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Endocrinology and Metabolism Unit, Division of the Fetal Origins of Adult Disease, School of Medicine, Southampton General Hospital (C.B.W., K.M.F.), Southampton, United Kingdom SO16 6YD; and Academic Division of Child Health, School of Human Development, University Hospital, Queen’s Medical Center (K.M.F., H.B., M.E.S.), Nottingham, United Kingdom NG7 2UH
Address all correspondence and requests for reprints to: Dr. Michael E. Symonds, Academic Division of Child Health, School of Human Development, E Floor, East Block, Queen’s Medical Centre, Nottingham, United Kingdom NG7 2UH. E-mail: michael.symonds{at}nottingham.ac.uk
We have investigated the effects of maternal nutrient restriction in the sheep during the period of rapid placental growth (i.e. 28–77 days gestation; term = 147 days) on feto-placental growth and expression of the glucocorticoid receptor (GR), types 1 and 2 11ß-hydroxysteroid dehydrogenase (11ßHSD1, 11ßHSD2), and types 1 and 2 angiotensin II receptor (AT1, AT2) in fetal and neonatal offspring. Ewes (n = 63) of similar age, body weight, and body composition were randomly allocated to a nutrient-restricted (NR) group in which they consumed 3.2 MJ/day metabolizable energy (ME; equivalent to 50% of predicted requirements) or to a control group in which they consumed 6.7 MJ/day ME (equivalent to 110% of predicted requirements). After 77 days gestation, ewes from both dietary groups consumed close to 100% of ME requirements up to term. Newborn offspring of NR ewes were of similar body weight, but had increased crown-rump length, greater placental weight, and increased placental/body weight ratio (P < 0.01) compared with controls. Their kidneys were heavier (P < 0.05), but shorter in length, with increased ratios of transverse width to length (P < 0.001).
GR messenger RNA (mRNA) expression in neonatal offspring from NR ewes was increased in adrenal, kidney, liver, lung, and perirenal adipose tissue (P < 0.01). Conversely, 11ßHSD1 mRNA expression was unaffected, except in perirenal adipose tissue, where it was higher in lambs born to NR ewes (P < 0.01). 11ßHSD2 mRNA expression was decreased in adrenals and kidney (P < 0.001). Maternal NR also resulted in significantly increased AT1 expression in those tissues in which expression of GR was increased and/or 11ßHSD2 was decreased, i.e. adrenals, kidney, liver, and lung. AT2 expression was unaffected by maternal NR. Although 11ßHSD2 mRNA was undetectable in term placenta, it was abundant in midgestation placenta and was lower after maternal NR (P < 0.001). There was close agreement between levels of 11ßHSD enzyme (i.e. 11ß-dehydrogenase and 11-oxoreductase) activities and abundance of 11ßHSD1 mRNA and 11ßHSD2 mRNA expression.
The persistence of tissue-specific increases in the expression of GR, 11ßHSD1 and AT1 and decreases in the expression of 11ßHSD2 in adrenals and kidney in newborn offspring in response to a defined period of maternal nutrient restriction during early to midgestation suggests that gene expression has been programmed by nutrient availability to the fetus before birth. These data suggest key potential mechanisms by which maternal nutrition prenatally programs physiological pathways, such as the renin-angiotensin system, in the offspring that may lead to raised blood pressure and other cardiovascular disease risk factors in later life.
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H. Budge, L.J. Edwards, I.C. McMillen, A. Bryce, K. Warnes, S. Pearce, T. Stephenson, and M.E. Symonds Nutritional Manipulation of Fetal Adipose Tissue Deposition and Uncoupling Protein 1 Messenger RNA Abundance in the Sheep: Differential Effects of Timing and Duration Biol Reprod, July 1, 2004; 71(1): 359 - 365. [Abstract] [Full Text] [PDF]
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S McMullen, J C Osgerby, L M Thurston, T S Gadd, P J Wood, D C Wathes, and A E Michael Alterations in placental 11{beta}-hydroxysteroid dehydrogenase (11{beta}HSD) activities and fetal cortisol:cortisone ratios induced by nutritional restriction prior to conception and at defined stages of gestation in ewes Reproduction, June 1, 2004; 127(6): 717 - 725. [Abstract] [Full Text] [PDF]
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D. S. Gardner, S. Pearce, J. Dandrea, R. Walker, M. M. Ramsay, T. Stephenson, and M. E. Symonds Peri-Implantation Undernutrition Programs Blunted Angiotensin II Evoked Baroreflex Responses in Young Adult Sheep Hypertension, June 1, 2004; 43(6): 1290 - 1296. [Abstract] [Full Text] [PDF]
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M. Dodic, T. Abouantoun, A. O'Connor, E. M. Wintour, and K. M. Moritz Programming Effects of Short Prenatal Exposure to Dexamethasone in Sheep Hypertension, November 1, 2002; 40(5): 729 - 734. [Abstract] [Full Text] [PDF]
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K. Moritz, A. Butkus, V. Hantzis, A. Peers, E. M. Wintour, and M. Dodic Prolonged Low-Dose Dexamethasone, in Early Gestation, Has No Long-Term Deleterious Effect on Normal Ovine Fetuses Endocrinology, April 1, 2002; 143(4): 1159 - 1165. [Abstract] [Full Text] [PDF]
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