The effects of maternal glucocorticoid exposure on the developing placenta

Cuffe, James Sebastian Martin (2012). The effects of maternal glucocorticoid exposure on the developing placenta PhD Thesis, School of Biomedical Sciences, The University of Queensland.

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Author Cuffe, James Sebastian Martin
Thesis Title The effects of maternal glucocorticoid exposure on the developing placenta
School, Centre or Institute School of Biomedical Sciences
Institution The University of Queensland
Publication date 2012
Thesis type PhD Thesis
Supervisor Karen Moritz
David Simmons
Total pages 240
Total colour pages 17
Total black and white pages 223
Language eng
Subjects 111401 Foetal Development and Medicine
111603 Systems Physiology
110306 Endocrinology
Formatted abstract
The development of a healthy fetus is dependent upon the formation of a healthy, fully functioning placenta. When the fetus is exposed to an adverse intrauterine environment, fetal and placental development can be disturbed. A number of long term health deficits have been linked with an adverse maternal environment and disturbed placental growth. Maternal exposure to glucocorticoids has been shown to alter the development of the fetus in a number of animal models and result in long term programming of disease. Women are frequently exposed to synthetic glucocorticoids for the treatment of a number of medical conditions. In addition, synthetic glucocorticoids are administered prior to preterm delivery to increase the chances of survival for the premature infant. Natural glucocorticoids are produced endogenously in times of stress and may be elevated in a number of women during pregnancy. While the placenta is thought to largely protect the developing fetus from high levels of natural glucocorticoids via the actions of the placental glucocorticoid barrier, the effects of glucocorticoids on the developing placenta itself are relatively unknown. As such, the primary aim of this thesis was to investigate the effects of maternal exposure to both the natural glucocorticoid, corticosterone (Cort) and the synthetic glucocorticoid, dexamethasone (Dex) on the developing murine placenta.

At embryonic day (E) 12.5, pregnant mice were implanted with osmotic mini-pumps containing glucocorticoids (Dex- 1μg/kg/h or Cort-33μg/kg/h) which released their contents continuously for 60 hours. Control animals were either implanted with pumps containing saline (0.9%) or left untreated. As Cort exposed animals represented pregnant individuals exposed to stress, the untreated group, free from the stress of surgery, was chosen as the appropriate control for this group. Mice were killed at E14.5 (during glucocorticoid exposure) or at E17.5 (60 hours after the completion of exposure) for the collection of fetuses and placentas.

Dex exposure caused a transitory decrease in fetal weight in both males and females but a decrease in placental weight in females only at E14.5. This reduction in placental weight was due to a reduction in the size of the placental junctional zone. After the completion of Dex exposure at E17.5, fetal and placental weights were similar to saline exposed animals. On the other hand, Cort exposure did not directly affect fetal or placental weight at E14.5 but resulted in heavier placentas from male fetuses at E17.5. This increase in placental weight was associated with an increase in placental junctional zone volume. In addition to these sex and glucocorticoid specific changes in fetal and placental size, sex specific changes in the placental glucocorticoid barrier were identified. In response to both Dex and Cort, the protein levels of the protective glucocorticoid barrier enzyme 3 11β-HSD2 were increased in placentas from female but not male fetuses. This thesis further investigated a number of systems which may have contributed to the above changes in placental growth and identified glucocorticoid specific and sex specific changes in factors such as Igf2, VEGFA and MAPK. In addition, changes in the placental renin angiotensin system were identified which may contribute to the induced changes in placental growth seen following glucocorticoid exposure. Finally, this thesis showed for the first time, a complete temporal expression profile for each of the components of the renin-angiotensin system in the mouse placenta.

In conclusion, this thesis has identified sex and GC specific placental outcomes following maternal GC exposure that may infer short term deficits to the developing fetus and contribute to long term programming of adult onset disease. Results suggest, maternal exposure to increased stress (Cort) during pregnancy, may be particularly harmful for the developing male placenta and fetus. As such, the effects of stress should not be considered a minor risk or overlooked in pregnant women.
Keyword Placenta
Fetal programming
11-beta hydroxysteroid dehydrogenase type 2
Renin angiotensin system
Glucocorticoid receptor
Vascular Endothelial Growth Factor
Insulin like growth factor
Mitogen activated protein kinase

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Created: Fri, 22 Mar 2013, 12:59:34 EST by James Cuffe on behalf of Scholarly Communication and Digitisation Service