Glucocorticoids as regulatory signals during intrauterine development.

What is the topic of this review? This review discusses the role of the glucocorticoids as regulatory signals during intrauterine development. It examines the functional significance of these hormones as maturational, environmental and programming signals in determining offspring phenotype. What advances does it highlight? It focuses on the extensive nature of the regulatory actions of these hormones. It highlights the emerging data that these actions are mediated, in part, by the placenta, other endocrine systems and epigenetic modifications of the genome. Glucocorticoids are important regulatory signals during intrauterine development. They act as maturational, environmental and programming signals that modify the developing phenotype to optimize offspring viability and fitness. They affect development of a wide range of fetal tissues by inducing changes in cellular expression of structural, transport and signalling proteins, which have widespread functional consequences at the whole organ and systems levels. Glucocorticoids, therefore, activate many of the physiological systems that have little function in utero but are vital at birth to replace the respiratory, nutritive and excretory functions previously carried out by the placenta. However, by switching tissues from accretion to differentiation, early glucocorticoid overexposure in response to adverse conditions can programme fetal development with longer term physiological consequences for the adult offspring, which can extend to the next generation. The developmental effects of the glucocorticoids can be direct on fetal tissues with glucocorticoid receptors or mediated by changes in placental function or other endocrine systems. At the molecular level, glucocorticoids can act directly on gene transcription via their receptors or indirectly by epigenetic modifications of the genome. In this review, we examine the role and functional significance of glucocorticoids as regulatory signals during intrauterine development and discuss the mechanisms by which they act in utero to alter the developing epigenome and ensuing phenotype.We would like to thank the many members of the Department of Physiology, Development and Neuroscience who have contributed to discussions and helped with our own studies cited here. We are also grateful for financial support from the BBSRC (BB/I011773/1), Horserace Betting Levy Board (VET/PRJ/736) and the Centre for Trophoblast Research at the University of Cambridge.This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1113/EP08521

Endocrine regulation of placental phenotype

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.We would like to thank the many members of the Department of Physiology, Development and Neuroscience who have contributed to discussions and helped with our own studies cited here. We are also grateful for financial support from the BBSRC (BB/I011773/1), Horserace Betting Levy Board (VET/PRJ/726 and 736), the Wellcome Trust 084804/2/08/Z and the Centre for Trophoblast Research at the University of Cambridge.This is the accepted manuscript. The final version is available from Elsevier at http://dx.doi.org/10.1016/j.placenta.2014.11.01

Maternal Dexamethasone Treatment Alters Tissue and Circulating Components of the Renin-Angiotensin System in the Pregnant Ewe and Fetus.

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 pregnant ewe and fetus. From 125 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 second injection, 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 renal renin, or AII type 1 or 2 receptors in the lungs and kidneys; or in pulmonary, renal or cardiac protein 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 study was supported by the Biotechnology and Biological Sciences Research Council and Tommy’s, the baby charity.This is the final version. It was first published by the Endocrine Society at http://press.endocrine.org/doi/abs/10.1210/en.2015-119

Developmental Expression and Glucocorticoid Control of the Leptin Receptor in Fetal Ovine Lung.

The effects of endogenous and synthetic glucocorticoids on fetal lung maturation are well-established, 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 or maternal 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. Leptin mRNA 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.This work was supported by the Biotechnology and Biological Sciences Research Council (grant numbers S18103 and BB/H01697X/1).This is the final version of the article. It first appeared from PLoS via http://dx.doi.org/10.1371/journal.pone.013611

Thyroid hormones in fetal growth and prepartum maturation

The thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are essential for normal growth and development of the fetus. Their bioavailabilityin uterodepends 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 T4and T3concentrations are also affected by gestational age, nutritional and endocrine conditionsin 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 theprepartummaturational 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 T4and T3bioavailability 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.</jats:p

Differential associations of leptin with adiposity across early childhood

Objective: We examined associations of perinatal and 3-year leptin with weight gain and adiposity through 7 years. Design and Methods In Project Viva, we assessed plasma leptin from mothers at 26–28 weeks’ gestation (n=893), umbilical cord vein at delivery (n=540), and children at 3 years (n=510) in relation to body mass index (BMI) z-score, waist circumference, skinfold thicknesses, and dual X-ray absorptiometry body fat. Results: 50.1% of children were male and 29.5% non-white. Mean(SD) maternal, cord, and age 3 leptin concentrations were 22.9(14.2), 8.8(6.4), and 1.8(1.7) ng/mL, respectively, and 3- and 7-year BMI z-scores were 0.46(1.00) and 0.35(0.97), respectively. After adjusting for parental and child characteristics, higher maternal and cord leptin was associated with less 3- year adiposity. For example, mean 3-year BMI z-score was 0.5 lower (95%CI:−0.7,−0.2; p-trend=0.003) among children whose mothers’ leptin concentrations were in the top vs. bottom quintile. In contrast, higher age 3 leptin was associated with greater weight gain and adiposity through age 7 [e.g., change in BMI z-score from 3 to 7 years was 0.2 units (95%CI:−0.0,0.4; p-trend=0.05)]. Conclusions: Higher perinatal leptin was associated with lower 3-year adiposity, whereas higher age 3 leptin was associated with greater weight gain and adiposity by 7 years

Glucocorticoid programming of intrauterine development.

Glucocorticoids (GCs) are important environmental and maturational signals during intrauterine development. Toward term, the maturational rise in fetal glucocorticoid receptor concentrations decreases fetal growth and induces differentiation of key tissues essential for neonatal survival. When cortisol levels rise earlier in gestation as a result of suboptimal conditions for fetal growth, the switch from tissue accretion to differentiation is initiated prematurely, which alters the phenotype that develops from the genotype inherited at conception. Although this improves the chances of survival should delivery occur, it also has functional consequences for the offspring long after birth. Glucocorticoids are, therefore, also programming signals that permanently alter tissue structure and function during intrauterine development to optimize offspring fitness. However, if the postnatal environmental conditions differ from those signaled in utero, the phenotypical outcome of early-life glucocorticoid receptor overexposure may become maladaptive and lead to physiological dysfunction in the adult. This review focuses on the role of GCs in developmental programming, primarily in farm species. It examines the factors influencing GC bioavailability in utero and the effects that GCs have on the development of fetal tissues and organ systems, both at term and earlier in gestation. It also discusses the windows of susceptibility to GC overexposure in early life together with the molecular mechanisms and long-term consequences of GC programming with particular emphasis on the cardiovascular, metabolic, and endocrine phenotype of the offspring.We would also like to thank the BBSRC, the Horserace Betting Levy Board and the Centre for Trophoblast for their financial support

Low carbon innovation in China: from overlooked opportunities and challenges to transitions in power relations and practices

This paper explores environmental innovation in the largest emerging economy – China - and its potential for contributing to global transitions to low-carbon, more sustainable patterns of development. It builds on earlier studies bringing alternative forms of low(er)-technology, ‘below-the-radar’, ‘disruptive’ and/or social innovation into its analysis. In addition, however, the paper develops our understanding of low-carbon innovation by paying particular attention to issues of changing power relations and social practices; theoretical issues that need attention in the literature generally but are notably absent when studying transitions in China. This shift in perspective allows four neglected questions to be introduced and, in each case, points to both opportunities and challenges to low-carbon system transition that are overlooked by an orthodox focus on technological innovations alone. These are briefly illustrated by drawing on examples from three key domains of low-carbon innovation: solar-generated energy; electric urban mobility; and food and agriculture

Pancreas deficiency modifies bone development in the ovine fetus near term.

Hormones have an important role in the regulation of fetal growth and development, especially in response to nutrient availability in utero. Using micro-CT and an electromagnetic three-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 pancreatectomized fetuses compared to control fetuses, limb lengths were shorter, and trabecular (Tb) bone in the metatarsi showed greater bone volume fraction, Tb thickness, degree of anisotropy and porosity, and lower fractional bone surface area and Tb 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 the 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