Title page, table of contents and abstract only. The complete thesis in print form is available from the University of Adelaide Library. / A range of epidemiological, clinical and experimental studies have demonstrated that exposure of an embryo to a suboptimal environment in vivo or ex vivo during early embryo development is associated with altered development of cardiovascular, neuroendocrine and metabolic disorders in adult life. A number of perturbations during early embryo development result in developmental adaptations by the embryo to ensure immediate survival, whilst programming the embryo for altered fetal and placental development, resulting in the eventual onset of adult disease. It has been previously shown that maternal nutrient restriction during the periconceptional period results in a hyperactivation of the pituitary - adrenal axis and increased mean arterial blood pressure in twin but not singleton pregnancies. It was therefore the first aim of this thesis to interrogate the impact of maternal undernutrition during the periconceptional period (defined as from at least 45 days prior until 7 days after conception) on fetal and placental development during early pregnancy at - day 55 of pregnancy, which coincides with the period of maximal placental growth. In Chapter 2, it has been demonstrated that there are important relationships between maternal weight gain during the periconceptional period and feto-placental growth during the first - 55 days of pregnancy and that periconceptional undernutrition has a differential effect on these relationships in singleton and twin pregnancies. In singleton pregnancies, periconceptional undernutrition disrupts the relationship between maternal weight gain during the periconceptional period and utero-placental growth and in twin pregnancies, periconceptional undernutrition results in the emergence of an inverse relationship between maternal weight gain during early pregnancy and uteroplacental growth and in a dependence of fetal growth on placental growth. (Chapter 2) In order to investigate the origins of the physiological adaptations that lead to the development of hyperactivation of the pituitary - adrenal axis and increased mean arterial blood pressure in late gestational fetuses after exposure as an embryo to periconceptional undernutrition, we investigated the development and steroidogenic capacity of the fetal adrenal gland and development of the fetal heart and kidney at - 55 days gestation (Chapter 3 and 4). The relative weight of the fetal adrenal and adrenal IGF-1, IGF-1 R, IGF-2, IGF-2R and CYP 17 mRNA expression were lower in twin compared to singleton fetuses. There was evidence that in control singletons, IGF-2R expression plays an important role in the regulation of adrenal growth and CYP 17 mRNA expression during early pregnancy. In control twins, however, whilst there was a significant positive relationship between adrenal CYP 17 and IGF-2 mRNA expression, adrenal weight was directly related to the level of adrenal IGF-1 mRNA expression. There was no effect of periconceptional undernutrition on the level of expression of any of the placental or adrenal genes in the study. In PCUN ewes, carrying singletons, however, there was a loss of the relationships between either adrenal IGF-2, IGF-2R and IGF-1 mRNA expression and adrenal growth and CYP 17 expression which were present in control singletons. Similarly in ewes carrying twins, maternal undernutrition during the periconceptional period resulted in the loss of the relationships between adrenal growth and IGF-1 expression and between _ adrenal CYP 17 and IGF-2 expression which were present in control twin fetuses. Whilst there was no effect of fetal number on fetal heart growth at - d55 in twin fetuses, there was a direct relationship between relative fetal heart and adrenal weights, which was present in both the PCUN and control groups. There was also a significant inverse relationship between maternal weight at conception and relative fetal heart weight in PCUN twin, but not PCUN singleton or control fetuses (Chapter 3). In control pregnancies maternal weight gain during the periconceptional period is inversely related to the relative weight of the fetal kidney at -55d pregnancy. In this group, relative kidney weight was also directly related to renal IGF-1 mRNA expression. In control twins maternal weight gain was inversely related to fetal kidney weight and this effect was ablated when the effects of maternal cortisol was controlled for in the analysis. In the PCUN group, whilst there was an inverse relationship between maternal weight gain during the periconceptional period and relative kidney weight, it was not possible to separate the independent effects of maternal weight loss during the periconceptional period and the subsequent weight gain during the period of refeeding. Renal IGF-1 mRNA expression was higher and renal lGF-1 R and 2R expression were lower in twin fetuses compared to singletons. After exposure to PCUN, renal IGF-1 expression was also higher than in control pregnancies independent of the fetal number (Chapter 4). Superovulation, artificial insemination, embryo transfer and in vitro embryo culture are used in a range of assisted reproductive technologies, and it has been demonstrated that varying the composition of the culture media can result in a change in pre and postnatal development. Culture of sheep embryos in media containing serum is associated with fetal overgrowth which is phenotypic of the Large Offspring Syndrome. It is not known how the combination of superovulation, artificial insemination and embryo transfer alone impacts fetoplacental development in late gestation of the sheep. There have been no studies, however, examining the differential impact of superovulation, artificial insemination and embryo transfer with or without in vitro embryo culture in the absence or presence of human serum on feto-placental development in Singleton and twin pregnancies (Chapter 5). I have therefore tested the hypothesis that superovulation, artificial insemination and embryo transfer with or without in vitro embryo culture in the presence or absence of human serum differentially alters the growth of the placenta, fetus and fetal organs during late gestation when compared to naturally conceived controls and that these effects are different in singleton and twin pregnancies. The fetal weight, CRL and abdominal circumference were significantly larger in IVCHS singleton fetuses. A novel finding in this study was lower fetal weights of twin fetuses in the ET and IVCNS groups compared to NM control twin fetuses. In addition, placental weights were lighter in twin fetuses in the ET, IVCNS and IVCHS treatment groups and this is partially due to a failure to initiate compensatory growth of placentomes in twin pregnancies (Chapter 5). The results of this thesis therefore highlight the complex interactions between the periconceptional environment (in vivo or ex vivo) and embryo or fetal number on the programming fetal and placental development. Maternal undernutrition during the periconceptional period and superovulation, artificial insemination and embryo transfer with or without in vitro culture in the absence or presence of serum alters fetal development, and I have demonstrated that these changes in fetal growth can be explained by changes in placental growth trajectory. Furthermore, a novel finding of this study is that perturbations of the periconceptional environment affect feto-placental development differently in singleton and twin pregnancies. / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2006

Title page, table of contents and abstract only. The complete thesis in print form is available from the University of Adelaide Library. / A range of epidemiological, clinical and experimental studies have demonstrated that exposure of an embryo to a suboptimal environment in vivo or ex vivo during early embryo development is associated with altered development of cardiovascular, neuroendocrine and metabolic disorders in adult life. A number of perturbations during early embryo development result in developmental adaptations by the embryo to ensure immediate survival, whilst programming the embryo for altered fetal and placental development, resulting in the eventual onset of adult disease. It has been previously shown that maternal nutrient restriction during the periconceptional period results in a hyperactivation of the pituitary - adrenal axis and increased mean arterial blood pressure in twin but not singleton pregnancies. It was therefore the first aim of this thesis to interrogate the impact of maternal undernutrition during the periconceptional period (defined as from at least 45 days prior until 7 days after conception) on fetal and placental development during early pregnancy at - day 55 of pregnancy, which coincides with the period of maximal placental growth. In Chapter 2, it has been demonstrated that there are important relationships between maternal weight gain during the periconceptional period and feto-placental growth during the first - 55 days of pregnancy and that periconceptional undernutrition has a differential effect on these relationships in singleton and twin pregnancies. In singleton pregnancies, periconceptional undernutrition disrupts the relationship between maternal weight gain during the periconceptional period and utero-placental growth and in twin pregnancies, periconceptional undernutrition results in the emergence of an inverse relationship between maternal weight gain during early pregnancy and uteroplacental growth and in a dependence of fetal growth on placental growth. (Chapter 2) In order to investigate the origins of the physiological adaptations that lead to the development of hyperactivation of the pituitary - adrenal axis and increased mean arterial blood pressure in late gestational fetuses after exposure as an embryo to periconceptional undernutrition, we investigated the development and steroidogenic capacity of the fetal adrenal gland and development of the fetal heart and kidney at - 55 days gestation (Chapter 3 and 4). The relative weight of the fetal adrenal and adrenal IGF-1, IGF-1 R, IGF-2, IGF-2R and CYP 17 mRNA expression were lower in twin compared to singleton fetuses. There was evidence that in control singletons, IGF-2R expression plays an important role in the regulation of adrenal growth and CYP 17 mRNA expression during early pregnancy. In control twins, however, whilst there was a significant positive relationship between adrenal CYP 17 and IGF-2 mRNA expression, adrenal weight was directly related to the level of adrenal IGF-1 mRNA expression. There was no effect of periconceptional undernutrition on the level of expression of any of the placental or adrenal genes in the study. In PCUN ewes, carrying singletons, however, there was a loss of the relationships between either adrenal IGF-2, IGF-2R and IGF-1 mRNA expression and adrenal growth and CYP 17 expression which were present in control singletons. Similarly in ewes carrying twins, maternal undernutrition during the periconceptional period resulted in the loss of the relationships between adrenal growth and IGF-1 expression and between _ adrenal CYP 17 and IGF-2 expression which were present in control twin fetuses. Whilst there was no effect of fetal number on fetal heart growth at - d55 in twin fetuses, there was a direct relationship between relative fetal heart and adrenal weights, which was present in both the PCUN and control groups. There was also a significant inverse relationship between maternal weight at conception and relative fetal heart weight in PCUN twin, but not PCUN singleton or control fetuses (Chapter 3). In control pregnancies maternal weight gain during the periconceptional period is inversely related to the relative weight of the fetal kidney at -55d pregnancy. In this group, relative kidney weight was also directly related to renal IGF-1 mRNA expression. In control twins maternal weight gain was inversely related to fetal kidney weight and this effect was ablated when the effects of maternal cortisol was controlled for in the analysis. In the PCUN group, whilst there was an inverse relationship between maternal weight gain during the periconceptional period and relative kidney weight, it was not possible to separate the independent effects of maternal weight loss during the periconceptional period and the subsequent weight gain during the period of refeeding. Renal IGF-1 mRNA expression was higher and renal lGF-1 R and 2R expression were lower in twin fetuses compared to singletons. After exposure to PCUN, renal IGF-1 expression was also higher than in control pregnancies independent of the fetal number (Chapter 4). Superovulation, artificial insemination, embryo transfer and in vitro embryo culture are used in a range of assisted reproductive technologies, and it has been demonstrated that varying the composition of the culture media can result in a change in pre and postnatal development. Culture of sheep embryos in media containing serum is associated with fetal overgrowth which is phenotypic of the Large Offspring Syndrome. It is not known how the combination of superovulation, artificial insemination and embryo transfer alone impacts fetoplacental development in late gestation of the sheep. There have been no studies, however, examining the differential impact of superovulation, artificial insemination and embryo transfer with or without in vitro embryo culture in the absence or presence of human serum on feto-placental development in Singleton and twin pregnancies (Chapter 5). I have therefore tested the hypothesis that superovulation, artificial insemination and embryo transfer with or without in vitro embryo culture in the presence or absence of human serum differentially alters the growth of the placenta, fetus and fetal organs during late gestation when compared to naturally conceived controls and that these effects are different in singleton and twin pregnancies. The fetal weight, CRL and abdominal circumference were significantly larger in IVCHS singleton fetuses. A novel finding in this study was lower fetal weights of twin fetuses in the ET and IVCNS groups compared to NM control twin fetuses. In addition, placental weights were lighter in twin fetuses in the ET, IVCNS and IVCHS treatment groups and this is partially due to a failure to initiate compensatory growth of placentomes in twin pregnancies (Chapter 5). The results of this thesis therefore highlight the complex interactions between the periconceptional environment (in vivo or ex vivo) and embryo or fetal number on the programming fetal and placental development. Maternal undernutrition during the periconceptional period and superovulation, artificial insemination and embryo transfer with or without in vitro culture in the absence or presence of serum alters fetal development, and I have demonstrated that these changes in fetal growth can be explained by changes in placental growth trajectory. Furthermore, a novel finding of this study is that perturbations of the periconceptional environment affect feto-placental development differently in singleton and twin pregnancies. / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2006

[Truncated abstract] Saltbush is one of the few types of forage that will grow on salt affected land but, sheep struggle to maintain weight when grazing saltbush mainly because of its high salt content. Therefore, a strategy to improve salt tolerance of sheep would be beneficial to the profitable use of revegetated saline land. This could be done by manipulating the dietary salt load of pregnant or lactating ewes which could 'program', or permanently alter the physiology of their offspring to allow them to cope better with a high-salt diet as adults. When rat dams consume a high amount of salt during pregnancy, the salt balance mechanisms of their offspring are 'programmed' due to suppression of the offspring's renin-angiotensin system in early development. If this occurs in offspring from ewes grazing saltbush, beneficial adaptations may be programmed in these offspring which could allow them to better cope with the high-salt content of saltbush. I tested the general hypothesis that offspring born to ewes that consumed a high-salt or saltbush diet from mid-pregnancy to early lactation would have an increased capacity to cope with salt that would allow them gain weight when grazing saltbush in later life. To test this hypothesis, I pair-fed ewes either a high-salt diet (14% NaCl) or control diet (2% NaCl) in an animal house from day 60 of gestation until day 21 of lactation. During the same period, I also conducted a field experiment where ewes grazed on saltbush (supplemented with barley) or on pasture (supplemented with lupins). ... This led to the high-salt offspring retaining more salt than control animals. In contrast, the renin activity of saltbush was consistently lower than pasture offspring which allowed them to excrete salt more rapidly. In experiment three, the saltbush offspring gained tissue weight after grazing saltbush for 8 weeks, whereas the offspring in the other three treatments lost weight. High-salt and saltbush offspring also had higher greasy fleece weights at 22 months of age than their respective control groups. Feeding saltbush to ewes from mid-pregnancy to early lactation induces physiological adaptations in their offspring that allow them to cope better with salt and gain weight when grazing saltbush as adults, supporting my hypothesis. However, contrary to expectations, the high-salt offspring did not gain weight when grazing saltbush because their physiological adaptations, such as salt retention, did not allow them to cope better with a salt load. The reason that saltbush offspring showed different adaptations to highsalt offspring is likely to be because saltbush contains not only NaCl but also high amounts of other minerals such as potassium, and other plant compounds, which may influence the adaptive responses of the offspring. This research has direct implications for farmers because it shows they could utilize otherwise unproductive saltland by grazing pregnant ewes on saltbush to 'program' their offspring to gain weight when they graze saltbush later in life.

[Truncated abstract] The dramatic increase in the expression of allergic diseases such as asthma and allergy over the last 20-30 years has highlighted the urgent need to identify causative factors. It was hypothesised that direct immune interactions between mother and fetus contribute to the cytokine milieu of pregnancy, thus influencing immune maturation after birth. Further it was speculated that the cytokine responses produced as a result of maternalfetal interactions are Th-2 skewed in women allergic disease, which programmes their offspring towards developing an allergic phenotype after birth. To test this hypothesis a cohort of 169 pregnant women were recruited at 20 weeks gestation and defined as allergic or non-allergic based on both clinical history and skin prick test sensitisation. These women and their infants were followed up throughout pregnancy (20 weeks, 30 weeks, 36 weeks gestation and 6 weeks post-partum) and up to 2.5 years of age. Mixed lymphocyte reactions (MLR) were used to measure maternal cytokine (IL-6, IL-10, IL-13 and IFN-) and lymphoproliferative responses to fetal alloantigens at each pregnancy time-point. Human leukocyte antigen (HLA) typing of mothers and infants were performed to assess the effect of HLA mismatch on maternal MLR responses to their fetus. After delivery, mononuclear cells (MNC) were isolated from cord blood (CB) and stimulated with allergens, mitogen and toll-like receptor (TLR) ligands. .... As IL-6 also participates in adaptive immunity by promoting Th-2 differentiation it is proposed that the production of IL-6 as a results of maternal encounters with paternal antigens during pregnancy, contribute to the Th-2 skewed responses observed universally in most infants at birth. Associations between maternal-fetal interaction and clinical outcomes in infancy: Although clinical signs of allergy in infancy were not the main outcome measure of this thesis, there were interesting, yet complex relationships between the production of these maternal cytokines towards the fetus and allergic disease at infant follow-ups. Increased maternal IFN-¿ to fetal alloantigen was associated with asthma at 2.5 years and a trend towards recurrent wheeze at 12 months. In contrast decreased maternal IL-13 production was associated with IgE mediated food allergy at 12 months. Adjusting for maternal allergy and other potential confounders including infant gender, method of delivery, HLA mismatch, and paternal allergy did not account for these relationships. Further follow-ups of these infants are required to determine if these relationship last in to early childhood. In conclusion, the findings of this thesis provides further support for the hypothesis that immune responses at birth are programmed prenatally, and that this programming has implications later in life. Importantly, the placenta is the immunologically active interface between mother and fetus during pregnancy. Therefore it is emphasised that there is a crucial need for future research to focus on early immune programming at the placental level before the aetiological pathways of immune mediated diseases can be fully elucidated.

The developmental origins of health and disease hypothesis suggests that exposure to adverse prenatal environmental influences can determine an individual’s susceptibility to obesity in adult life. However, the specific causal mechanisms which underlie this hypothesis have yet to be identified. Focusing on the potential mechanistic role of the leptin endocrine axis, the main objective of this thesis was to investigate the long term effects of prenatal undernutrition and different levels of postnatal nutrition on leptin sensitivity and the development of diet-induced obesity (DIO) in the Wistar rat. A well established animal model of maternal undernutrition during pregnancy was used to induce prenatal undernutrition in experimental offspring. To investigate the interaction between prenatal nutrition and postnatal diet, and its effects on obesity development, female offspring were placed on three different diets: standard chow, a high fat diet or a calorie restricted diet. The effects of prenatal undernutrition and postnatal diet on leptin sensitivity were investigated, in adult offspring, by measuring the response to 14 days of peripheral leptin treatment. Changes in gene expression in the liver, retroperitoneal adipose tissue and soleus muscle were then characterised by custom microarray and quantitative real-time RT-PCR (QPCR) analysis. Adult female offspring exposed to prenatal undernutrition (UN offspring) were found to exhibit leptin resistance in adulthood, independent of postnatal DIO. This result demonstrates for the first time that exposure to prenatal undernutrition has a long term effect on adult leptin sensitivity. In UN offspring fed on a high-fat diet, leptin resistance significantly accelerated the development of DIO while in contrast, offspring maintained on calorie restriction remained lean. These findings suggest that prenatal nutrition can shape future susceptibility to DIO by altering postnatal leptin sensitivity. An analysis of gene expression suggests that prenatal undernutrition causes the development of peripheral tissue-specific leptin resistance, and may also further enhance an offspring’s susceptibility to DIO by altering the regulation of peripheral tissue lipogenesis, mitochondrial function, glucocorticoid metabolism and insulin sensitivity. In conclusion, these studies identify peripheral leptin resistance as a key mechanism that can influence postnatal susceptibility to DIO in female offspring exposed to prenatal undernutrition. Furthermore, the identification of specific changes in peripheral gene expression highlights four additional metabolic mechanisms which may also facilitate the development of DIO in leptin resistant UN offspring.

Maternal exposure to viral and bacterial infection during pregnancy is associated with fetal dysmorphology and neurodevelopmental disorders including schizophrenia, cerebral palsy, autism and mental retardation. Previous studies in our laboratory using an established mouse model of endotoxin-induced fetal dysmorphology have led to the hypothesis that birth defects caused by infections during pregnancy are the result of fetal zinc deficiency resulting from the induction of a zinc-binding protein, metallothionein (MT) in the maternal liver as part of the maternal inflammatory response. Thus, we predicted that zinc deficiency would exacerbate the negative fetal outcomes caused by bacterial endotoxin lipopolysaccharide (LPS) and that zinc supplementation would protect against LPS-mediated teratogenicity. This premise was investigated herein and was extended to investigate underlying molecular mechanism, including the identification of markers of neurodevelopmental damage following LPS administration in early and late pregnancy, and to determine the influence of zinc treatment on any changes in expression of these markers. In Chapter 2 it was demonstrated that prenatal exposure to LPS on gestational day (GD) 8 resulted in the development of physical birth defects including exencephaly, microcephaly, cleft lip and or palate, and micrognathia in GD 18 fetuses. Dietary zinc supplementation throughout pregnancy was found to prevent the LPS-related abnormalities. Furthermore, low dietary zinc and LPS exposure were found to be synergistic on teratogenicity. In addition, an inverse linear relationship was observed between the concentration of zinc in the diet and teratogenicity with a reduction in the incidence of birth defects observed with increasing concentration of dietary zinc, a finding suggesting that even small increments of zinc above normal dietary intake are likely to have a beneficial impact on teratogenicity. Maternal infection during late pregnancy has also been linked with prenatal brain damage. A major causal link underpinning this relationship is thought to be the cytokines released following a maternal inflammatory response to infection. In Chapter 3, the presence of cytokines released in response to LPS given on GD 16 was demonstrated by an increased number of tumour necrosis factor-alpha (TNF-!)-reactive cells and astrogliosis accompanied by extensive apoptotic cell death in GD 18 fetal brain. Recently our laboratory has reported that dietary zinc supplementation throughout pregnancy, prevented impairments in object recognition memory in offspring from dams exposed to prenatal LPS on GD 8. The question arises as to whether zinc is protective against LPS-exposure in late pregnancy. In Chapter 3, it is further demonstrated that LPS-induced brain injury was prevented by concurrent zinc treatment at the time of LPS exposure. In Chapter 4, the expression of activity-dependent neuroprotective protein (ADNP) mRNA was identified as a marker of changes occurring in the fetus as a result of LPS exposure in early pregnancy. ADNP has been found to be essential for organogenesis and is a sensitive indicator of brain injury. Here it was demonstrated that LPS caused a rapid increase in embryonic ADNP expression, which was highly significant 24 hours after exposure. Whether the elevation in ADNP expression is in response to inflammatory damage or is induced by cytokines released by the maternal inflammatory response is not clear. However, a major finding of the study is that concomitant zinc treatment prevented the LPS-induced increase in ADNP activity. The mechanism of protection by zinc is presumed to be centred on preventing the fall in plasma zinc and associated fetal zinc deficiency caused by LPS induction of MT, but may also include MT-independent actions of zinc including prevention of apoptosis and oxidative damage, or enhance tissue repair processes. Taken together the findings in this thesis support earlier evidence that maternal MTmediated transient fetal zinc deficiency in early pregnancy underpins LPS-induced teratogenicity. This is the first study to demonstrate that this mechanism may also apply to LPS-induced neurodevelopmental damage in early and late pregnancy. However, further studies are warranted to discriminate between the influence of MT and that of other inflammatory reactants (e.g. cytokines) on LPS-mediated damage late in pregnancy. The major finding of the thesis is that zinc treatment (either given subcutaneously with LPS or as dietary zinc supplementation throughout pregnancy) prevents the negative fetal outcomes including neurodevelopmental damage caused by prenatal exposure to LPS. This finding highlights the importance of zinc nutrition in pregnancy and the benefits that might be gained as a potential prophylactic treatment to minimise fetal damage caused by infections during pregnancy. / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2009

[Truncated abstract] In obstetric practice, pregnant women at risk of pre-term delivery between 24 and 34 weeks of gestation are administered synthetic glucocorticoids (betamethasone or dexamethasone) to induce fetal organ maturation. During this gestational period, the fetal kidney is undergoing a phase of rapid organogenesis with an increase in renal growth and active nephrogenesis occurring. The studies comprising this thesis examine the effects of prenatal betamethasone exposure on the fetal and adult ovine kidney. The central hypothesis of these studies was that exposure of the fetal kidney to betamethasone in late gestation would change renal structure and induce long-term alterations in the expression of glucocorticoid-sensitive genes and proteins. In the fetal studies, pregnant Merino ewes bearing single fetuses received single or repeated-weekly intra-muscular (i.m.) injections of betamethasone (0.5 mg/kg body weight) or saline commencing on day 104 of gestation (term is 150 days). Kidneys were collected from fetuses at 109, 116, 121 and 146 days of gestation (d). Using gold standard unbiased stereological techniques, the physical disector/fractionator method, total glomerular (nephron) number and glomerular volume were determined in 146 d fetal kidneys exposed to repeated maternal saline or betamethasone administration. In the adult study, kidneys were collected from 3.5-year-old sheep that had been exposed to ... In this thesis I have demonstrated that renal growth restriction as a result of betamethasone exposure is associated with a reduction in fetal nephron endowment. Although betamethasone does not appear to consistently alter nephron number or glomerular size, it may indirectly affect total nephron endowment through effects on renal growth. I have also provided evidence which suggests that lategestation betamethasone exposure in sheep does not program permanent alterations in the renal expression of genes or proteins involved in glucocorticoid hormone action or components of the renin-angiotensin system. Therefore, exposure of the fetal kidney to betamethasone during nephrogenesis may alter renal structure if kidney growth is perturbed; however, there are no persistent alterations in the expression of glucocorticoid-sensitive genes. These findings are consistent with the preservation of normal basal blood pressure in the adult sheep I studied and with the limited results from human studies of late-gestation maternal glucocorticoid administration.

Tez (Yüksek Lisans) - Süleyman Demirel Üniversitesi, Sağlık Bilimleri Enstitüsü, Anatomi Anabilim Dalı, 2005. / Bibliyografya var.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 6 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 5 uppsatser.