy. Endocrinology 144, 4947–4954.
CrossRef | PubMed |

Mühlhäusler, B. S. , McMillen, I. C. , Rouzaud, G. , Findlay, P. A. , Marrocco, E. , Rhind, S. M. , and Adam, C. L. (2004). Appetite regulatory neuropeptides are expressed in the sheep hypothalamus before birth. Neuroendocrinology 16, 502–507.


Oliver, M. H. , Hawkins, P. , and Harding, J. E. (2005). Periconceptional undernutrition alters growth trajectory and metabolic and endocrine responses to fasting in late-gestation fetal sheep. Pediatr. Res. 57, 591–598.
CrossRef | PubMed |

Ookuwa, H. , Takata, S. , Ogawa, J. , Iwase, N. , Ikeda, T. , and Hattori, N. (1987). Abnormal cardiopulmonary baroreflexes in normotensive young subjects with a family history of essential hypertension. J. Clin. Hypertens. 3, 596–604.
PubMed |

Painter, R. C. , Roseboom, T. J. , van Montfrans, G. A. , Bossuyt, P. M. , Krediet, R. T. , Osmond, C. , Barker, D. J. , and Bleker, O. P. (2005). Microalbuminuria in adults after prenatal exposure to the Dutch famine. J. Am. Soc. Nephrol. 16, 189–194.
CrossRef | PubMed |

Pantaleon, M. , and Kaye, P. L. (1996). IGF-I and insulin regulate glucose transport in mouse blastocysts via IGF-I receptor. Mol. Reprod. Dev. 44, 71–76.
CrossRef | PubMed |

Pantaleon, M. , Whiteside, E. J. , Harvey, M. B. , Barnard, R. T. , Waters, M. J. , and Kaye, P. L. (1997). Functional growth hormone (GH) receptors and GH are expressed by preimplantation mouse embryos: a role for GH in early embryogenesis? Proc. Natl Acad. Sci. USA 94, 5125–5130.
CrossRef | PubMed |

Pearce, S. , Budge, H. , Mostyn, A. , Korur, N. , Wang, J. , Ingleton, P. M. , Symonds, M. E. , and Stephenson, T. (2005). Differential effects of maternal cold exposure and nutrient restriction on prolactin receptor and uncoupling protein 1 abundance in adipose tissue during development in young sheep. Adipocytes 1, 57–64.


Petry, C. J. , Ozanne, S. E. , Wang, C. L. , and Hales, C. N. (1997). Early protein restriction and obesity independently induce hypertension in 1-year-old rats. Clin. Sci. 93, 147–152.
PubMed |

Poston, L. , Briley, A. L. , Seed, P. T. , Kelly, F. J. , and Shennan, A. H. (2006). Vitamin C and vitamin E in pregnant women at risk for pre-eclampsia (VIP trial): randomised placebo-controlled trial. Lancet 367, 1145–1154.
CrossRef | PubMed |

Power, G. (1989). Biology of temperature: the mammalian fetus. J. Dev. Physiol. 12, 295–304.
PubMed |

Ravelli, A. C. J. , Stein, Z. A. , and Susser, M. W. (1976). Obesity in young men after famine exposure in utero and early infancy. N. Engl. J. Med. 295, 349–353.
PubMed |

Ravelli, A. C. J. , van der Meulin, J. H. P. , Michels, R. P. J. , Osmond, C. , Barker, D. J. P. , Hales, C. N. , and Bleker, O. P. (1998). Glucose tolerance in adults after in utero exposure to the Dutch famine. Lancet 351, 173–177.
CrossRef | PubMed |

Ray, J. G. , Meier, C. , Vermeulen, M. J. , Boss, S. , Wyatt, P. R. , and Cole, D. E. (2002). Association of neural tube defects and folic acid food fortification in Canada. Lancet 360, 2047–2048.
CrossRef | PubMed |

Robinson, J. J. , and Symonds, M. E. (1995). Whole-body fuel selection: reproduction. Proc. Nutr. Soc. 54, 283–299.
CrossRef | PubMed |

Roseboom, T. J. , van der Meulen, J. H. P. , Osmond, C. , Barker, D. J. P. , Ravelli, A. C. J. , Schroeder-Tanka, J. M. , von Montfrans, G. A. , Michels, R. P. J. , and Blecker, O. P. (2000). Coronary heart disease in adults after perinatal exposure to famine. Heart 84, 595–598.
CrossRef | PubMed |

Roxborough, H. E. , Burton, G. W. , and Kelly, F. J. (2000). Inter- and intra-individual variation in plasma and red blood cell vitamin E after supplementation. Free Radic. Res. 33, 437–445.
CrossRef | PubMed |

Simonetta, G. , Walker, D. W. , and McMillen, I. C. (1991). Effect of feeding on the diurnal rhythm of plasma cortisol and adrenocorticotrophic hormone concentrations in the pregnant ewe and sheep fetus. Exp. Physiol. 76, 219–229.
PubMed |

Stegmann, J. H. J. (1974). Placental development in sheep. Bijdragen tot de Dierkunde 44, 4–72.


Symonds, M. E. , and Clarke, L. (1998). Influence of maternal body weight on adaptation after birth in near-term lambs delivered by caesarean section. Reprod. Fertil. Dev. 10, 333–339.
CrossRef | PubMed |

Symonds M. E., and Gardner D. S. (2006). Development of obesity. In ‘Developmental Origins of Health and Disease’. (Eds P. D. Gluckman and M. A. Hanson.) pp. 397–403. (Cambridge University Press: Cambridge.)

Symonds, M. E. , Bryant, M. J. , and Lomax, M. A. (1986). The effect of shearing on the energy metabolism of the pregnant ewe. Br. J. Nutr. 56, 635–643.
CrossRef | PubMed |

Symonds, M. E. , Bryant, M. J. , Clarke, L. , Darby, C. J. , and Lomax, M. A. (1992). Effect of maternal cold exposure on brown adipose tissue and thermogenesis in the neonatal lamb. J. Physiol. 455, 487–502.
PubMed |

Symonds, M. E. , Bird, J. A. , Clarke, L. , Gate, J. J. , and Lomax, M. A. (1995). Nutrition, temperature and homeostasis during perinatal development. Exp. Physiol. 80, 907–940.
PubMed |

Symonds, M. E. , Heasman, L. , Clarke, L. , Firth, K. , Owens, J. A. , and McMillen, I. C. (1997). Maternal nutrition during late gestation and placental growth. Contemp. Rev. Obstet. Gynaecol. 9, 165–172.


Symonds, M. E. , Phillips, I. D. , Anthony, R. V. , Owens, J. A. , and McMillen, I. C. (1998). Prolactin receptor gene expression and foetal adipose tissue. J. Neuroendocrinol. 10, 885–890.
CrossRef | PubMed |

Symonds, M. E. , Budge, H. , and Stephenson, T. (2000). Limitations of models used to examine the influence of nutrition during pregnancy and adult disease. Arch. Dis. Child. 83, 215–219.
CrossRef | PubMed |

Symonds, M. E. , Budge, H. , Stephenson, T. , and McMillen, I. C. (2001). Fetal endocrinology and development: manipulation and adaptation to long term nutritional and environmental challenges. Reproduction 121, 853–862.
CrossRef | PubMed |

Symonds M. E., Budge H., and Stephenson T. (2003a). Physiological and nutritional aspects of the placenta. In ‘Nutritional in Early Life: Concepts and Practice’. (Eds J. B. Morgan and J. W. T. Dickerson.) pp. 91–121. (Wiley & Sons: Chichester.)

Symonds, M. E. , Mostyn, A. , Pearce, S. , Budge, H. , and Stephenson, T. (2003b). Endocrine and nutritional regulation of fetal adipose tissue development. J. Endocrinol. 179, 293–299.
CrossRef | PubMed |

Symonds M. E., Gardner D. S., Pearce S., and Stephenson T. (2004a). Endocrine responses to fetal undernutrition: the growth hormone (GH): insulin-like growth factor (IGF) axis. In ‘Fetal Nutrition and Adult Disease: Programming of Chronic Disease Through Fetal Exposure to Undernutrition’. (Ed. S. C. Langley-Evans.) pp. 353–380. (CAB International: Oxford.)

Symonds, M. E. , Pearce, S. , Bispham, J. , Gardner, D. S. , and Stephenson, T. (2004b). Timing of nutrient restriction and programming of fetal adipose tissue development. Proc. Nutr. Soc. 63, 397–403.
CrossRef | PubMed |

Symonds, M. E. , Budge, H. , Stephenson, T. , and Gardner, D. S. (2005). Leptin, fetal nutrition and long term outcomes for adult hypertension. Endothelium 12, 73–79.
PubMed |

Symonds, M. E. , Budge, H. , Mostyn, A. , Stephenson, T. , and Gardner, D. S. (2006). Nutritional programming of fetal development: endocrine mediators and long-term outcomes for cardiovascular health. Curr. Nutr. Food Sci. 2, 389–398.
CrossRef |

Symonds M. E., Budge H., Mostyn A., Stephenson T., and Gardner D. S. (2007). Maternal diet through pregnancy: the key to future good health of the next generation? In ‘Reducing Diets: New Research’. (Ed. F. Columbus.) In press. (Nova Science Publishers: New York.)

Thompson, G. E. , Bassett, J. M. , Samson, D. E. , and Slee, J. (1982). The effect of cold exposure of pregnant sheep on fetal plasma nutrients, hormones and birth weight. Br. J. Nutr. 48, 59–64.
CrossRef | PubMed |

Vickers, M. H. , Breier, B. H. , McCarthy, D. , and Gluckman, P. D. (2003). Sedentary behavior during postnatal life is determined by the prenatal environment and exacerbated by postnatal hypercaloric nutrition. Am. J. Physiol. Regul. Intergr. Comp. Physiol. 285, R271–R273.


Warnes, K. , Morris, M. J. , Symonds, M. E. , Phillips, I. D. , Owens, J. A. , and McMillen, I. C. (1998). Effects of gestation, cortisol and maternal undernutrition on hypothalamic neuropeptide Y mRNA levels in the sheep fetus. J. Neuroendocrinol. 10, 51–57.
CrossRef | PubMed |

Waterland, R. A. , and Jirtle, R. L. (2003). Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol. Cell. Biol. 23, 5293–5300.
CrossRef | PubMed |

Waterland, R. A. , Lin, J. R. , Smith, C. A. , and Jirtle, R. L. (2006). Post-weaning diet affects genomic imprinting at the insulin-like growth factor 2 (Igf2) locus. Hum. Mol. Genet. 15, 705–716.
CrossRef | PubMed |

White, B. D. , Dean, R. G. , and Martin, R. J. (1994). Short-term dexamethasone treatment increases food intake, but apparently not through changes in NPY content in the PVN. Ann. N.Y. Acad. Sci. 739, 339–340.
PubMed |

Whorwood, C. B. , Firth, K. M. , Budge, H. , and Symonds, M. E. (2001). Maternal undernutrition during early- to mid-gestation programmes tissue-specific alterations in the expression of the glucocorticoid receptor, 11β-hydroxysteroid dehydrogenase isoforms and type 1 angiotensin II receptor in neonatal sheep. Endocrinology 142, 2854–2864.
CrossRef | PubMed |

Widdowson, E. M. (1950). Chemical composition of newly born animals. Nature 166, 626–628.
CrossRef | PubMed |

Wintour, E. M. , and Moritz, K. M. (1997). Comparative aspects of fetal renal development. Equine Vet. J. 24, 51–58.


Wintour, E. M. , Alcorn, D. , McFarlane, A. , Moritz, K. , Potocnik, S. J. , and Tangalakis, K. (1994). Effect of maternal glucocorticoid treatment on fetal fluids in sheep at 0.4 gestation. Am. J. Physiol. 266, R1174–R1181.
PubMed |

Woods, L. L. (2006). Maternal glucocorticoids and prenatal programming of hypertension. Am. J. Physiol. Regul. Intergr. Comp. Physiol. 291, R1069–R1075.


Woods, L. L. , and Weeks, D. A. (2005). Prenatal programming of adult blood pressure: role of maternal corticosteroids. Am. J. Physiol. Regul. Intergr. Comp. Physiol. 289, R955–R962.


Woods, L. L. , Ingelfinger, J. R. , Nyengaard, J. R. , and Rasch, R. (2001). Maternal protein restriction suppresses the newborn renin-angiotensin system and programs adult hypertension in rats. Pediatr. Res. 49, 460–467.
PubMed |

Young, L. E. , Fernandes, K. , McEvoy, T. G. , Butterwith, S. C. , and Gutierrez, C. G. , et al. (2001). Epigenetic change in IGF2R is associated with fetal overgrowth after embryo culture. Nat. Genet. 27, 153–154.
CrossRef | PubMed |



Rent Article (via Deepdyve) Export Citation Cited By (90)