Alison J. Forhead

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.

Programming placental nutrient transport capacity

Many animal studies and human epidemiological findings have shown that impaired growth in utero is associated with physiological abnormalities in later life and have linked this to tissue programming during suboptimal intrauterine conditions at critical periods of development. However, few of these studies have considered the contribution of the placenta to the ensuing adult phenotype. In mammals, the major determinant of intrauterine growth is the placental nutrient supply, which, in turn, depends on the size, morphology, blood supply and transporter abundance of the placenta and on synthesis and metabolism of nutrients and hormones by the uteroplacental tissues. This review examines the regulation of placental nutrient transfer capacity and the potential programming effects of nutrition and glucocorticoid over‐exposure on placental phenotype with particular emphasis on the role of the Igf2 gene in these processes.

The Placenta and Intrauterine Programming

Intrauterine programming is the process by which the structure and function of tissues are altered permanently by insults acting during early development. In mammals, the placenta controls intrauterine development by supplying oxygen and nutrients, and by regulating the bioavailability of specific hormones involved in foetal growth and development. Consequently, the placenta is likely to have a key role in mediating the programming effects of suboptimal conditions during development. This review examines placental phenotype in different environmental conditions and places particular emphasis on regulation of placental nutrient transfer capacity and endocrine function by insults known to cause intrauterine programming. More specifically, it examines the effects of a range of environmental challenges on the size, morphology, blood flow and transporter abundance of the placenta and on its rate of consumption and production of nutrients. In addition, it considers the role of hormone synthesis and metabolism by the placenta in matching intrauterine development to the prevailing environmental conditions. The adaptive responses that the placenta can make to compensate for suboptimal conditions in utero are also assessed in relation to the strategies adopted to maximise foetal growth and viability at birth. Environmentally‐induced changes in placental phenotype may provide a mechanism for transmitting the memory of early events to the foetus later in gestation, which leads to intrauterine programming of tissue development long after the original insult.

Effect of maternal iron restriction during pregnancy on renal morphology in the adult rat offspring.

In rats, maternal anaemia during pregnancy causes hypertension in the adult offspring, although the mechanism is unknown. The present study investigated the renal morphology of adult rats born to mothers who were Fe-deficient during pregnancy. Rats were fed either a control (153 mg Fe/kg diet, n 7) or low-Fe (3 mg/kg diet, n 6) diet from 1 week before mating and throughout gestation. At delivery, the Fe-restricted (IR) mothers were anaemic; the IR pups were also anaemic and growth-retarded at 2 d of age. At 3 and 16 months, systolic blood pressure in the IR offspring (163 (sem 4) and 151 (sem 4) mmHg respectively, n 13) was greater than in control animals (145 (sem 3) and 119 (sem 4) mmHg respectively, n 15, P<0.05). At post mortem at 18 months, there was no difference in kidney weight between treatment groups, although relative kidney weight as a fraction of body weight in the IR offspring was greater than in control animals (P<0.05). Glomerular number was lower in the IR offspring (11.4 (sem 1.1) per 4 mm(2), n 13) compared with control rats (14.8 (sem 0.7), n 15, P<0.05). Maternal treatment had no effect on glomerular size, but overall, female rats had smaller and more numerous glomeruli per unit area than male rats. When all animals were considered, inverse relationships were observed between glomerular number and glomerular size (r-0.73, n 28, P<0.05), and glomerular number and systolic blood pressure at both 3 months (r-0.42, n 28, P<0.05) and 16 months of age (r-0.64, n 28, P<0.05). Therefore, in rats, maternal Fe restriction causes hypertension in the adult offspring that may be due, in part, to a deficit in nephron number.

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 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 T4 and T3 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 T4 and T3 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.

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.

Long-term programming of blood pressure by maternal dietary iron restriction in the rat

We have reported that blood pressure was elevated in 3-month-old rats whose mothers were Fe-restricted during pregnancy. These animals also had improved glucose tolerance and decreased serum triacylglycerol. The aim of the present study was to determine whether these effects of maternal nutritional restriction, present in these animals at 3 months of age, can be observed in the same animals in later life. Pulmonary and serum angiotensin converting enzyme (ACE) concentrations were also measured to investigate whether the renin-angiotensin system was involved in the elevation of blood pressure observed in the offspring of Fe-restricted dams. Systolic blood pressure was higher in the offspring of Fe-restricted dams at 16 months of age. Heart and kidney weight were increased as a proportion of body weight in the offspring of Fe-restricted dams. The pulmonary ACE concentration was not significantly different between the groups. The serum ACE concentration was significantly elevated in the offspring of Fe-restricted dams at 3 but not 14 months of age. There was a strong correlation between serum ACE levels at 3 and 14 months of age. Glucose tolerance and serum insulin were not different between the maternal diet groups. Serum triacylglycerol tended to be lower in the offspring of Fe-restricted dams. There were no differences in serum non-esterified fatty acids or serum cholesterol between the maternal diet groups. This study provides further evidence that maternal nutrition has effects on the offspring that persist throughout life. At 16 months of age, the elevation of blood pressure in Fe-restricted offspring does not appear to be mediated via changes in ACE levels. Both cardiac hypertrophy and decreased serum triacylglycerol have also been observed in Fe-restricted fetuses, suggesting that these changes may be initiated in utero.

The effects of birth weight on basal cardiovascular function in pigs at 3 months of age

In man, epidemiological studies have shown that low birth weight (BW) is associated with an increased risk of cardiovascular disease in later life. In this study, the long‐term consequences of variations in natural BW on basal cardiovascular function were investigated in pigs at 3 months of postnatal age. Low (< 1.41 kg; n= 20) and high (> 1.52 kg; n= 20) BW Large White piglets were selected from a total of 12 litters for study at 3 months of age. Basal mean arterial pressure (MAP) and heart rate (HR) were recorded for ∼30 min using standard recording equipment and basal arterial blood samples were taken for hormone analyses. Concentrations of angiotensin‐converting enzyme (ACE) were also measured in kidney, lung and plasma. Basal MAP, but not HR, in 3‐month‐old pigs was significantly inversely related to BW and positively related to the ratio of head length to BW. Postnatal growth rate of low BW pigs was slower than that of high BW pigs such that low BW piglets remained significantly smaller at 3 months of age. There were no differences in basal plasma adrenaline or cortisol concentrations between low and high BW pigs. However, basal plasma noradrenaline concentrations were significantly elevated in low BW compared to high BW pigs. Renal and pulmonary ACE levels were significantly reduced in low BW compared to high BW pigs. These data show that basal MAP in 3‐month‐old pigs is negatively associated with BW and positively correlated to disproportionate size at birth. This effect was associated with an increase in basal plasma noradrenaline concentrations.