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Discipline of Physiology, School of Molecular and Biomedical Sciences, and Department Obstetrics and Gynaecology, University of Adelaide, Adelaide, Australia
ABSTRACT I. EARLY ORIGINS OF ADULT DISEASE: HYPOTHESES AND CONTROVERSIES A. Origins of the Hypothesis B. The Thrifty Phenotype Hypothesis, Programming, and Developmental Plasticity 1. Evolution, developmental plasticity, and predictive adaptive responses 2. Fetal growth and birth weight 3. Interaction between prenatal and postnatal growth 4. Twin studies II. CARDIOVASCULAR DISEASE AND HYPERTENSION A. Epidemiological Evidence for the Association Between Low Birth Weight, Cardiovascular Disease, and Hypertension 1. Cardiovascular disease 2. Hypertension B. Perinatal Nutrition and the Programming of Hypertension 1. Fetal nutrient restriction and programming of hypertension in the guinea pig and rat 2. Maternal nutrition in the preimplantation period 3. Interaction between prenatal and postnatal nutrition 4. Maternal undernutrition and the programming of hypertension in the sheep C. Prenatal Glucocorticoid Exposure and the Programming of Hypertension 1. Rat 2. Sheep D. Targets for Programming: the Kidney and the Intrarenal Renin-Angiotensin System 1. Human 2. Rat and sheep 3. The intrarenal RAS and the programming of hypertension A) RAT. B) SHEEP. E. Targets for Programming: the Renin-Angiotensin System and Vascular Smooth Muscle 1. Rat 2. Sheep F. Targets for Programming: the Endothelium 1. Human 2. Rat 3. Sheep G. Targets for Programming: the Heart 1. Rat: cardiomyocyte hyperplasia, hypertrophy, and apoptosis 2. Sheep: cardiomyocyte hyperplasia, hypertrophy, and apoptosis 3. Myocardial growth and vascularization 4. Glucocorticoids and cardiac programming H. IUGR, the Sympathoadrenal System and the Programming of Hypertension 1. Human 2. Sheep and pig 3. Rat III. INSULIN RESISTANCE AND TYPE 2 DIABETES A. Epidemiological Evidence for the Association Between Low Birth Weight and Type 2 Diabetes 1. Gestational diabetes B. Targets for Programming: Pancreatic Growth and Function 1. Pancreatic development 2. Rat 3. Human 4. Intrauterine nutrition and fetal pancreatic development in the rat 5. Intrauterine nutrition and postnatal pancreatic development in the rat 6. Maternal diabetes, fetal growth, and pancreatic development in the rat 7. Postnatal nutrition and pancreatic development in the rat 8. Fetal undernutrition and glucose tolerance in the rat 9. Fetal undernutrition and glucose tolerance in the sheep and pig C. Targets for Programming: the Liver and Glucose Tolerance 1. Rat 2. Sheep D. Targets for Programming: Skeletal Muscle and Insulin Sensitivity 1. Skeletal muscle development 2. Rat 3. Sheep and pig E. Targets for Programming: the Adipocyte and Insulin Sensitivity 1. Rat IV. OBESITY AND THE METABOLIC SYNDROME A. Epidemiological Evidence for the Association Between Birth Weight and Obesity in Adult Life 1. High birth weight and adult obesity 2. Low birth weight and central obesity in later life B. Targets for Programming: the Appetite Regulatory Neural Network 1. Development of the appetite regulatory neural network: rat 2. Development of the appetite regulatory neural network: human and sheep 3. Programming of appetite: rat 4. Programming of appetite: human and sheep C. Targets for Programming: the Adipocyte and Adipocyte Hormone Secretion 1. Leptin and the early programming of human obesity 2. Leptin and the programming of adult obesity in the rat 3. Leptin, fetal nutrition, and the programming of obesity in the sheep V. THE HYPOTHALAMO-PITUITARY-ADRENAL AXIS: A TARGET AND MEDIATOR IN THE DEVELOPMENTAL ORIGINS OF ADULT DISEASE A. Maternal Undernutrition and the Programming of the HPA Axis in the Rat and Guinea Pig B. Undernutrition and the Programming of the HPA Axis in the Sheep C. Glucocorticoid Exposure During Pregnancy and the Programming of the HPA Axis in the Rat D. Glucocorticoid Exposure During Pregnancy and the Programming of the HPA Axis in the Sheep VI. CONCLUSIONS AND FUTURE DIRECTIONS A. Epigenetics, Imprinting, and Programming B. Species Differences: Developmental Deficits Versus Developmental Plasticity C. Gender, Plasticity, and Programming ACKNOWLEDGMENTS REFERENCES
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I. EARLY ORIGINS OF ADULT DISEASE: HYPOTHESES AND CONTROVERSIES |
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The "early" or "fetal" origins of adult disease hypothesis describes a hypothesis that was originally put forward by David Barker and colleagues in Southampton in the United Kingdom which stated that environmental factors, particularly nutrition, act in early life to program the risks for the early onset of cardiovascular and metabolic disease in adult life and premature death. Before the fetal origins hypothesis was articulated, an association between early life events and later cardiovascular disease had been proposed on more than one occasion. In 1934, Kermack et al. (251) demonstrated that death rates from all causes in the United Kingdom and Sweden fell between 1751 and 1930, and they concluded that this was the result of better childhood living conditions during this period. Subsequently, Forsdahl (150) reported that there was a correlation within different geographical regions of Norway between coronary heart disease in 1964–1967 and infant mortality rates, some 70 years earlier. Forsdahl (150) postulated that poverty may act through a nutritional deficit to result in a life-long vulnerability to a more affluent adult life-style. In 1985, Wadsworth et al. (524) in the United Kingdom reported that adult blood pressure was inversely related to birth weight in men and women born in 1946. In 1986, Barker and colleagues were searching for an explanation of the different rates of mortality from stroke and cardiovascular diseases in geographical regions of England and Wales. They noted that the geographical distribution of mortality rates from stroke and cardiovascular diseases in 1968–1978 was closely related to neonatal mortality in 1921–1925, and they concluded that poor health and physique of mothers were important determinants of the risk of stroke in their offspring (21). Soon afterwards, they proposed that environmental influences, which impair growth and development in early life, result in an increased risk for ischemic heart disease (22), and indeed, further studies showed that low birth weight and low weight at 1 yr were associated with the highest rates of cardiovascular death (251, 388). There then followed a worldwide series of epidemiological studies that extended the initial observations on the association between pre- and postnatal growth and cardiovascular disease to include associations between early growth patterns and an increased risk for hypertension, impaired glucose tolerance, non-insulin-dependent or type 2 diabetes, insulin resistance, and obesity in adult life. Insulin resistance (with or without glucose intolerance), raised blood pressure, atherogenic dyslipidemia [elevated triglyceride, small low-density lipoprotein (LDL) particles, low high-density lipoprotein (HDL) cholesterol], central or abdominal obesity, and prothrombotic and proinflammatory states are all major components of the metabolic syndrome (137), and it has been suggested on the basis of these epidemiological data that the metabolic syndrome be renamed "the small baby syndrome" (24). The fetal or developmental origins of adult disease hypothesis therefore extended to include the antecedents of the separate and combined pathologies of the metabolic syndrome. This review focuses specifically on the early origins of hypertension, insulin resistance, glucose intolerance, and obesity as the major components of the metabolic syndrome and as risk factors for cardiovascular disease and type 2 diabetes.
B. The Thrifty Phenotype Hypothesis, Programming, and Developmental Plasticity
During the past decade there have been a number of mechanistic frameworks proposed to explain the biological basis of the associations observed between birth weight and health outcomes in the epidemiological studies. In 1992, Hales and Barker (187) coined the term the "thrifty phenotype" hypothesis, derived from the prior "thrifty genotype" hypothesis (362, 363). Neel (362) had proposed that "thrifty" genes were selected during evolution at a time when food resources were scarce and that they resulted in a "fast insulin trigger" and thus an enhanced capacity to store fat, which placed the individual at risk of insulin resistance and type 2 diabetes. The thrifty phenotype hypothesis, however, suggested that when the fetal environment is poor, there is an adaptive response, which optimizes the growth of key body organs to the detriment of others and leads to an altered postnatal metabolism, which is designed to enhance postnatal survival under conditions of intermittent or poor nutrition. It was proposed that these adaptations only became detrimental when nutrition was more abundant in the postnatal environment, than it had been in the prenatal environment (187, 189). The concept that there are embryonic and fetal adaptive responses to a suboptimal intrauterine environment that result in permanent adverse consequences is consistent with the definition of "programming" by Lucas in 1991 (320) as either the induction, deletion, or impaired development of a permanent somatic structure or the "setting" of a physiological system by an early stimulus or insult operating at a "sensitive" period, resulting in long-term consequences for function.
One of the crucial elements of this definition is the concept of a sensitive or "critical" period during which specific nutritional perturbations may operate to cause long-term changes in development and adverse outcomes in later life (26, 144, 506, 539, 540). The existence of critical periods during which nutritional influences can have long-lasting consequences for growth and metabolism had also been highlighted by the early work of McCance and Widdowson (342), who showed that early undernutrition had a permanent effect on the subsequent growth of rats, whereas later undernutrition only had a transient effect. The term metabolic imprinting has also been used to describe the biological phenomena that may underlie the relationship between intrauterine nutritional experiences and subsequent health outcomes (530). This term is intended to encompass adaptive responses of the organism to specific nutritional conditions in early life that are characterized by 1) a susceptibility limited to a critical ontogenic window early in development; 2) a persistent effect lasting through adulthood; 3) a specific and measurable outcome, which may differ quantifiably among individuals; and 4) a dose-response or threshold relation between a specific exposure and outcome (530). The term metabolic imprinting was based on the historical precedent set by Konrad Lorenz who used imprinting to refer to the setting of certain animal behaviors that resulted from early experience. There has been a debate on the appropriateness of both programming (because this term could be misconstrued as referring to events which are reversible, rather than irreversible) and metabolic imprinting (because this term implies early events are exclusively metabolic in origin and because of the possible confusion between metabolic imprinting and "imprinted" genes). It has also been recently stated that whereas developmental physiologists and physicians may use programming to describe the process whereby a stimulus or insult at a sensitive or critical period of development, has lasting effects on the structure or function of the body, that this term has alternative meanings in ethology and other areas of biology, and that therefore programming should no longer be used in the context of the developmental origins of adult disease (23). It has been proposed that the term developmental plasticity rather than programming would be more appropriate. The formal definition of developmental plasticity is the ability of a single genotype to produce more than one alternative form of structure, physiological state, or behavior in response to environmental conditions (23). There has also been a view that the original concept of the thrifty phenotype hypothesis, which applied specifically to conditions of intrauterine deprivation, may be too limited as an overarching hypothesis for the developmental origins of adult disease and that that the adaptive responses of the embryo or fetus to a range of prenatal environments should be viewed in a broader, evolutionary context (28).
1. Evolution, developmental plasticity, and predictive adaptive responses
It is clear from a range of diverse fields including evolutionary ecology and molecular biology that a given genotype can give rise to different phenotypes, depending on environmental conditions. There are many different species where the impact of an environment experienced by one generation determines the development and behavior of the next generation. Female birds are able to alter many aspects of the composition of the egg in response to a range of environmental factors including food availability, levels of sibling competition, and the quality of their mates (311). Such maternal effects can result in the effects of a specific environmental factor persisting across several generations (28, 311). If the effects of the past conditions produce mismatches with current, changed conditions, however, then developmental plasticity may have a detrimental effect on survival and reproductive success (28). Thus Bateson et al. (28) propose that for individuals whose early environment has predicted a high level of nutrition in adult life and who develop a large phenotype, the better the postnatal conditions, the better will be their adult health. For individuals whose conditions in fetal life predicted poor adult nutrition and who develop a small phenotype, the expected outcomes may vary, although they are predicted to be worse off when there is a relative excess of nutrition in postnatal life (28). There has also been a proposal to separate those homeostatic responses that represent fetal adaptations to changes in the intrauterine environment and that may have long-term consequences, from those which need not confer immediate advantage but are induced in the expectation of future adaptive changes; this latter group of responses has been defined as "predictive adaptive" (174). In this model, selection across generations operates to favor protection of those predictive adaptive responses that aid survival to reproductive age (174). The programmed or plastic responses made during development that have immediate adaptive advantage might also act to limit the range of postnatal adaptive responses to a new environment and would be considered to be "inappropriate" predictive adaptive responses (174). This general model is therefore consistent with the original thrifty phenotype hypothesis which stated that fetal adaptations to a poor intrauterine environment may have adverse consequences if there is a relative excess of nutrition available in adult life.
Although the evolutionary view provides a clear biological framework to understand the importance of the prenatal environment for the continued reproductive success and health of subsequent adult populations, it is recognized that not all responses to the current prenatal environment may be potentially predictive of the postnatal environment. As summarized in the remainder of this review, in conditions of severe intrauterine deprivation, there is the capacity to lose structural units such as nephrons, cardiomyocytes, or pancreatic 
-cells within developing organ systems. Such decreases in structural and hence the life-long functional capacity of an organ system may be an inadvertent consequence of a decrease in energy supply across the placenta or a selective trade off to maintain the development of more important tissues, such as the brain. At this stage it is not clear that such responses are either adaptive or predictive, although it is clear that they will result in the programming of a reduced functional capacity for life. For this reason we will retain programming as an overarching term that usefully allows the inclusion of such developmental deficits and their consequences in this review of the developmental origins of adult disease (Fig. 1).
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The mechanisms through which specific tissues could be affected permanently by nutritional perturbations in early life have been the focus of a range of commentaries (320, 530) and include epigenetic changes in gene regulation, variations in organ structure, alterations in cell number, hepatocyte polyploidization or cardiomyocyte multincleation, clonal selection of specific populations of cells, apoptotic remodeling, and metabolic differentiation (530, 531). Similarly a range of endocrine signals have been implicated as key mediators of the impact of prenatal nutrition on subsequent development, consistent with the concept of "hormonal imprinting" whereby the concentrations of hormones and hormone analogs present during critical windows of development can permanently alter the hormonal responses to specific stimuli and/or tissue sensitivity to specific hormones (85). This review considers the molecular, cellular, metabolic, neuroendocrine, and physiological responses that occur when there is an alteration in fetal substrate supply and highlight those specific responses that appear to have immediate adaptive benefit but which result in a permanent alteration of the developmental pattern of cellular proliferation and differentiation in key tissue and organ systems to result in pathological consequences in adult life (Fig. 2).
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One important issue that has been flagged in discussions of the importance of the fetal origins of adult disease is the contribution of low birth weight to the burden of adult disease and the extent to which birth weight is a useful measure or surrogate of fetal growth (440). Term is defined as a pregnancy which lasts 37–41 wk, and 
2% of term babies are of low birth weight, i.e., weigh <2,500 g. Infants can also be characterized as small or large for their gestational age in the context of a larger reference population (453). Being small for gestational age is defined as having a birth weight and/or length at least two standard deviations below the mean for gestational age in the reference population (294). While these definitions identify infants that are relatively smaller at birth, they do not distinguish the different growth patterns by which infants may have arrived at their weight at birth. Importantly, some small babies have achieved their genetic growth potential and are simply in the lower tail of the birth weight distribution, whereas other babies may have experienced a prenatal nutritional deficit which slowed their growth but still have a birth weight that falls within the "normal" portion of the birth weight distribution. Currently there are no clinical measures routinely available to enable the distinction to be made between babies with the same birth weight which have experienced different patterns of growth. A second and related area of debate is to what extent maternal nutrition is implicated in the fetal origins of adult disease. It has been argued that it is likely that maternal nutrition has been adequate in the majority of the populations in which the fetal origins hypothesis has been tested (205) and that long-term surveys of maternal nutrition indicate that variation in food supply produce a relatively minor effect on birth weight (437). It is well established, however, that fetal growth in late gestation is normally limited by maternal size and her capacity to supply nutrients to her fetus, a phenomenon known as "maternal constraint" (504). Furthermore, while fetal growth in late gestation is normally regulated by fetal nutrient supply, large changes in maternal diet may have a relatively small impact on this supply if there is a large margin of "safety" in the capacity of the placenta to ensure adequate transport of maternal nutrients to the fetus (196). A further important factor is the balance of macro- and micronutrients in the maternal diet. It has been shown, in a relatively well-nourished population, that a combination of high carbohydrate in early pregnancy and low protein intake in late pregnancy was associated with a reduced placental weight, birth weight, low ponderal index, and reduced placental weight (175, 176). It is also the case that common clinical causes of impaired fetal growth such as maternal hypertension associated with reduced uterine blood flow, or placental infarcts, resulting in a reduced placental transfer capacity, may severely limit fetal nutrient supply in the absence of any change in maternal nutrition. Thus there may not be a direct and obvious relationship between the level of maternal nutrition and fetal nutrition, and this may confound attempts to draw inferences on the role of maternal nutrition in determining the fetal growth trajectory.
In humans, size at birth has been associated with cord blood levels of insulin, insulin-like growth factor (IGF)-I, IGF-II and their binding proteins, and the IGF-II receptor (IGF2R), which acts to remove IGF-II within tissues (377). It has been proposed that genetically determined insulin resistance could result in poor insulin-mediated fetal growth, low birth weight, and insulin resistance in childhood and in adult life (198). For instance, a mutation in the glycolytic enzyme glucokinase in the fetus results in a 500 g decrease in fetal size as a consequence of a decrease in fetal insulin secretion (197). Although such rare monogenic disorders cannot explain the variation in birthweight within a normal population, it has been argued that undefined polygenic genetic factors that increase insulin resistance both in utero and in adult life would produce the two phenotypes of a small, thin baby and an adult with insulin resistance (198). While it is theoretically possible that there is a common genetic cause of low birth weight and type 2 diabetes, studies of identical twins have shown that the effect of low birth weight can operate independently of a genetic change (433). Furthermore, continuing impairment in insulin secretion or action in early postnatal life would be unlikely to support the rapid weight gain or "catch up" growth that commonly occurs in those infants who were growth restricted in utero.
3. Interaction between prenatal and postnatal growth
"Catch up" and "catch down" growth have been defined on the clinical basis of a change in weight or length standard deviation score that results in significant centile crossing on standard infant growth charts. With the use of this definition in a contemporary well-nourished population, it was found that 30% of all infants show catch up growth, 25% show catch down growth, and the remainder follow the same weight or length centile from birth (380). In this cohort the children who showed catch up growth had a lower birth weight, length, and ponderal index at birth; they had taller fathers and their mothers had lower birth weights and were more likely to smoke during pregnancy (380). It has been suggested that postnatal growth acts to restore infant size back towards their genetic growth trajectory by 2 yr of age (502). Thus 90% of infants who are born small for their gestational age show some catch up growth within the first 6 mo of life (248). In affluent communities, infants who were growth restricted at birth and show early postnatal catch up growth tend to overshoot their genetic target and have a higher body mass index (BMI), fat mass, and truncal fat distribution during childhood (380). It has been proposed that tissues that were previously exposed to low concentrations of insulin and IGF-I during fetal life may develop insulin resistance as a metabolic defense against hypoglycemia when exposed to relatively higher concentrations of these hormones during rapid postnatal growth and that the crucial time for the development of long-term consequences of fetal growth restriction is therefore the early postnatal period (78). Other commentators have argued, however, that given the biological interaction between the prenatal and postnatal environments, it may not be possible to separate the precise contribution of each of these environments to subsequent adverse health outcomes (191). Again, while rapid postnatal growth in the context of a reduced endowment of cell numbers or specific cell types within key body organs of the growth restricted fetus may produce detrimental outcomes for tissue function, it has been argued that "buying" survival to reproductive age at the expense of adaptations which are detrimental in much later life is a strategy with a positive evolutionary advantage. An alternative, but convergent, view is that the high rate of genetic mutation combined with suboptimal levels of nutrition during most of human history may have allowed the selection of a variety of genotypes that favor survival from fetal life through infancy to reproductive age and also maternal mechanisms that act to restrain fetal growth. Such genotypes may, however, confer an increased risk of insulin resistance and associated cardiovascular and metabolic disease (378, 379). Ong and Dunger (378) have revisited the thrifty genotype hypothesis as originally proposed by Neel (362) and argued that fetal metabolic adaptation to undernutrition could be related to thrifty genotypes that enhance these adaptive mechanisms and therefore in utero survival. Potential fetal thrifty genotypes include the insulin gene variable number of tandem repeats class III/III genotype (INS VNTR class III allele), which is associated with larger size at birth and has been associated with insulin-resistant states such as type 2 diabetes in adults (381). Similarly there may be a number of thrifty fetal genotypes with moderate but cumulative effects on fetal survival advantage, and their predisposition to adult disease risk may be enhanced by rapid growth after birth, obesity, and the associated exacerbation of insulin resistance (379). In contrast, mechanisms that restrain fetal growth and protect maternal survival may be inherited on mitochondrial DNA or maternally expressed genes such as IGF2R. Furthermore, Ong and Dunger (378) propose that larger postnatal size may have a major impact on improving infant survival and that this may explain the rapid, catch up growth that occurs in the growth-restricted fetus after birth. Whereas some genotypes might therefore promote growth in infancy, they may also predispose to insulin resistance, type 2 diabetes, obesity, and cardiovascular disease in later life. This is consistent with the recent findings that infants who are small for gestational age are initially insulin sensitive with respect to glucose disposal (32) but become more resistant by 1 yr of age (489). In this cohort there were significant associations of insulin VNTR genotype and insulin sensitivity and secretion at 1 yr of age (31).
Although there are importance associations between specific prenatal and postnatal growth patterns in causation of adult disease, there has been a reluctance to begin intervention studies in humans or to reduce or abolish the effects of constraint of fetal growth. This is not surprising given the history of unexpected consequences of attempts to improve maternal and fetal outcomes of pregnancy (68, 265, 458). The main conclusion that can be drawn from the recently updated systematic review of randomized trials of energy and protein intake in pregnancy (264) is that balanced protein energy supplements reduced perinatal mortality and the number of small for gestational age babies, but only has a small effect on birthweight (264).
There has been considerable debate about the usefulness or appropriateness of using twin pregnancies to investigate the fetal origins of adult diseases. Morley et al. (355) have argued that twin pregnancies should be used to study the early origins of adult disease, as "the nutritional supply line will be more stretched." They also argue that a comparison of twins with singletons allow easier identification of maternal factors that influence later health. Others including one of the authors of this review have argued that there are too many problems associated with studies of twin pregnancies and that these limit the use of twins in unraveling of mechanisms underlying the fetal origins of adult diseases (415, 416).
Spontaneous twin pregnancy is relatively uncommon and poses greater problems than for singleton pregnancies for implantation, miscarriage, preterm labor, abnormalities and perinatal death, and survivor effects for one or both twins after birth (415). There may also be different mechanisms setting the initial growth rate of twins, and this can be compounded more often in monozygotic pregnancies by the presence of a shared circulation causing the twin-twin transfusion syndrome. It has not been possible to examine the role of birth order for twins in subsequent outcomes, yet it has been reported the first twin when born prematurely is more mature than the second. None of the recent studies has reported use of steroids in twin pregnancies, yet this may have been different for these pregnancies and newborns before or after birth. An example of the comparatively poor outcome of twin pregnancies is the different outcomes of singleton and twin pregnancies after in vitro fertilization (IVF) and advanced reproductive technologies (ART). In singleton pregnancy, ART is associated with increased incidence of preterm birth, growth restriction, and perinatal death. However, ART does not increase these outcomes in twin pregnancies above the much higher rate observed for spontaneous twins compared with singletons (203). Despite these ranges of issues, the debate about the relevance of studies in twins as a test of the fetal origins hypothesis has not stopped publication of studies in monozygotic and dizygotic twin pairs. Because twins are generally smaller than singletons, the fetal origins hypothesis should indicate a higher all-cause mortality or deaths from ischemic heart disease in twins than in singletons, but this is not so (77, 512). However, mortality for dizygotic compared with monozygotic female twins was higher between 30 and 59 yr (77). In twins, as has been reported for singletons, there was a positive association between birth weight and blood pressure in infants (301). In keeping with these findings, blood pressure was lower in twins aged nine compared with singletons after appropriate adjustments had been made for gestational age (544). In this study smoking, which constrains growth, was associated with an increase in blood pressure. Furthermore, at age seven, there was no association between birth size in twins and blood pressure (569). It might be concluded from these studies that the mechanisms setting growth and cardiovascular outcomes are different in twins compared with singletons.
Although the setting of growth of twins in utero may be different, there are intertwin differences in growth rate that are likely to be due to growth retardation, as in singletons. The shorter twin has been found to be more likely to die from heart disease (512), and lighter, shorter twins or those with smaller head circumferences are more prone to acute myocardial infarction than external matched twins, although this relationship did not hold for intratwin pairs (222). Thus studies have examined whether being the smaller rather than the larger twin is consistent with the fetal origins hypothesis for risk factors for heart disease. It has been reported that there is no difference in blood pressure between larger and smaller twins (16, 569). In contrast, in female twins, higher blood pressure was found in the smaller twin, and there was a trend for this to increase with the intertwin difference in birthweight (434). The effect was greater when women taking antihypertensives were excluded from the analysis, and this raises the concern about the best way to account for those taking antihypertensives, since in singletons more adults who were light than heavy at birth require antihypertensive treatment. Dwyer et al. (117) reported that blood pressure decreased by 1.94 mmHg for every additional kilogram in weight at birth in singletons and by 7.0 mmHg in twins. They concluded that a principal causal pathway must include the fetoplacental unit.
In singletons, there are associations between birth weight and endocrine function with a common finding of hormone resistance. Glucose tolerance and insulin sensitivity have been examined in only a few studies. It has been reported that there is (237) or is no (318) difference in insulin sensitivity. In summary, there is more evidence against than support for the application of the fetal origins hypothesis to twin pregnancy in women.
This review first considers the epidemiological evidence for the association between the perturbation of the early nutritional environment and the major risk factors (hypertension, insulin resistance, and obesity) for cardiovascular disease, diabetes, and the metabolic syndrome in adult life. Second, we focus on those experimental studies that have investigated the critical windows during which specific perturbations of the intrauterine environment have major effects; the nature of the structural and functional adaptive responses of the embryo, fetus, and neonate to such perturbations which may result in a permanent programming of cardiovascular and metabolic function; and the role of the interaction between the pre- and postnatal environment in determining final health outcomes.
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II. CARDIOVASCULAR DISEASE AND HYPERTENSION |
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In 1987, Barker and colleagues (22, 388) found that lower birth weight and weight at 1 yr of age were associated with an increased risk of death from cardiovascular disease and stroke in a cohort of men and women born in Hertfordshire, England between 1911 and 1930. Early criticisms of the association of death rate from coronary heart disease with lower birth weight raised questions about completeness of follow-up (244), although it was recognized that loss of subjects from cohorts was inevitable with the requirement for follow-up over many decades (263). This criticism was largely answered in a study of 15,000 Swedish men and women with a 97% follow-up over a period of more than 50 yr. In this study the death rates from ischemic heart disease were increased in individuals in the lower quartiles of birth weight compared with those in the highest quartile (296). Also of note was the Nurses Study in the United States which includes 121,700 women who have been followed since 1976. In one retrospective study of more than 70,000 women from this group, there were strong negative trends between self-reported birth weight and nonfatal coronary heart disease and stroke (451). The association of cardiovascular death and birth weight has now been reported in many (156, 157, 335, 493) but not all studies (224), particularly those involving twins (512).
The importance of environmental influences that impair fetal and infant growth was raised when it was reported that men with the lowest weights at birth and at 1 yr of age had the highest death rates from ischemic heart disease (25). Although the death rate increased with decreases in birth weight in both males and females, the effect of reduced infant growth on subsequent cardiovascular disease was present in men only (388). It was suggested that promotion of fetal and infant growth might reduce cardiovascular deaths, and a special emphasis was given to the importance of promoting growth in the first year of life of boys who weighed <7.5 lbs. (3.5 kg) at birth (22). Although low weight gain in the first year of life was associated with increased cardiovascular mortality, it has also been shown in a cohort of Finnish men that increased weight gain as early as 3 yr of age is also associated with increased cardiovascular mortality (134). Men who died were obese with above average BMI at all ages from 7 to 15 years of age (135). These effects may be greatest in males born to mothers who were obese (152). Short birth length of female infants followed by increase in height was also associated with increased risk of death from coronary heart disease (151). These women tended to have tall mothers (151), which suggests that prenatal growth of these female infants was constrained. Thus the most adverse cardiovascular disease risk profile is found in men and women who were small at birth but became obese in adult life (136), and the effects of adult BMI on high blood pressure, type 2 diabetes, and insulin resistance were greater in individuals of low birth weight (133, 157). Whatever the mechanisms, the possibility of a biological link between birth weight and adult BMI complicates interpretation of studies that link birth weight and adult BMI to other adult outcomes such as cardiovascular disease, hypertension, and insulin resistance. Whilst many authors adjust for current BMI when evaluating associations between birth weight and adult outcomes, it has been argued that there may be statistical implications with this approach that should be taken into consideration when interpreting the interaction between birth weight, BMI, and cardiovascular or metabolic health outcomes (58, 322, 530).
In the late 1980s, a study in Sweden reported that the risk of increased diastolic blood pressure was significantly higher in a group of male army conscripts who had been small at birth. The authors concluded that being born small for gestational age might be a predictor of raised blood pressure in adult life (170) and, by implication, increased risk of cardiovascular death. Soon afterwards, the association between low birth weight and high blood pressure in adult life was extended to include the normal range of birth weight (22). In addition to raised blood pressure at age 10, children living in areas with higher rates of death from cardiovascular disease also had high resting pulse rates. The children and their mothers were shorter than those living in areas with low cardiovascular mortality, raising the possibility of environmental or inherited/genetic effects (22).
A small number of studies have examined the contribution of the placenta to the association between size at birth and blood pressure later in life. In cohorts in Preston in the United Kingdom and in Adelaide in Australia, blood pressure increased with decreasing birth weight and increasing placental weight (19, 349). In the Adelaide cohort, however, the effect of placental weight was no longer apparent when the blood pressure was measured when the subjects were 20 yr of age. In this group, the amplification of blood pressure from 8–20 yr of age was greatest in those with lower birth weights (349). No support for an effect of placental size or birth weight was found in the New Zealand cohort followed from birth to 18 yr of age (545) or for other indices of fetal or placental growth in 8-yr-old Australians (58).
Four systematic reviews have examined the association between birth weight and blood pressure in later life (226, 227, 291, 292). The first review summarized data from 1,895 children and 3,240 adults. There was a negative relationship between blood pressure and birth weight, which amplified with increasing age in adult life. The number of subjects and studies increased rapidly to 66,000 in 34 studies (292) and to 440,000 in 80 studies (227). In the earlier reviews the association of blood pressure with birth weight was not evident in adolescence; however, with increased numbers, an attenuated relationship was found (227). The conclusion drawn by Huxley et al. (227) was that both birth weight and head circumference at birth were inversely related to systolic pressure and that accelerated postnatal growth was also associated with raised blood pressure. Many of the studies had been completed with automated blood pressure devices that calculate but do not measure diastolic pressure. It is uncertain how this might have effected the conclusions about diastolic pressure. Certainly with publication of this third systematic review, it seemed as though there could be little room for further debate about the existence of the association of blood pressure throughout life after infancy and birth weight. This conclusion was challenged, however, with the publication of a fourth systematic review (226), which was confined to 55 studies that reported regression coefficients of systolic blood pressure on birth weight. The authors reported "a clear trend (P < 0.001) towards a weaker association in the larger studies." The regression coefficient was –1.9 mmHg/kg for studies with <1,000 subjects and –0.6 mmHg for studies with >3,000 subjects. In twins, the summary coefficient did not achieve statistical significance (226). It was also noted that the studies from the group in Southampton reported larger regression coefficients. Huxley et al. (226) concluded that "the claims for a strong inverse association between birth weight and subsequent blood pressure may chiefly reflect the impact of random error, selective emphasis on particular results and inappropriate adjustment for current weight and confounding factors." A similar note of caution has been expressed with an analysis, suggesting that there has been publication bias and that the association with birth weight is reduced when a correction is made for this factor (463).
The criticism about adjustment for current weight has been addressed (204), and problems with studies in twins were discussed in detail above. Others criticized the use of a single regression coefficient, which effectively excludes the phenomenon of tracking and catch-up. Other problems raised with the conclusions of the systematic review (226) included emphasis on large studies that included self-report of blood pressure and inclusion in these large studies of measurements of blood pressure of subjects who were taking antihypertensive agents (84). This latter point is important since the number requiring treatment decreases progressively with increasing birth weight (20, 132). In the large Shanghai Women's study, the women who were above average weight at 15 and were of low birth weight were 4 times more likely to have hypertension than women of average weight with birth weights between 2,500 and 3,249 g. Women who were above average weight and below average height and who were of low birth weight had the highest odds of developing hypertension OR 7.64 (95% CI 2.85–20.44) (570). In a smaller Danish case-control study of juvenile obese men, body weight history after the age of 7 had no influence on blood pressure in addition to current BMI. The authors concluded that there was an adverse effect of low intrauterine weight or of a high gain in weight before the age of 7 on adult systolic blood pressure (462). In parallel with the worldwide series of epidemiological studies on the association between low birth weight and adult blood pressure, there have been a range of animal-based experimental studies that have investigated the mechanisms that could underlie the association between poor fetal growth and adult hypertension.
B. Perinatal Nutrition and the Programming of Hypertension
1. Fetal nutrient restriction and programming of hypertension in the guinea pig and rat
One of the first studies to provide experimental evidence for the fetal origins of adult disease hypothesis was carried out by Persson and Jansson (405) in which one uterine horn was ligated in pregnant guinea pigs to restrict fetal growth. This resulted in severe fetal growth restriction and relative hypertension in the restricted pups. In 1994, Langley and Jackson reported that feeding low-protein diets (60–120 g protein/kg diet) to pregnant rats resulted in an increase in blood pressure in the offspring, compared with control animals (277). This low-protein diet (the Southampton low-protein diet) is composed of casein, sucrose, starch, and corn oil and is supplemented with vitamins, minerals, and methionine (277). Subsequent studies showed that when rat dams are fed this low-protein diet (90 g/kg: 9% protein diet) during pregnancy, fetal growth is enhanced until day 20 of gestation (term = 21 day gestation), and this is followed by a period of growth restriction over the last 2 days of gestation such that the pups tend to be of low or low-normal birth weight (282). The offspring of rats fed the low-protein diet have raised systolic blood pressure by weaning at 4 wk of age (277, 286). When dams were fed the low-protein diet for single weeks during pregnancy, the magnitude of the effect of the diet on postnatal blood pressure was greatest when the low-protein diet was consumed during the last week of gestation (287). Subsequent studies, using a low-protein diet (6%) from 12 days gestation or a low-protein (9%) diet throughout gestation also reported that the offspring developed hypertension by 8 and 21 wk of age, respectively (332, 516, 557). The hypertension associated with prenatal exposure to a low-protein diet appears to be a consequence of an increased peripheral resistance as the pulse rate tends to be lower, and there is no cardiac hypertrophy, suggesting that cardiac output is not elevated (232). Interestingly, a balanced reduction (a 50–70% decrease) in maternal nutrient intake produces a less consistent effect on later blood pressure than does the specific restriction of maternal protein intake (216, 390, 517, 519, 520, 555) (see Table 1). Furthermore, when different low-protein diets have been compared, it has been demonstrated that they elicit different programming effects on blood pressure in the offspring (278). Prenatal exposure to an alternative low-protein diet, the Hope Farm diet, results in normotensive, insulin-resistant offspring (321, 397, 398). The Hope Farm low-protein diet differs from the Southampton low-protein diet in fat source and fat (Hope Farm: soybean oil 4.3%, Southampton: corn oil 10%), methionine (Hope Farm: 0.2%, Southampton: 0.5%), and carbohydrate content (Hope Farm: 8% starch and 66.7% glucose, Southampton: 48.5% starch and 24.3% sucrose).
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-synthase, it is compelled to eliminate homocysteine through the synthesis of S-adenosyl homocysteine, which is then remethylated to S-adenosyl methionine. The remethylation of S-adenosyl homocysteine also increases the demand for methyl groups derived from tetrahydrofolate, reducing the availability of folates for deoxynucleoside triphosphate synthesis. The degree of DNA methylation has been shown to depend on dietary composition in adult rats (429), and it has been suggested that changes in methionine metabolism increase homocysteine production, which may in turn lead to changes in DNA methylation in the fetus and perturb key events in organogenesis and in embryonic vasculogenesis (492). One of the consequences of the Southampton low-protein diet is a fall in maternal plasma and fetal body concentrations of the essential amino acid threonine (406, 446). Cystathionine and homoserine are by-products of cysteine synthesis and share the same oxidative pathway as threonine; therefore, the induction of transulfuration increases threonine oxidation (445). In one study it was reported that supplementation of the low-protein diet with threonine during the initial phases of pregnancy reduced maternal circulating concentrations of homocysteine (406), whereas in a second study it was reported that threonine supplementation resulted in increased concentrations of maternal serum homocysteine in later pregnancy (445). Furthermore, in the latter study, the endogenous methylation of DNA was greater in the liver (although not the heart or kidney) of fetuses from dams fed the low-protein diet and increased further when the diet was supplemented with threonine (445).
In a study in which nonessential nitrogen was added to a 9% protein diet in the form of glycine, alanine, or urea, the hypertensive effect of the low-protein diet during pregnancy on the blood pressure of the offspring was effectively reversed by supplemental glycine, but not alanine or urea (232). There is a large fetal requirement for glycine as it appears to be a conditionally essential amino acid for a number of metabolic compounds including nucleic acids, collagen, heme, and keratin (231). Any marginal decrease in glycine can be exacerbated if dietary methionine is increased as glycine is used in the detoxification of an excess of methionine by enhancing methionine breakdown via the transulfuration pathway (15), and methionine and homocysteine levels are influenced by glycine availability in the S-amino acid metabolic pathway. Supplementing the Southampton low-protein diet with glycine, which as well as folate supplementation results in a decrease in plasma homocysteine, results in a normalization of blood pressure in the offspring, which again suggests that hyperhomocysteinemia may be important in the programming effect of the Southampton low-protein diet.
In summary, it is therefore unlikely that protein undernutrition per se is the critical factor in the impact of the low-protein diet on programming of cardiovascular function. The balance of specific amino acids and other nutrients may be critical in determining DNA methylation and specific outcomes for the cardiovascular and metabolic systems and long-term health effects of maternal undernutrition in pregnancy (279).
It has also recently been demonstrated that deprivation of omega-3 polyunsaturated fatty acids from conception to 9 wk of age resulted in a maintained elevation of mean arterial blood pressure in rats at around 33 wk of age (534). It has been argued that it is feasible that increased blood pressure measured in adult offspring subjected to a low-protein diet may in some instances be the result of an omega-3 fatty acid deficiency as the corn oil used as a lipid source in some low-protein diets is deficient in omega-3 polyunsaturated fatty acid (PUFA).
Finally, although there are a range of models of nutrient restriction utilized to study the programming of hypertension, it has also been reported that arterial blood pressure is also raised in 6- and 12-mo-old female offspring of pregnant rats fed a diet rich in lard from 10 days before conception through pregnancy and lactation (254).
A further important issue that needs to be considered when reviewing the extensive literature on the programming of postnatal blood pressure in rats is that many of these studies have investigated the effects of perturbing maternal nutrition on blood pressure using tail cuff plethysmography which entails restraint of the animal. There is therefore a potential contribution of a programmed "stress response" contributing to the increase in arterial blood pressure in these studies which is discussed in the sections below.
2. Maternal nutrition in the preimplantation period
Interestingly, male offspring of pregnant rats fed the Southampton low-protein diet during the preimplantation period (days 0–4.5) also develop increased blood pressure at 4–12 wk of age (266). One possibility is that maternal undernutrition during the preimplantation period may act through epigenetic gene regulatory mechanisms. The genome of the preimplantation embryo undergoes extensive demethylation, and patterns of cytosine methylation are reestablished after implantation (447). These methylation patterns are then maintained throughout fetal and postnatal development. Maternal nutrition and, in particular, the availability of dietary methyl donors and cofactors during critical periods, including the preimplantation period might therefore influence DNA methylation and subsequent gene expression patterns (97, 531). There is therefore significant interest in the impact of maternal diets, which may result in increased serum homocysteine concentrations and/or functional folate deficiencies around the time of conception and implantation and their longer term consequences.
3. Interaction between prenatal and postnatal nutrition
There is also an interaction between the perinatal and postweaning diets in the induction of high blood pressure (412). When rats are exposed to a low-protein diet (8% protein) throughout gestation and lactation and then fed either standard lab chow or a highly palatable cafeteria-style diet from 70 days, there are additive effects of perinatal protein restriction and obesity (induced by the cafeteria-style diet) on blood pressure in these rats at 1 yr of age, suggesting that early protein restriction, and later obesity, are independent risk factors for the development of hypertension (412). Similarly in rats exposed to a 70% reduction in maternal energy intake throughout gestation, and fed either a control or hypercaloric (30% fat) diet from weaning, there were separate effects of prenatal undernutrition and the hypercaloric diet on systolic blood pressure at 14 wk of age (517). In an additional series of experiments, these authors measured systolic blood pressure in the same treatment groups before and after a 14-day period of treatment with IGF-I. IGF-I treatment alleviated the effect of early undernutrition on systolic blood pressure (520). It was suggested that this effect might be a consequence of the actions of IGF-I on insulin sensitivity, vasodilation, or improved renal function (520).
4. Maternal undernutrition and the programming of hypertension in the sheep
In sheep that had been severely undernourished for either 10 or 20 days from 105 days gestation (term 147 ± 3 days gestation), it was found that blood pressure increased with current weight and decreased with increasing birth weight at 5, but not 30 mo of age, and that prenatal nutrition did not affect systolic blood pressure in postnatal life when the current weight and birth weight were taken into account (375). Whilst these data could suggest that size at birth is more closely related to processes that determine postnatal phenotype than is maternal nutrition in late gestation, a number of caveats (size of the cohort, length of undernutrition, and follow-up period) were expressed about this conclusion by the authors (375).
Furthermore, in pregnant ewes which were undernourished (a 30% reduction) during the periconceptional/preimplantation period (60 days before and for 7 days after conception), there was an increase in fetal arterial blood pressure some 100 days later at 115–147 days gestation in twin pregnancies (123). Lambs born after a period of undernutrition (15% reduction) for the first 70 days of pregnancy also have a higher arterial blood pressure in postnatal life (200). The impact of periconceptional undernutrition on the cardiovascular system in the sheep therefore appears to persist into adulthood in the sheep, as in the rat. When sheep were fed 50% equivalent food intake of control ewes from 1 to 30 days gestation, it was reported that the offspring of the nutrient-restricted sheep had increased pulse pressure, a reduced rate pressure product, and a leftward shift in their baroreflex function curve in adult life (161). Baroreflex sensitivity during angiotensin II infusion was also blunted in sheep that had been exposed to early nutrient restriction in utero, but the tachycardia following a reduction in central blood pressure appeared potentiated, relative to controls. Thus peri-implantation undernutrition in both the rat and sheep appears to result in an increased risk of hypertension later in life.
In summary, exposure to a period of maternal nutrient restriction during different stages of gestation results in the programming of high blood pressure in a range of species. The mechanisms underlying these programming events are likely to be different, multifactorial, and depend on the relative influence of fetal nutrient deprivation and the maternal and fetal neuroendocrine adaptations to undernutrition during critical periods of organogenesis and the development of fetal cardiorenal function. Evidence for some of the main candidate mechanisms underlying the intrauterine programming of hypertension is summarized in the following sections.
C. Prenatal Glucocorticoid Exposure and the Programming of Hypertension
Treatment of pregnant rats fed a low-protein diet with an inhibitor of maternal glucocorticoid synthesis (metyrapone) resulted in offspring that did not have raised blood pressure, and corticosterone replacement of metyrapone-treated dams restored the hypertensive effect of the diet in female offspring (280, 281). Treatment of pregnant rats with the synthetic glucocorticoid dexamethasone or with carbenoxolone, an inhibitor of the placental enzyme, 11-hydroxysteroid dehydrogenase-2 (11HSD2), which metabolizes corticosterone to the inert 11-dehydrocorticosterone, also results in a lower mean birth weight and persistent elevations of arterial blood pressure in the adult offspring (33, 303, 310). This effect requires the presence of the maternal adrenal, as carbenoxolone administered to adrenalectomized pregnant rats had no effect on birth weight or blood pressure (310). These data support the hypothesis that excess exposure of the fetoplacental unit to maternal glucocorticoids reduces birth weight and programs subsequent hypertension and indicates a key role for placental 11HSD2 in controlling such exposure (119). It has also been shown that treatment of pregnant rats with dexamethasone for 48 h on days 13 and 14, 15 and 16, and 17 and 18 of gestation resulted in elevated blood pressures in male rats at 6 mo of age (384, 385).
Undernutrition of pregnant rats (50% reduction in energy intake) results in an increase in maternal and neonatal glucocorticoids (299), and similarly in the guinea pig, a 40% reduction in maternal energy in maternal nutrition also increased maternal and fetal plasma cortisol concentrations (116). Low-protein diets are also associated with a decrease in placental 11HSD2 activity, which would in turn increase access of endogenous maternal corticosterone to the fetus (285). The dependence of low-protein diet-induced hypertension on glucocorticoids appears to extend beyond the prenatal period as adrenalectomy of 4-wk-old rats, exposed to a maternal low protein intake in utero, also resulted in a normalization of blood pressure to levels similar to controls (160).
Treatment of the pregnant ewe with either dexamethasone (12 mg/day) or with cortisol (120 mg/day) for 2 days between 26 and 28 days gestation resulted in hypertensive offspring at 3–4 mo of age (105, 111). The hypertension induced by dexamethasone exposure at 26–28 days gestation amplified with postnatal age and was associated with an increased cardiac output that was attributable to an increase in stroke volume (107). Interestingly, this programming effect was specific in timing as the same dose of dexamethasone administered for 48 h between 59 and 66 days gestation or a lower dose of dexamethasone given for a longer period (25–45 days gestation) did not produce hypertension in the offspring (110, 111, 350). Similarly in sheep, single or repeated maternal injections of betamethasone between 104 and 125 days gestation or repeated injections of dexamethasone, starting on day 103 of gestation, did not result in hypertension in the offspring at 5–12 mo of age (347, 356). Thus the impact of exposure of the fetus to excess glucocorticoids on blood pressure in adult life appears to be greatest when exposure occurs in late gestation in the rat and early gestation in the sheep. These differences relate to differences in the critical windows of development of the kidney and key tissues in the cardiovascular system.
D. Targets for Programming: the Kidney and the Intrarenal Renin-Angiotensin System
It has been proposed that maternal undernutrition may lead to permanent structural alterations within the kidneys that contribute to a propensity for adult cardiorenal disease. Brenner and colleagues (53, 54) originally proposed the theory that essential hypertension, including that associated with intrauterine growth restriction, is a consequence of a reduced total number of nephrons, leading to sodium retention. This theory was developed further by the proposal that reduction of nephron number is followed by increasing single-nephron GFR and where increased pressure within single nephrons is sustained, focal glomerulosclerosis occurs, resulting in nephron loss. The individual therefore enters a cycle in which mean arterial pressure continues to rise to maintain hemodynamic function with progressive and irreversible renal injury (55, 324, 325) (Fig. 3). In the human, nephrogenesis is complete by 32–34 wk, and therefore, a nephron deficit present at birth would persist through life. Two studies have reported that the nephron number in still-born intrauterine growth restricted (IUGR) human fetuses was significantly lower than in their normally grown counterparts (209, 330) and that there was a correlation between nephron number and increased glomerular volume with birth weight (330). Furthermore, ultrasound studies have shown that growth in the longitudinal plane of fetal kidneys was similar in small- and appropriate-for-gestational age groups; however, growth in the anterio-posterior, transverse, and circumference planes of the kidneys was significantly slower in the small-for-gestational-age group after 26 wk gestation. Differences in growth rate in the two groups were most marked between 26 and 34 wk and persisted until delivery when the anterior-posterior diameter was significantly smaller in the small-for-gestational-age group (259). These authors suggested that the 26–34 wk gestation could be the "critical period" during which the insult that leads to in utero programming for the development of adult hypertension occurs.
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In the rat, nephrogenesis begins at around day 12 of gestation and is not complete until 8 days after birth (288) and involves rapid remodeling of structures and apoptosis (83, 260). Recently, it has been demonstrated in a model of uteroplacental insufficiency, induced by bilateral uterine ligation of the pregnant rat at 19 days of gestation, tha
