Abigail L. Fowden

Glucocorticoids and the preparation for life after birth: are there long-term consequences of the life insurance?

In mammals, survival both before and after birth depends on a number of key physiological processes such as the provision of 02, a supply of oxidative substrates and a means of removing the waste products of metabolism. In adults these processes are carried out by a number of different tissues, whereas in the fetus they are carried out primarily by the placenta. The successful transition from intrato extra-uterine life, therefore, depends on the ability of specific tissues and organ systems to take over the functions of the placenta at birth. Consequently, organs such as the lungs, liver, kidneys and gut undergo maturational changes during late gestation in preparation for extra-uterine life. Most of these changes are glucocorticoid dependent and can be induced prematurely by exogenous glucocorticoid administration (Silver, 1990; Liggins, 1994; Fowden, 1995). As a consequence, synthetic glucocorticoids are now routinely administered to women in threatened preterm labour to improve neonatal viability (NIH Consensus Development Conference, 1995). In all species studied so far, there is an increase in the circulating glucocorticoid concentration in the fetus towards term (Fig. 1). The magnitude and timing of this cortisol surge vary between species, as does the precise mechanism by which it occurs (Fig. 1; Fowden & Silver, 1995; Wood & Cudd, 1997). In most species, the prepartum cortisol surge is due to increased adrenal cortisol output, but in certain animals, such as the rat and horse, its effect is enhanced by a fall in the level of plasma corticosteroidbinding globulin (Challis et al. 1993; Wood & Cudd, 1997). In normal conditions, therefore, fetal tissues are exposed to increasing levels of bioactive glucocorticoid for periods of up to 10-15 d before delivery.

Placental efficiency and adaptation: endocrine regulation

Size at birth is critical in determining life expectancy and is dependent primarily on the placental supply of nutrients. However, the fetus is not just a passive recipient of nutrients from the placenta. It exerts a significant acquisitive drive for nutrients, which acts through morphological and functional adaptations in the placenta, particularly when the genetically determined drive for fetal growth is compromised by adverse intrauterine conditions. These adaptations alter the efficiency with which the placenta supports fetal growth, which results in optimal growth for prevailing conditions in utero. This review examines placental efficiency as a means of altering fetal growth, the morphological and functional adaptations that influence placental efficiency and the endocrine regulation of these processes.

Adaptations in placental nutrient transfer capacity to meet fetal growth demands depend on placental size in mice

Experimental reduction in placental growth often leads to increased placental efficiency measured as grams of fetus produced per gram of placenta, although little is known about the mechanisms involved. This study tested the hypothesis that the smallest placenta within a litter is the most efficient at supporting fetal growth by examining the natural intra‐litter variation in placental nutrient transfer capacity in normal pregnant mice. The morphology, nutrient transfer and expression of key growth and nutrient supply genes (Igf2P0, Grb10, Slc2a1, Slc2a3, Slc38a1, Slc38a2 and Slc38a4) were compared in the lightest and heaviest placentas of a litter at days 16 and 19 of pregnancy, when mouse fetuses are growing most rapidly in absolute terms. The data show that there are morphological and functional adaptations in the lightest placenta within a litter, which increase active transport of amino acids per gram of placenta and maintain normal fetal growth close to term, despite the reduced placental mass. The specific placental adaptations differ with age. At E16, they are primarily morphological with an increase in the volume fraction of the labyrinthine zone responsible for nutrient exchange, whereas at E19 they are more functional with up‐regulated placental expression of the glucose transporter gene, Slc2a1/GLUT1 and one isoform the System A family of amino acid transporters, Slc38a2/SNAT2. Thus, this adaptability in placental phenotype provides a functional reserve capacity for maximizing fetal growth during late gestation when placental growth is compromised.

The sodium channel β‐subunit SCN3b modulates the kinetics of SCN5a and is expressed heterogeneously in sheep heart

1 Cardiac sodium channels are composed of a pore‐forming α‐subunit, SCN5a, and one or more auxiliary β‐subunits. The aim of this study was to investigate the role of the recently discovered member of the β‐subunit family, SCN3b, in the heart. 2 Northern blot and Western blot studies show that SCN3b is highly expressed in the ventricles and Purkinje fibres but not in atrial tissue. This is in contrast to the uniform expression of SCN1b throughout the heart. 3 Co‐expression of SCN3b with the cardiac‐specific α‐subunit SCN5a in Xenopus oocytes resulted in a threefold increase in the level of functional sodium channel expression, similar to that observed when SCN1b was co‐expressed with SCN5a. These results suggest that both SCN1b and SCN3b improve the efficiency with which the mature channel is targeted to the plasma membrane. 4 When measured in cell‐attached oocyte macropatches, SCN3b caused a significant depolarising shift in the half‐voltage of steady‐state inactivation compared to SCN5a alone or SCN5a + SCN1b. The half‐voltage of steady‐state activation was not significantly different between SCN5a alone and SCN5a + SCN3b or SCN5a + SCN1b. 5 The rates of inactivation for SCN5a co‐expressed with either subunit were not significantly different from that for SCN5a alone. However, recovery from inactivation at −90 mV was significantly faster for SCN5a + SCN1b compared to SCN5a + SCN3b, and both were significantly faster than SCN5a alone. 6 Thus, SCN1b and SCN3b have distinctive effects on the kinetics of activation and inactivation, which, in combination with the different patterns of expression of SCN3b and SCN1b, could have important consequences for the integrated electrical activity of the intact heart.

The Prenatal Development and Glucocorticoid Control of Brush-Border Hydrolases in the Pig Small Intestine

The development of brush-border enzymes and the possible regulatory role of cortisol were investigated in the small intestine of the fetal and neonatal pig. With the sows under pentobarbitone anesthesia, osmotic minipumps containing either saline or cortisol were inserted s.c. into 25 fetuses from 10 pregnant sows (82–96 d gestation). Six d later, the infused fetuses were removed by cesarean section and samples of the proximal, middle, and distal intestine taken for analysis. Samples were also obtained from 48 piglets that did not undergo an operation (controls) and that were removed at intervals from 82 d gestation until term (114 ± 2 d). In the proximal and middle intestine, the mean levels of lactase-phlorizin hydrolase (EC 3.2.1.23–62), maltase-glucoamylase (EC 3.2.1.20), aminopeptidase N (EC 3.4.11.2), and aminopeptidase A (EC 3.4.11.7) increased during the last 10–15 d before term, correlated positively with log10 plasma cortisol values, and were higher in cortisol-infused than in saline-infused fetuses (p < 0.05). Activity of sucrase-isomaltase (EC 3.2.1.48–10) was low in fetal pigs, and this enzyme and dipeptidyl peptidase IV (EC 3.4.14.5) were not significantly affected by fetal age or exogenous cortisol. Maltase (EC 3.2.1.48–10 and EC 3.2.1.20) activity was significantly decreased in the middle and distal intestine of cortisol-infused fetuses. The results suggest that the prepartum rise in endogenous cortisol secretion stimulates the prenatal expression of certain brush-border enzymes in the pig small intestine at this critical time. However, the effects of cortisol on the developing intestine were highly idiosyncratic for particular enzymes and intestinal regions.

Endocrine Regulation of Feto-Placental Growth

Hormones are both growth stimulatory and growth inhibitory in utero. They regulate tissue growth and development by controlling the rates of cell proliferation, apoptosis and differentiation in many fetal tissues. They also signal the level of resources available for intrauterine growth to the fe- tal tissues and relay back to the placenta the degree of mismatch between the actual fetal nutrient supply and the fetal nutrient demands for growth. They affect intrauterine growth by anabolic and catabolic actions on fetal metabolism and by altering the nutrient transfer capacity and endocrine function of the placenta. By modifying the fetal growth trajectory, hormones have a central role in programming development in utero and in determining the phenotypic outcome of changes in feto-placental growth during adverse intrauterine conditions. This review examines the role of hormones in feto-placental growth with particular emphasis on insulin, the insulin-like growth factors and glucocorticoids.

Hormones as epigenetic signals in developmental programming

In mammals, including man, epidemiological and experimental studies have shown that a range of environmental factors acting during critical periods of early development can alter adult phenotype. Hormones have an important role in these epigenetic modifications and can signal the type, severity and duration of the environmental cue to the developing feto‐placental tissues. They affect development of these tissues both directly and indirectly by changes in placental phenotype. They act to alter gene expression, hence the protein abundance in a wide range of different tissues, which has functional consequences for many physiological systems both before and after birth. By producing an epigenome specific to the prevailing condition in utero, hormones act as epigenetic signals in developmental programming, with important implications for adult health and disease. This review examines the role of hormones as epigenetic signals by considering their responses to environmental cues, their effects on phenotypical development and the molecular mechanisms by which they programme feto‐placental development, with particular emphasis on the glucocorticoids.

The hungry fetus? Role of leptin as a nutritional signal before birth

In adult animals, leptin is an adipose‐derived hormone that is important primarily in the regulation of energy balance during short‐ and long‐term changes in nutritional state. Expression of leptin and its receptors is widespread in fetal and placental tissues, although the role of leptin as a nutritional signal in utero is unclear. Before birth, leptin concentration correlates with several indices of fetal growth, and may be an endocrine marker of fetal size and energy stores in the control of metabolism and maturation of fetal tissues. In addition, leptin synthesis and plasma concentration can be modified by insulin, glucocorticoids, thyroid hormones and oxygen availability in utero, and therefore, leptin may be part of the hormonal response to changes in the intrauterine environment. Evidence is emerging to show that leptin has actions before birth that are tissue‐specific and may occur in critical periods of development. Some of these actions are involved in the growth and development of the fetus and others have long‐term consequences for the control of energy balance in adult life.

How does the foetal gastrointestinal tract develop in preparation for enteral nutrition after birth

a ˚ Abstract At birth, the gastrointestinal tract (GIT) must be able to cope with the shift from parenteral nutrition before birth (via the placenta) to enteral nutrition after birth (oral colostrum / milk intake). In preparation for this event, the GIT grows and matures very rapidly in the weeks before birth. A series of studies in foetal pigs and sheep have shown that both hormonal and luminal factors influence this rapid phase of GIT development in farm animals. Among the potential hormonal regulators of development, cortisol plays a pivotal role. Thus, the normal developmental increases in stomach acid and gastrin secretion, and in certain enzyme activities (chymosin, pepsin, amylase, lactase, aminopeptidases), are stimulated by circulating cortisol. Cortisol also affects the intestinal absorption of immunoglobulins at birth but has limited effects on the GIT in the postnatal period. Ingestion of amniotic fluid by the foetus and of colostrum by the neonate also modulates GIT growth and enzyme activities. These effects may be mediated via luminal actions of growth factors, hormones and nutrients present in the fluids. However, luminal influences on the developing GIT are less pronounced in the foetus than in the neonate. In conclusion, both circulating and luminal factors affect prenatal GIT development to ensure that the foetal GIT is sufficiently mature to support the dramatic changes in nutrition that occur at birth.

An obesogenic diet during mouse pregnancy modifies maternal nutrient partitioning and the fetal growth trajectory

In developed societies, high‐sugar and high‐fat (HSHF) diets are now the norm and are increasing the rates of maternal obesity during pregnancy. In pregnant rodents, these diets lead to cardiovascular and metabolic dysfunction in their adult offspring, but the intrauterine mechanisms involved remain unknown. This study shows that, relative to standard chow, HSHF feeding throughout mouse pregnancy increases maternal adiposity (+30%, P<0.05) and reduces fetoplacental growth at d 16 (–10%, P<0.001). At d 19, however, HSHF diet group pup weight had normalized, despite the HSHF diet group placenta remaining small and morphologically compromised. This altered fetal growth trajectory was associated with enhanced placental glucose and amino acid transfer (+35%, P<0.001) and expression of their transporters (+40%, P<0.024). HSHF feeding also up‐regulated placental expression of fatty acid transporter protein, metabolic signaling pathways (phosphoinositol 3‐kinase and mitogen‐activated protein kinase), and several growth regulatory imprinted genes (Igf2, Dlk1, Snrpn, Grb10, and H19) independently of changes in DNA methylation. Obesogenic diets during pregnancy, therefore, alter maternal nutrient partitioning, partly through changes in the placental phenotype, which helps to meet fetal nutrient demands for growth near term. However, by altering provision of specific nutrients, dietary‐induced placental adaptations have important roles in programming development with health implications for the offspring in later life.—Sferruzzi‐Perri, A N., Vaughan, O. R., Haro, M., Cooper, W. N., Musial, B., Charalambous, M., Pestana, D., Ayyar, S., Ferguson‐Smith, A C., Burton, G. J., Con‐stancia, M., Fowden, A. L., An obesogenic diet during mouse pregnancy modifies maternal nutrient partitioning and the fetal growth trajectory. FASEB J. 27, 3928–3937 (2013). www.fasebj.org