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Department of Biological and Medical Sciences
Faculty of Health and Life Sciences
+44 (0)1865 483625
My research interests are in mammalian endocrinology and the endocrine regulation of physiology and development in the fetus. Currently, my research work is focussed on two main areas:
Development and regulation of endocrine systems in the fetusThese studies have examined the bioavailability of hormones in the fetus, in particular, the glucocorticoids, thyroid hormones, leptin, insulin-like growth factors and the renin-angiotensin system. Our analyses of hormone systems in utero have included measurements of circulating concentrations, tissue metabolism and metabolic enzymes, cellular uptake mechanisms and receptor expression. These studies have demonstrated complex interactions between endocrine systems before birth and have elucidated a variety of cellular and molecular mechanisms of developmental control. Endocrine control of fetal growth, development and maturationMy research has also investigated the role of hormones in the regulation of normal fetal development. These studies have an integrative approach to systems animal biology by examining a wide variety of fetal tissues and organs, and aspects of fetal physiology, including growth, cardiovascular and renal function, nutrition and metabolism. In particular, several of these studies have established the importance of endocrine signals in fetal maturation near to delivery and in the successful transition from the intrauterine to extrauterine environment at birth. We have investigated the mechanisms of glucocorticoid action in several physiological systems, and demonstrated the important roles of other hormones, such as thyroid hormones and angiotensin II, in mediating many of the maturational effects of glucocorticoids. Overall, my research has an integrative approach to the study of mammalian endocrinology and systems animal physiology. The research findings have important implications for the understanding of normal fetal growth and development, the consequences of prematurity and fetal endocrine disorders, and the mechanisms underlying the intrauterine programming of adult (patho)physiology.
Background. The fetal hypothalamic-pituitary-adrenal (HPA) axis plays a key role in the control of parturition and maturation of organ systems in preparation for birth. In hypothyroid fetuses, gestational length may be prolonged and maturational processes delayed. The extent to which the effects of thyroid hormone deficiency in utero on the timing of fetal maturation and parturition are mediated by changes to the structure and function of the fetal HPA axis is unknown. Methods. In twin sheep pregnancies where one fetus was thyroidectomized and the other sham-operated, this study investigated the effect of hypothyroidism on circulating concentrations of adrenocorticotrophic hormone (ACTH) and cortisol, and the structure and secretory capacity of the anterior pituitary and adrenal glands. The relative population of pituitary corticotrophs, and the masses of the adrenal zones, were assessed by immunohistochemical and stereological techniques. Adrenal mRNA abundances of key steroidogenic enzymes and growth factors were examined by qPCR.Results. Hypothyroidism in utero reduced plasma concentrations of ACTH and cortisol. In thyroid-deficient fetuses, the mass of corticotrophs in the anterior pituitary gland was unexpectedly increased, while the mass of the zona fasciculata and its proportion of the adrenal gland were decreased. These structural changes were associated with lower adrenocortical mRNA abundances of insulin-like growth factor-I (IGFI) and its receptor, and key steroidogenic enzymes responsible for glucocorticoid synthesis. The relative mass of the adrenal medulla and its proportion of the adrenal gland were increased by thyroid hormone deficiency in utero, without any change in expression of phenylethanolamine N-methyltransferase or the IGF system. Conclusions. Thyroid hormones are important regulators of the structure and secretory capacity of the pituitary-adrenal axis before birth. In hypothyroid fetuses, low plasma cortisol may be due to impaired adrenocortical growth and steroidogenic enzyme expression, secondary to low circulating ACTH concentration. Greater corticotroph population in the anterior pituitary gland of the hypothyroid fetus indicates compensatory cell proliferation and that there may be abnormal corticotroph capacity for ACTH synthesis and/or impaired hypothalamic input. Suppression of the development of the fetal HPA axis by thyroid hormone deficiency may contribute to the delay in fetal maturation and delivery observed in hypothyroid offspring.
Prenatal glucocorticoid overexposure has been shown to program adult cardiovascular function in a range of species but much less is known about the long-term effects of neonatal glucocorticoid overexposure. In horses, prenatal maturation of the hypothalamus-pituitary-adrenal axis and the normal prepartum surge in fetal cortisol occur late in gestation compared to other precocious species. Cortisol levels continue to rise in the hours after birth of full term foals and increase further in the subsequent days in premature, dysmature and maladapted foals. Thus, this study examined the adult cardiovascular consequences of neonatal cortisol overexposure induced by adrenocorticotropic hormone (ACTH) administration to full-term male and female pony foals. After catheterisation at 2-3 years of age, basal arterial blood pressures (BP) and heart rate (HR) were measured together with the responses to phenylephrine (PE) and sodium nitroprusside (SNP). These data were used to assess cardiac baroreflex sensitivity. Neonatal cortisol overexposure reduced both the pressor and bradycardic responses to PE in the young adult males, but not females. It also enhanced the initial hypotensive response to SNP, slowed recovery of BP after infusion and reduced the gain of the cardiac baroreflex in the females, but not males. Basal diastolic pressure and cardiac baroreflex sensitivity also differed with sex, irrespective of neonatal treatment. The results show that there is a window of susceptibility for glucocorticoid programming during the immediate neonatal period that alters cardiovascular function in young adult horses in a sex-linked manner.
Birth is a significant metabolic challenge with exposure to a pro-oxidant environment and the increased energy demands for neonatal survival. This study investigated the development of mitochondrial density and activity in ovine biceps femoris skeletal muscle during the perinatal period and examined the role of thyroid hormones in these processes. Muscle capacity for oxidative phosphorylation increased primarily after birth but was accompanied by prepartum increases in mitochondrial density and abundance of electron transfer system (ETS) complexes I-IV and ATP synthase as well as by neonatal upregulation of uncoupling proteins. This temporal disparity between prepartum maturation and neonatal upregulation of mitochondrial oxidative capacity may protect against oxidative stress associated with birth while ensuring energy availability to the neonate. Fetal thyroid hormone deficiency reduced oxidative phosphorylation and prevented the prepartum upregulation of mitochondrial density and ETS proteins in fetal skeletal muscle. Overall, the data shows that mitochondrial function matures over the perinatal period and is dependent on thyroid hormones, with potential consequences for neonatal viability and adult metabolic health.
Background. Development of adipose tissue before birth is essential for energy storage and thermoregulation in the neonate and for cardiometabolic health in later life. Thyroid hormones are important regulators of growth and maturation in fetal tissues. Offspring hypothyroid in utero are poorly adapted to regulate body temperature at birth and are at risk of becoming obese and insulin resistant in childhood. The mechanisms by which thyroid hormones regulate the growth and development of adipose tissue in the fetus, however, are unclear. Methods. This study examined the structure, transcriptome and protein expression of perirenaladipose tissue (PAT) in a fetal sheep model of thyroid hormone deficiency during late gestation. Proportions of unilocular (white) and multilocular (brown) adipocytes, and unilocular adipocyte size, were assessed by histological and stereological techniques. Changes to the adipose transcriptome were investigated by RNA-sequencing and bioinformatic analysis, and proteins of interest were quantified by Western blotting. Results. Hypothyroidism in utero resulted in elevated plasma insulin and leptin concentrations and overgrowth of PAT in the fetus, specifically due to hyperplasia and hypertrophy of unilocular adipocytes with no change in multilocular adipocyte mass. RNA-sequencing and genomic analyses showed that thyroid deficiency affected 34% of the genes identified in fetal adipose tissue. Enriched KEGG and gene ontology pathways were associated with adipogenic, metabolic and thermoregulatory processes, insulin resistance, and a range of endocrine and adipocytokine signalling pathways. Adipose protein levels of signalling molecules, including phosphorylated S6-kinase (pS6K), glucose transporter isoform 4 (GLUT4) and peroxisome proliferator-activated receptor γ (PPARγ), were increased by fetal hypothyroidism. Fetal thyroid deficiency decreaseduncoupling protein 1 (UCP1) protein and mRNA content, and UCP1 thermogenic capacity withoutany change in multilocular adipocyte mass. Conclusions. Growth and development of adipose tissue before birth is sensitive to thyroid hormone status in utero. Changes to the adipose transcriptome and phenotype observed in the hypothyroid fetus may have consequences for neonatal survival and the risk of obesity and metabolic dysfunction in later life.
Antenatal synthetic glucocorticoids promote fetal maturation in pregnant women at risk of preterm delivery and their mechanism of action may involve other endocrine systems. This study investigated the effect of maternal dexamethasone treatment, at clinically relevant doses, on components of the renin-angiotensin system (RAS) in the pregnanteweandfetus.From125 days of gestation (term, 145 2 d), 10 ewes carrying single fetuses of mixed sex (3 female, 7 male) were injected twice im, at 10-11 PM, with dexamethasone (2×12 mg, n=5) or saline (n=5) at 24-hour intervals. At 10 hours after the secondinjection, maternal dexamethasone treatment increased angiotensin-converting enzyme(ACE) mRNA levels in the fetal lungs, kidneys, and heart and ACE concentration in the circulation and lungs, but not kidneys, of the fetuses. Fetal cardiac mRNA abundance of angiotensin II (AII) type 2 receptor decreased after maternal dexamethasone treatment. Between the two groups of fetuses, there were no significant differences in plasma angiotensinogen or renin concentrations; in transcript levels of renalrenin,orAIItype1or2receptorsinthelungsandkidneys;orinpulmonary,renalorcardiacprotein content of the AII receptors. In the pregnant ewes, dexamethasone administration increased pulmonary ACE and plasma angiotensinogen, and decreased plasma renin, concentrations. Some of the effects of dexamethasone treatment on the maternal and fetal RAS were associated with altered insulin and thyroid hormone activity. Changes in the local and circulating RAS induced by dexamethasone exposure in utero may contribute to the maturational and tissue-specific actions of antenatal glucocorticoid treatment.
The effects of endogenous and synthetic glucocorticoids on fetal lung maturation are wellestablished, although the role of leptin in lung development before birth is unclear. This study examined mRNA and protein levels of the signalling long-form leptin receptor (Ob-Rb) in fetal ovine lungs towards term, and after experimental manipulation of glucocorticoid levels in utero by fetal cortisol infusion ormaternal dexamethasone treatment. In fetal ovine lungs, Ob-Rb protein was localised to bronchiolar epithelium, bronchial cartilage, vascular endothelium, alveolar macrophages and type II pneumocytes. Pulmonary Ob-Rb mRNA abundance increased between 100 (0.69 fractional gestational age) and 144 days (0.99) of gestation, and by 2-4-fold in response to fetal cortisol infusion and maternal dexamethasone treatment. In contrast, pulmonary Ob-Rb protein levels decreased near term and were halved by glucocorticoid treatment, without any significant change in phosphorylated signal transducer and activator of transcription-3 (pSTAT3) at Ser727, total STAT3 or the pulmonary pSTAT3: STAT3 ratio. LeptinmRNA was undetectable in fetal ovine lungs at the gestational ages studied. These findings demonstrate differential control of pulmonary Ob-Rb transcript abundance and protein translation, and/or post-translational processing, by glucocorticoids in utero. Localisation of Ob-Rb in the fetal ovine lungs, including alveolar type II pneumocytes, suggests a role for leptin signalling in the control of lung growth and maturation before birth.
The present study tested the hypothesis that overexposure to endogenous glucocorticoids in neonatal life alters the reactivity of the hypothalamic-pituitary-adrenal (HPA) axis in ponies at 1 and 2yr of age. Newborn foals received saline (0.9% NaCl, n = 8, control) or long-acting adrenocorticotropic hormone (ACTH) (Depot Synacthen 0.125mg intramuscularly twice daily, n = 9) for 5d after birth to raise cortisol concentrations 5- to 6-fold. At 1 and 2yr of age, HPA axis function was assessed by bolus administration of short-acting ACTH (1μg/kg intravenous) and insulin (0.5 U/kg intravenous) to induce hypoglycemic on separate days. Arterial blood samples were taken at 5 to 30-min intervals before and after drug administration to measure plasma ACTH and/or cortisol concentrations. There were no differences in the basal plasma ACTH or cortisol concentrations or in the cortisol response to exogenous ACTH with neonatal treatment or age. At 1 and 2yr of age, the increment in plasma ACTH but not cortisol at 60min in response to insulin-induced hypoglycemia was greater in ponies treated neonatally with ACTH than saline (P < 0.05). Neonatal cortisol overexposure induced by neonatal ACTH treatment, therefore, alters functioning of the HPA axis in adult ponies.
Hormones have an important role in regulating fetal development. They act as environmental signals and integrate tissue growth and differentiation with relation to nutrient availability. While hormones control the developmental fate of resources available to the fetus, the actual supply of nutrients and oxygen to the fetus depends on the placenta. However, much less is known about the role of hormones in regulating placental development, even though the placenta has a wide range of hormone receptors and produces hormones itself from early in gestation. The placenta is, therefore, exposed to hormones by autocrine, paracrine and endocrine mechanisms throughout its lifespan. It is known to adapt its phenotype in response to environmental cues and fetal demand signals, particularly when there is a disparity between the fetal genetic drive for growth and the nutrient supply. These adaptive responses help to maintain fetal growth during adverse conditions and are likely to depend, at least in part, on the hormonal milieu. This review examines the endocrine regulation of placental phenotype with particular emphasis on the glucocorticoid hormones. It focuses on the availability of placental hormone receptors and on the effects of hormones on the morphology, transport capacity and endocrine function of the placenta.