Dr Alison Forhead

Adverse environmental conditions before birth are known to program adult metabolic and endocrine phenotype in several species. However, whether increments in fetal cortisol concentrations of the magnitude commonly seen in these conditions can cause developmental programming remains unknown. Thus, this study investigated the outcome of physiological increases in fetal cortisol concentrations on glucose-insulin dynamics and pituitary-adrenal function in adult sheep. Compared to saline treatment, intravenous fetal cortisol infusion for 5 days in late gestation did not affect birthweight but increased lamb
body weight at 1-2 weeks after birth. Adult glucose dynamics, insulin sensitivity and insulin secretion were unaffected by prenatal cortisol overexposure, assessed by glucose tolerance tests, hyperinsulinaemic-euglycaemic clamps and acute insulin administration. In contrast, prenatal cortisol infusion induced adrenal hypo-responsiveness in adulthood with significantly reduced cortisol responses to insulin-induced hypoglycaemia and exogenous adrenocorticotropic hormone (ACTH) administration relative to saline treatment. The area of adrenal cortex expressed as a percentage of the total cross-sectional area of the adult adrenal gland was also lower after prenatal cortisol than saline infusion. In adulthood, basal circulating ACTH but not cortisol concentrations were significantly higher in the cortisol than saline treated group. The results show that cortisol overexposure before birth programs pituitary-adrenal development with consequences for adult stress responses. Physiological variations in cortisol concentrations before birth may, therefore, have an important role in determining adult phenotypical diversity and adaptability to environmental challenges.

Growth and maturation of the fetal gastrointestinal tract near term prepares the offspring for the onset of enteral nutrition at birth. Structural and functional changes are regulated by the prepartum rise in cortisol in the fetal circulation, although the role of the coincident rise in plasma tri-iodothyronine (T3) is unknown. This study examined the effect of hypothyroidism on the structural development of the gastrointestinal tract and the activity of brush-border digestive enzymes in the ovine fetus near term. In intact fetuses studied between 100 and 144 days of gestation (dGA; term ~ 145 days), plasma concentrations of T3, cortisol and gastrin; the mucosal thickness in the abomasum, duodenum, jejunum and ileum; and intestinal villus height and crypt depth increased with gestational age. Removal of the fetal thyroid gland at 105-110 dGA suppressed plasma thyroxine (T4) and T3 concentrations to the limit of assay detection in fetuses studied at 130 and 144 dGA, and decreased plasma cortisol and gastrin near term, compared to age-matched intact fetuses. Hypothyroidism was associated with reductions in the relative weights of the stomach compartments and small intestines, the outer perimeter of the intestines, the thickness of the gastric and intestinal mucosa, villus height and width, and crypt depth. The thickness of the mucosal epithelial cell layer and muscularis propria in the small intestines were not affected by gestational age or treatment. Activities of the brush border enzymes varied with gestational age in a manner that depended on the enzyme and region of the small intestines studied. In the ileum, maltase and dipeptidyl peptidase IV (DPPIV) activities were lower, and aminopeptidase N (ApN) were higher, in the hypothyroid compared to intact fetuses near term. These findings highlight the importance of thyroid hormones in the structural and functional development of the gastrointestinal tract near term, and indicate how hypothyroidism in utero may impair the transition to enteral nutrition and increase the risk of gastrointestinal disorders in the neonate. 

Prenatal glucocorticoid overexposure causes adult metabolic dysfunction in several species but its effects on adult mitochondrial function remain largely unknown. Using respirometry, this study examined mitochondrial substrate metabolism of fetal and adult ovine biceps femoris (BF) and semitendinosus (ST) muscles after cortisol infusion before birth. Physiological increases in fetal cortisol concentrations pre-term induced muscle- and substrate-specific changes in mitochondrial oxidative phosphorylation capacity in adulthood. These changes were accompanied by muscle-specific alterations in protein content, fibre composition and abundance of the mitochondrial electron transfer system (ETS) complexes. In adult ST, respiration using palmitoyl-carnitine and malate was increased after fetal cortisol treatment but not with other substrate combinations. There were also significant increases in protein content and reductions in the abundance of all four ETS complexes, but not ATP synthase, in the ST of adults receiving cortisol prenatally. In adult BF, intrauterine cortisol treatment had no effect on protein content, respiratory rates, ETS complex abundances or ATP synthase. Activity of citrate synthase, a marker of mitochondrial content, was unaffected by intrauterine treatment in both adult muscles. In the ST but not BF, respiratory rates using all substrate combinations were significantly lower in the adults than fetuses, predominantly in the saline-infused controls. The ontogenic and cortisol-induced changes in mitochondrial function were, therefore, more pronounced in the ST than BF muscle. Collectively, the results show that fetal cortisol overexposure programmes mitochondrial substrate metabolism in specific adult muscles with potential consequences for adult metabolism and energetics.

Prenatal glucocorticoid overexposure causes adult metabolic dysfunction in several species but its effects on adult mitochondrial function remain largely unknown. Using respirometry, this study examined mitochondrial substrate metabolism of fetal and adult ovine biceps femoris (BF) and semitendinosus (ST) muscles after cortisol infusion before birth. Physiological Increases in fetal cortisol concentrations pre-term induced muscle- and substrate-specific changes in mitochondrial oxidative phosphorylation capacity in adulthood. These changes were accompanied by muscle-specific alterations in protein content, fibre composition and abundance of the mitochondrial electron transfer system (ETS) complexes.  In adult ST, respiration using palmitoyl-carnitine and malate was increased after fetal cortisol treatment but not with other substrate combinations.  There were also significant increases in protein content and reductions in the abundance of all four ETS complexes, but not ATP synthase, in the ST of adults receiving cortisol prenatally.  In adult BF, intrauterine cortisol treatment had no effect on protein content, respiratory rates, ETS complex abundances or ATP synthase.  Activity of citrate synthase, a marker of mitochondrial content, was unaffected by intrauterine treatment in both adult muscles. In the ST but not BF, respiratory rates using all substrate combinations were significantly lower in the adults than fetuses, predominantly in the saline-infused controls. The ontogenic and cortisol-induced changes in mitochondrial function were, therefore, more pronounced in the ST than BF muscle. Collectively, the results show that fetal cortisol overexposure programs mitochondrial substrate metabolism in specific adult muscles with potential consequences for adult metabolism and energetics.

In adults, glucocorticoids are stress hormones that act, partly, through actions on mitochondrial oxidative phosphorylation (OXPHOS) to increase energy availability. Before birth, glucocorticoids are primarily maturational signals that prepare the fetus for new postnatal challenges. However, the role of the normal prepartum glucocorticoid rise in preparing mitochondria for the increased postnatal energy demands remains largely unknown. This study examined the effect of physiological increases in the fetal cortisol concentration on cerebral mitochondrial OXPHOS capacity near term (~130 days gestation, term ~145 days gestation). Fetal sheep were infused with saline or cortisol for 5 days at ~0.8 of gestation before the mitochondrial content, respiratory rates, abundance of the electron transfer system proteins and OXPHOS efficiency were measured in their cortex and cerebellum. Cerebral morphology was assessed by immunohistochemistry and stereology. Cortisol treatment increased the mitochondrial content, while decreasing Complex I-linked respiration in the cerebellum. There was no effect on the cortical mitochondrial OXPHOS capacity. Cortisol infusion had regional effects on cerebral morphology, with increased myelination in the cerebrum. The findings demonstrate the importance of cortisol in regulating the cerebral mitochondrial OXPHOS capacity prenatally and have implications for infants born preterm or after glucocorticoid overexposure due to pregnancy complications or clinical treatment.

Mature granulated trophoblast binucleate cells (BNC) have been found in all ruminant placentas examined histologically so far. BNC are normally fairly evenly distributed throughout the fetal villus and all their granules contain a similar variety of hormones and pregnancy associated glycoproteins (PAGs). Only the Giraffe is reported to show a different BNC protein expression, this paper is designed to investigate that. Gold labelled Lectin histochemistry and protein immunocytochemistry were used on deplasticised 1 μm sections of a wide variety of ruminant placentomes with a wide range of antibodies and lectins. In the Giraffe placentomes, even though the lectin histochemistry shows an even distribution of BNC throughout the trophoblast of the placental villi, the protein expression in the BNC granules is limited to the BNC either in the apex or the base of the villi. Placental lactogens and Prolactin (PRL) are present only in basally situated BNC: PAGs only in the apical BNC. PRL is only found in the Giraffe BNC which react with many fewer of the wide range of antibodies used here to investigate the uniformity of protein expression in ruminant BNC. The possible relevance of these differences to ruminant function and evolution is considered to provide a further example of the versatility of the BNC system.

Hormones have an important role in the regulation of fetal growth and development, especially in response to nutrient availability in utero.  Using micro-computed tomography and an electromagnetic 3-point bend test, this study examined the effect of pancreas removal at 0.8 fraction of gestation on the developing bone structure and mechanical strength in fetal sheep.  When fetuses were studied at 10 and 25 days after surgery, pancreatectomy caused hypoinsulinaemia, hyperglycaemia and growth retardation which was associated with low plasma concentrations of leptin and a marker of osteoclast activity and collagen degradation.  In pancreatectomised fetuses compared to control fetuses, limb lengths were shorter and trabecular bone in the metatarsi showed greater bone volume fraction, trabecular thickness, degree of anisotropy and porosity, and lower fractional bone surface area and trabecular spacing.  Mechanical strength testing showed that pancreas deficiency was associated with increased stiffness and a greater maximal weight load at fracture in a subset of fetuses studied near term.  Overall, pancreas deficiency in utero slowed growth of the fetal skeleton and adapted the developing bone to generate a more compact and connected structure.  Maintenance of bone strength in growth-retarded limbs is especially important in a precocial species in preparation for skeletal loading and locomotion at birth.

In adults, glucocorticoids act to match the supply and demand for energy during physiological challenges, partly through actions on tissue mitochondrial oxidative phosphorylation (OXPHOS) capacity. However, little is known about the role of the natural prepartum rise in fetal glucocorticoid concentrations in preparing tissues for the increased postnatal energy demands. This study examined the effect of manipulating cortisol concentrations in fetal sheep during late gestation on mitochondrial OXPHOS capacity of two skeletal muscles with different postnatal locomotive functions. Mitochondrial content, biogenesis markers, respiratory rates and expression of proteins and genes involved in the electron transfer system (ETS) and OXPHOS efficiency were measured in the biceps femoris (BF) and superficial digital flexor (SDF) of fetuses either infused with cortisol before the prepartum rise or adrenalectomised to prevent this increment. Cortisol infusion increased mitochondrial content, biogenesis markers, substrate-specific respiration rates and abundance of ETS Complex I and adenine nucleotide translocator (ANT1) in a muscle-specific manner that was more pronounced in the SDF than BF. Adrenalectomy reduced mitochondrial content and expression of PGC1α and ANT1 in both muscles, and ETS Complex IV abundance in the SDF near term. Uncoupling protein gene expression was unaffected by cortisol manipulations in both muscles. Gene expression of the myosin heavy chain isoform, MHCIIx, was increased by cortisol infusion and reduced by adrenalectomy in the BF alone. These findings show that cortisol has a muscle-specific role in prepartum maturation of mitochondrial OXPHOS capacity with important implications for the health of neonates born pre-term or after intrauterine glucocorticoid overexposure.

Thyroid hormones regulate adult metabolism partly through actions on mitochondrial oxidative phosphorylation (OXPHOS). They also affect neurological development of the brain, but their role in cerebral OXPHOS before birth remains largely unknown, despite the increase in cerebral energy demand during the neonatal period. Thus, this study examined prepartum development of cerebral OXPHOS in hypothyroid fetal sheep. Using respirometry, Complex I (CI), Complex II (CII), and combined CI&CII OXPHOS capacity were measured in the fetal cerebellum and cortex at 128 and 142 days of gestational age (dGA) after surgical thyroidectomy or sham operation at 105 dGA (term ~145 dGA). Mitochondrial electron transfer system (ETS) complexes, mRNA transcripts related to mitochondrial biogenesis and ATP production, and mitochondrial density were quantified using molecular techniques. Cerebral morphology was assessed by immunohistochemistry and stereology. In the cortex, hypothyroidism reduced CI-linked respiration and CI abundance at 128 dGA and 142 dGA, respectively, and caused upregulation of PGC1α (regulator of mitochondrial biogenesis) and thyroid hormone receptor β at 128 dGA and 142 dGA, respectively. In contrast, in the cerebellum, hypothyroidism reduced CI&II- and CII-linked respiration at 128 dGA, with no significant effect on the ETS complexes. In addition, cerebellar glucocorticoid hormone receptor and adenine nucleotide translocase (ANT1) were downregulated at 128 dGA and 142 dGA, respectively. These alterations in mitochondrial function were accompanied by reduced myelination. The findings demonstrate the importance of thyroid hormones in the prepartum maturation of cerebral mitochondria and have implications for the etiology and treatment of the neurodevelopmental abnormalities associated with human prematurity and congenital hypothyroidism.

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 perirenal
adipose 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 decreased
uncoupling protein 1 (UCP1) protein and mRNA content, and UCP1 thermogenic capacity without
any 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.

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.

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.

Introduction and methods Tragulus, the mouse deer, is considered the most primitive ruminant, with a diffuse placenta grossly quite unlike the cotyledonary type of the other ruminants. This immunocytochemical investigation of placental transporters was designed to elucidate possible mechanisms of evolution to the cotyledonary form. Results and discussion Tragulus expresses several of the major transport systems characteristic of the ruminants: the trophoblast binucleate cell (BNC) dynamics, the requirement for two isoforms, GT1 and GT3, for glucose transport, the provision of Aquaporin 3 for water control, and uterine milk and histiotrophic secretion from uterine glands. However whereas the expression of the 9kD Calcium Binding Protein (9CBP) for calcium transport in ruminants is restricted to the intercotyledonary trophoblast with its areolae, Tragulus, having no intercotyledonary area, expresses 9CBP throughout the villus trophoblast. There is some localised development of areolar-like structures in the mid term Tragulus but it is insignificant at term. The strong expression of Glucose Transporter 1 (GT1) in the BNC granules is unique to Tragulus. Conclusion Tragulus relies on essentially similar transport and BNC dynamics as the other ruminants. Thus the evolutionary pressures driving the development of the cotyledonary placenta probably lie in the increase in body size and the consequent need for a larger placental area to ensure sufficient glucose for the fetus. The delivery in Tragulus of GT1 to the maternal facing side may be this species unique solution to maintain the glucose supply. © 2014 Elsevier Ltd. All rights reserved.

The thyroid hormones, thyroxine (T) and triiodothyronine (T), are essential for normal growth and development of the fetus. Their bioavailability in utero depends on development of the fetal hypothalamic-pituitary-thyroid gland axis and the abundance of thyroid hormone transporters and deiodinases that influence tissue levels of bioactive hormone. Fetal T and T concentrations are also affected by gestational age, nutritional and endocrine conditions in utero, and placental permeability to maternal thyroid hormones, which varies among species with placental morphology. Thyroid hormones are required for the general accretion of fetal mass and to trigger discrete developmental events in the fetal brain and somatic tissues from early in gestation. They also promote terminal differentiation of fetal tissues closer to term and are important in mediating the prepartum maturational effects of the glucocorticoids that ensure neonatal viability. Thyroid hormones act directly through anabolic effects on fetal metabolism and the stimulation of fetal oxygen consumption. They also act indirectly by controlling the bioavailability and effectiveness of other hormones and growth factors that influence fetal development such as the catecholamines and insulin-like growth factors (IGFs). By regulating tissue accretion and differentiation near term, fetal thyroid hormones ensure activation of physiological processes essential for survival at birth such as pulmonary gas exchange, thermogenesis, hepatic glucogenesis, and cardiac adaptations. This review examines the developmental control of fetal T and T bioavailability and discusses the role of these hormones in fetal growth and development with particular emphasis on maturation of somatic tissues critical for survival immediately at birth. © 2014 Society for Endocrinology.

First published October 19, 2010; doi:10.1152/ajpendo.00205.2010.-”In adults, the adrenal glands are essential for the metabolic response to stress, but little is known about their role in fetal metabolism. This study examined the effects of adrenalectomizing fetal sheep on glucose and oxygen metabolism in utero in fed conditions and after maternal fasting for 48 h near term. Fetal adrenalectomy (AX) had little effect on the rates of glucose and oxygen metabolism by the fetus or uteroplacental tissues in fed conditions. Endogenous glucose production was negligible in both AX and intact, sham-operated fetuses in fed conditions. Maternal fasting reduced fetal glucose levels and umbilical glucose uptake in both groups of fetuses to a similar extent but activated glucose production only in the intact fetuses. The lack of fasting-induced glucogenesis in AX fetuses was accompanied by falls in fetal glucose ultilization and oxygen consumption not seen in intact controls. The circulating concentrations of cortisol and total catecholamines, and the hepatic glycogen content and activities of key gluconeogenic enzymes, were also less in AX than intact fetuses in fasted animals. Insulin concentrations were also lower in AX than intact fetuses in both nutritional states. Maternal glucose utilization and its distribution between the fetal, uteroplacental, and nonuterine maternal tissues were unaffected by fetal AX in both nutritional states. Ovine fetal adrenal glands, therefore, have little effect on basal rates of fetal glucose and oxygen metabolism but are essential for activating fetal glucogenesis in response to maternal fasting. They may also be involved in regulating insulin sensitivity in utero.

DOI (broken, 2018.11.07): https://doi.org/10.1677/joe.0.1800449

https://doi.org/10.1677/joe.0.1810459

DOI [broken, 2018.11.07] https://doi.org/10.1677/joe.0.1760023

DOI [broken, 2018.11.07] https://doi.org/10.1677/joe.0.1730143

DOI [broken, 2018.11.07] https://doi.org/10.1677/joe.0.1720527

The present study investigated the ontogeny of pulmonary and renal angiotensin-converting enzyme (ACE) in foetal and postnatal pigs, and examined the effect of cortisol on tissue ACE in utero. Data were compared with those in sheep at similar ages. Under anaesthesia, tissues and umbilical blood were collected from pig foetuses between 81-115 days of gestation (term, 115±2 days). Twelve foetuses delivered at 97±2 days were infused with saline or cortisol (3-6 mgkgday) using osmotic mini-pumps implanted 6 days previously. Tissues were collected from newborn piglets, and from pigs at 2-4 weeks, 10-12 weeks and 10-12 months of age. Unlike in sheep, gestational age and exogenous cortisol had no effect on pulmonary or renal ACE in pigs. After birth, pulmonary ACE decreased to a nadir at 2-4 weeks and remained low thereafter. Renal ACE increased between 10-12 weeks and 10-12 months. Postnatal changes in tissue ACE may have consequences for cardiovascular, pulmonary and renal function in pigs. Copyright © 2001 Elsevier Science Ireland Ltd.