{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T23:18:05Z","timestamp":1791328685152,"version":"4.3.1"},"reference-count":47,"publisher":"The Endocrine Society","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2001,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>We have investigated the effects of maternal nutrient restriction in the sheep during the period of rapid placental growth (i.e. 28\u201377 days gestation; term = 147 days) on feto-placental growth and expression of the glucocorticoid receptor (GR), types 1 and 2 11\u03b2-hydroxysteroid dehydrogenase (11\u03b2HSD1, 11\u03b2HSD2), 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 &amp;lt; 0.01) compared with controls. Their kidneys were heavier (P &amp;lt; 0.05), but shorter in length, with increased ratios of transverse width to length (P &amp;lt; 0.001).<\/jats:p><jats:p>GR messenger RNA (mRNA) expression in neonatal offspring from NR ewes was increased in adrenal, kidney, liver, lung, and perirenal adipose tissue (P &amp;lt; 0.01). Conversely, 11\u03b2HSD1 mRNA expression was unaffected, except in perirenal adipose tissue, where it was higher in lambs born to NR ewes (P &amp;lt; 0.01). 11\u03b2HSD2 mRNA expression was decreased in adrenals and kidney (P &amp;lt; 0.001). Maternal NR also resulted in significantly increased AT1 expression in those tissues in which expression of GR was increased and\/or 11\u03b2HSD2 was decreased, i.e. adrenals, kidney, liver, and lung. AT2 expression was unaffected by maternal NR. Although 11\u03b2HSD2 mRNA was undetectable in term placenta, it was abundant in midgestation placenta and was lower after maternal NR (P &amp;lt; 0.001). There was close agreement between levels of 11\u03b2HSD enzyme (i.e. 11\u03b2-dehydrogenase and 11-oxoreductase) activities and abundance of 11\u03b2HSD1 mRNA and 11\u03b2HSD2 mRNA expression.<\/jats:p><jats:p>The persistence of tissue-specific increases in the expression of GR, 11\u03b2HSD1 and AT1 and decreases in the expression of 11\u03b2HSD2 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.<\/jats:p>","DOI":"10.1210\/endo.142.7.8264","type":"journal-article","created":{"date-parts":[[2014,1,8]],"date-time":"2014-01-08T16:11:43Z","timestamp":1389197503000},"page":"2854-2864","source":"Crossref","is-referenced-by-count":215,"title":["Maternal Undernutrition during Early to Midgestation Programs Tissue-Specific Alterations in the Expression of the Glucocorticoid Receptor, 11\u03b2-Hydroxysteroid Dehydrogenase Isoforms, and Type 1 Angiotensin II Receptor in Neonatal Sheep*"],"prefix":"10.1210","volume":"142","author":[{"given":"C. B.","family":"Whorwood","sequence":"first","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. M.","family":"Firth","sequence":"additional","affiliation":[{"name":"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"},{"name":"Academic Division of Child Health, School of Human Development, University Hospital, Queen\u2019s Medical Center (K.M.F., H.B., M.E.S.), Nottingham, United Kingdom NG7 2UH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.","family":"Budge","sequence":"additional","affiliation":[{"name":"Academic Division of Child Health, School of Human Development, University Hospital, Queen\u2019s Medical Center (K.M.F., H.B., M.E.S.), Nottingham, United Kingdom NG7 2UH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. E.","family":"Symonds","sequence":"additional","affiliation":[{"name":"Academic Division of Child Health, School of Human Development, University Hospital, Queen\u2019s Medical Center (K.M.F., H.B., M.E.S.), Nottingham, United Kingdom NG7 2UH"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","reference":[{"key":"2020071622251472800_R1","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1136\/bmj.312.7028.410","article-title":"Maternal nutrition in early and late pregnancy in relation to placental and fetal growth.","volume":"312","author":"Godfrey","year":"1996","journal-title":"Br Med J"},{"key":"2020071622251472800_R2","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1111\/j.1471-0528.1996.tb09718.x","article-title":"Diet in pregnancy and the offspring\u2019s blood pressure 40 years later.","volume":"103","author":"Campbell","year":"1996","journal-title":"Br J Obstet Gynaecol"},{"key":"2020071622251472800_R3","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1007\/s001250050086","article-title":"Thinness at birth and insulin resistance in adult life.","volume":"37","author":"Phillips","year":"1994","journal-title":"Diabetologia"},{"key":"2020071622251472800_R4","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1016\/0140-6736(93)91224-A","article-title":"Fetal nutrition and cardiovascular disease in adult life.","volume":"341","author":"Barker","year":"1993","journal-title":"Lancet"},{"key":"2020071622251472800_R5","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1111\/j.1748-1716.1992.tb09356.x","article-title":"Low birthweight is associated with elevated adult blood pressure in the chronically catheterized guinea-pig.","volume":"145","author":"Persson","year":"1992","journal-title":"Acta Physiol Scand"},{"key":"2020071622251472800_R6","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1203\/00006450-199609000-00012","article-title":"Chronic maternal undernutrition in the rat leads to delayed postnatal growth and elevated blood pressure of offspring.","volume":"40","author":"Woodall","year":"1996","journal-title":"Pediatr Res"},{"key":"2020071622251472800_R7","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1042\/cs0860217","article-title":"Increased systolic blood pressure in adult rats induced by fetal exposure to maternal low protein diet.","volume":"86","author":"Langley","year":"1994","journal-title":"Clin Sci"},{"key":"2020071622251472800_R8","first-page":"E559","article-title":"Altered regulation of hepatic glucose output in the male offspring of protein-malnourished rat dams","volume":"270","author":"Ozanne","year":"1996","journal-title":"Am J Physiol"},{"key":"2020071622251472800_R9","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/S0143-4004(96)80010-5","article-title":"Protein intake in pregnancy, placental glucocorticoid metabolism and the programming of hypertension.","volume":"17","author":"Langley-Evans","year":"1996","journal-title":"Placenta"},{"key":"2020071622251472800_R10","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1161\/01.HYP.27.6.1200","article-title":"Inhibition of 11\u03b2-hydroxysteroid dehydrogenase in pregnant rats and the programming of blood pressure in offspring.","volume":"27","author":"Lindsay","year":"1996","journal-title":"Hypertension"},{"key":"2020071622251472800_R11","doi-asserted-by":"crossref","first-page":"2174","DOI":"10.1172\/JCI1567","article-title":"Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult 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ribosomal ribonucleic acid.","volume":"259","author":"Chan","year":"1984","journal-title":"J Biol Chem"},{"key":"2020071622251472800_R37","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1677\/joe.0.1470405","article-title":"Differential expression of 11\u03b2-hydroxysteroid dehydrogenase 1 and 2 in the developing ovine fetal liver and kidney.","volume":"147","author":"Langlois","year":"1995","journal-title":"J Endocrinol"},{"key":"2020071622251472800_R38","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1677\/joe.0.1430121","article-title":"Opposite effects of glucocorticoid on hepatic 11\u03b2-hydroxysteroid dehydrogenase mRNA and activity in fetal and adult sheep.","volume":"143","author":"Yang","year":"1994","journal-title":"J Endocrinol"},{"key":"2020071622251472800_R39","doi-asserted-by":"crossref","first-page":"2533","DOI":"10.1210\/endo.135.6.7988441","article-title":"Epithelial cell localization of 11\u03b2-hydroxysteroid dehydrogenase in rat and human 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expression in fetal sheep kidney.","volume":"58","author":"Murotsuki","year":"1998","journal-title":"Biol Reprod"},{"key":"2020071622251472800_R43","first-page":"1354","article-title":"Characterization of regional and gender differences in glucocorticoid receptors and lipoprotein lipase activity in human adipose tissue.","volume":"78","author":"Pedersen","year":"1994","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071622251472800_R44","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1056\/NEJM197608122950701","article-title":"Obesity in young men after famine exposure in utero and early infancy.","volume":"29","author":"Ravelli","year":"1976","journal-title":"N Engl J Med"},{"key":"2020071622251472800_R45","doi-asserted-by":"crossref","first-page":"R19","DOI":"10.1016\/0303-7207(95)03574-Q","article-title":"Cellular localization of 11\u03b2-hydroxysteroid dehydrogenase gene expression in the ovine adrenal 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