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Title: Fetal glucocorticoid exposure and cardiovascular risk
Author: Lindsay, Robert S.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1997
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In this thesis I examine the hypothesis that exposure to glucocorticoids in utero alters birth weight and might act to determine later cardiovascular risk. I present evidence that administration of low pharmacological does of dexamethasone (100-200 μg/kg/day given s.c. to the dam) leads to reductions in birth weight of 10-20% without affecting fetal or maternal viability. Further, these lower birth weight offspring have higher blood pressure as adults, with an increase in systolic blood pressure of 13mmHg in males and females when measured by direct carotid cannulation. The mechanism of the rise in blood pressure induced by in utero glucocorticoid exposure is examined. The potential for glucocorticoid exposure in utero to influence later blood pressure in normal physiology is also examined. Experimental evidence is presented that inhibition of 11-beta hydroxysteroid dehydrogenase in vivo results in increased exposure of the fetus to glucocorticoids derived from the maternal circulation. Administration of carbenoxolone, an inhibitor of 11-beta hydroxysteroid dehydrogenase, in a dose of 2.5mg/day to dams throughout pregnancy resulted in a 16% reduction in offspring birth weight and blood pressure rises in adult life in the offspring of 9mmHg in males and 7mmHg. suggesting that exposure of the fetus to maternal glucocorticoids also results in programming of blood pressure. Finally, the offspring of carbenoxolone treated pregnancies are also examined with regard to glucose tolerance. Glucose levels are shown to be higher both fasting (6.0+ 0.3 vs 4.8+ 0.2 mmoI/1: P<0.01) and in response to an oral glucose load (repeated ANOVA F=5.9, P< 0.05) in the offspring of treated animals. The potential mechanisms for this effect are examined with experimental evidence showing no difference in insulin sensitivity to injected insulin or in insulin secretion following fat feeding of the offspring of carbenooxoxlone treated pregnancies. In summary, this thesis provides evidence that increased feto-placental exposure to glucocorticoids reduces birth weight and produces long term increases in offspring blood pressure, plasma glucose and corticosterone levels, providing a mechanism to understand the 'fetal origens' hypothesis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available