Vascular Compliance

Reduced vascular compliance is an identified risk factor for cardiovascular morbidity56 and it has been proposed that impaired growth in early development may be linked to reduced compliance in adulthood through early and permanent alteration in structure of the aorta and other larger arteries. A study in 9 year old low birth weight children in Sweden has reported increased carotid artery stiffness compared with normal birthweight controls13 and a study of 331 young adults (20-28 years of age)...

Programming Adult Neurological Disease Parkinsons Disease

A long-term effect of fetal neuromotor programming may be an increased predisposition to adult or later onset neurological disorders, for example, Parkinsons disease. Parkinson's disease is a progressive motor pathology characterised by the loss of capacity to initiate and control appropriate voluntary movements. Patients do not become symptomatic until they have lost more than 60-80 of their dopamine-producing neurons in the substantia nigra pars compacta of the basal ganglia, a process that...

Can the Perinatal Environment Influence Adult Metabolic Homeostasis

The concept that events in early life might be causally associated with later outcomes for health and disease has gained widespread acceptance since the seminal epidemiological studies in humans by Barker and others (reviewed in ref. 19). Lucas defined this process as programming, where an event occurring at a critical period in development has long-lasting or permanent effects.20 The initial evidence that the intrauterine environment could program subsequent metabolic health derived from...

Info

Relationship between plasma renin activity at 10 weeks of age (adolescent) and arterial blood pressure at 30 weeks of age (adult) measured in conscious individual male and female rabbits bom of hypertensive (grey) or normotensive (black) mothers. Male offspring R2 0.48, P < 0.001 Female offspring R2 0.31, P < 0.005. blood pressure in male offspring was increased (Fig. 2). The renin-angiotensin system (RAS) was implicated in this model with significantly lower plasma renin...

The Case for Neurophysiological Assessment

Determining on the basis of a single assessment whether a child's sub-optimal motor performance is due to developmental delay, long-term neurological impairment or variance within the normal range, is fraught with the high likelihood of a false-positive assessment when using motor assessments that rely on age-appropriate performance. The clumsy child is not a rare phenomenon, but the origins of this are poorly understood. Epidemiological studies estimate the international prevalence of...

Anaemia during Pregnancy

Of particular clinical import are studies examining the influence of diets low in iron. A physiological drop in haemagloblin (to -100 g 1) occurs in normal pregnancy, due to the increase in plasma volume. However, it has been shown that iron deficiency (70-100 g 1) occurs in -20 of pregnancies in 'first-world' countries, and up to 75 of pregnancies in developing countries.41 Three groups have now demonstrated that iron deficiency induced prior to, and continued throughout, pregnancy in rats...

The Developmental Origins of Health and Disease

The Breadth and Importance of the Concept Peter D. Gluckman* and Mark A. Hanson Fetal Origins of Adult Disease (FOAD) The concept of a 'fetal origins of adult disease' (FOAD) or 'fetal programming' was developed by Barker and colleagues to describe the relationship between birth size and subsequent risks of cardiovascular disease and insulin resistance Type 2 diabetes melli-tus. As a concept, FOAD was initially received with criticism. Some held the view that the answers lay within genetics and...

Vitamin D Insufficiency

Vitamin D deficiency has been defined in terms of bone health, and there is still debate about the levels below which there is deficiency and insufficiency.1214 At levels below 50 nmol L preosteomalacic changes are seen on bone biopsy.15 Recent studies have attempted to define sub-clinical deficiency in adults and children in terms of the basal level of 25(OH)D3 above which l,25(OH)2D3 did not rise and or PTH did not fall with supplementation.12,13 Surprisingly, this level was in the range...

Ageing and Longevity

Studies of rodents subject to intrauterine insult suggest that lifespan may be shortened and degenerative processes associated with ageing may be enhanced. Studies of rats and mice exposed to maternal low protein diets indicate that lifespan may be shortened by as much as 15 .7981 This is of considerable interest as the impact of prenatal undernutrition appears to be the opposite of postnatal restriction of energy intake. It is well-established that postnatal caloric restriction increases...

Late Gestational Glucocorticoids and Programming of Metabolism

In recent years the health of millions throughout the world has been threatened by an upsurge in the incidence of 'the metabolic syndrome' or 'Syndrome X', the constituents of which include type 2 diabetes (glucose intolerance insulin resistance), hyperlipidemia, hypertension and obesity.19 Since Prof. David Barkers initial investigations, demonstrating an association between birthweight and the incidence of type 2 diabetes,20 it has become well established that an individual's intrauterine...

Dyslipidaemia

The suggestion that low birth weight may contribute to later development of metabolic syndrome and attendant cardiovascular sequelae (including endothelial dysfunction) has been supported by studies documenting an association of birth weight and or catch-up growth and an altered adult lipid profile, although relationships are not always found.41'44 In one of the earliest studies, amongst children aged between 7-11 years involved in the Bogalusa Heart Study, an association between low...

Appetite and Obesity

A number of experimental approaches have been used to assess the impact of early life nutritional exposures on long-term feeding behaviour and obesity. Although the nature and severity of the insults applied vary gready, the general finding is that either balanced undernutrition or restriction of specific nutrients promotes increased food intake and relative adiposity in adult life.9,6567 We have noted that mild protein restriction in rat pregnancy leads to increased deposition of abdominal fat...

Possible Role of Epigenetics in Fetal Programming

Parentally imprinted genes could be involved in fetal programming. Imprinted genes such as Igf2, Pegl, Peg3, HI9, and Igf2r are frequently associated, either positively or negatively, with fetal and placental growth. The fact that parentally imprinted genes are often involved in growth of the embryo has led to the parent-offspring conflict theory. This theory aims to explain the function of parental imprinting, stating that in order to successfully propagate their genes into the next generation...

Regulation of Embryo Development

Early embryo development is distinguished by two distinct morphological developmental periods (Fig. 1). A reductive cleavage process, whereby the fertilized zygote cleaves into smaller cells, marks the precompaction period. There is no net growth during this period, indeed a reduction in protein7 and mRNA content8'9 occur over this period of development, both of which were laid down in the maturing oocyte and therefore represent primarily maternal transcription and translation products. During...

Ionic Composition andpH

Mammalian embryos are sensitive to both osmolarity24 and intracellular pH flux, especially to acidification.25'27 This is associated with relatively undeveloped homeostatic mechanisms for regulating intracellular osmolarity and buffering pH. For example, the generally ubiquitous Na+ H+ exchanger can be nonfunctional in early cleaving mouse embryos.26'27 A mild acidification of the culture medium can also result in changes in the ultrastructure of the early embryo.28 However, there is little...

Endocrine and Metabolic Mechanisms

The precise mechanisms underlying the programming of adult disease by maternal nutrient restriction remain a matter of debate. Maternal undernutrition or low protein diet during the last week of gestation in the pregnant rat leads to reduction of fetal pancreatic P-cell mass5 and increased apoptosis of immature P-cells.52 While insulin-stimulated glucose uptake in adipocytes is increased during early postnatal life due to increased insulin receptor number,53 there is greater age-dependent loss...

Epigenetic Modifications

Epigenetic modifications include methylation of cytosine residues in DNA and modifications (including methylation, acetylation, phosphorylation) of the proteins packaging the DNA, the histones, and they affect the transcriptional activity of genes. Covalent modification of DNA, through cytosine methylation, is perhaps the best studied type of epigenetic modification. DNA methylation occurs at CpG dinucleotides through the transfer of methyl groups by DNA methyltransferases (DNMTs)....

What Is Moderate Alcohol Consumption and What Are Common Pregnancy Exposures in Humans

In humans it is generally accepted that 1-2 standard drinks (10-20 grams of ethanol) per day is not harmful and may even confer health benefits. This amount of alcohol, when consumed within a relatively short time, produces a blood alcohol concentration (BAC) in the vicinity of 0.05 in a 50 kg woman. In countries such as Australia, the UK and US, alcohol consumption rates in women of childbearing age often appear to be somewhat higher than recommended levels.46 Once women learn they have become...

Programming Effects of Moderate and Binge Alcohol Consumption

Heavy, sustained consumption of alcohol by pregnant women is associated with the constellation of birth defects and symptoms known as fetal alcohol syndrome (FAS). Similarly, exposure to high concentrations of alcohol for extended periods in animal models of FAS reproduces the teratogenic effects. In contrast, far less is known regarding the more subde effects on offspring of lesser maternal ethanol ingestion. The most widely studied permanent consequence of...

Programming of Obesity Experimental Evidence

Krechowec and Mark H. Vickers Abstract Obesity and related metabolic disorders are prevalent health issues in modern society and are commonly attributed to lifestyle and dietary factors. However, the mechanisms by which environmental factors modulate the physiological systems that control weight regulation and the aetiology of metabolic disorders, which manifest in adult life, may have their roots before birth. The 'fetal origins' or 'fetal programming' paradigm...

Late Gestational Glucocorticoids and Programming of the Hypothalamic PituitaryAdrenal Axis

Normal physiology is dependent on adequate function of the HPA axis, which is responsible for regulating synthesis and release of a variety of corticosteroid hormones. Cortisol is the principle corticosteroid (in mammals other than rodents) produced by the adrenal cortex it regulates metabolic, immune and behavioural processes, and the body's response to stressful stimuli. Cortisol acts through glucocorticoid and mineralocorticoid receptors (GR and MR, respectively), which are present in many...

Hypoxia Fetal Growth and Developmental Origins of Health and Disease

The compelling evidence linking small size at birth with later cardiovascular disease, obtained from epidemiological studies of human populations of more than a dozen countries,1 has clearly renewed and amplified a clinical and scientific interest into the determinants of fetal growth, birth weight and the development of cardiovascular function and dysfunction before and after birth. As early as the 1950s Penrose2 highlighted that an important determinant of birth weight was the quality of the...

Growth Factor and Cytokine Environment and Long Term Development

In vivo, the growth and development of the preimplantation embryo as it traverses the female reproductive tract is influenced by cytokines and growth factors secreted from epithelial cells lining the oviduct and uterus. The identity and biological effects of growth factors and cytokines targeting the preimplantation embryo have been reviewed.6266 An array of different factors are secreted in precise spatial and temporal patterns such that the profile of factors experienced by the embryo would...

Excess Glucocorticoids and Direct Effects on Fetal Growth

The normal late gestational slowing of fetal growth in sheep can be abolished by adrenalectomy, and premature increases in Cortisol by exogenous infusion causes the fetal growth rate to slow early. Thus, in many species, intrauterine growth restriction (IUGR) is a direct consequence of late gestation exposure of the fetus to excess glucocorticoids. Administration of the synthetic glucocorticoid, betamethasone, to pregnant sheep, in doses and at times that mimics clinical use in pregnant women,...

Experimental Evidence for Programming of Obesity

Animal models have been used extensively to investigate the basic physiological principles of the FOAD hypothesis. The variety of models that have been developed is essential to the search for the mechanistic links between prenatal influences and postnatal pathophysiological outcomes. An example is the diabetic pregnant rat, in which the long-term effects on offspring following diabetic pregnancy can be investigated, a study which would not be possible in humans as treatment is ethically...

Nutritional Programming

Fetal undernutrition has been highlighted as a primary factor involved in the early life origins of adult disease. Within the laboratory, fetal undernutrition can most commonly be achieved through maternal dietary restriction during pregnancy. Manipulation of maternal nutrition during pregnancy has been known to alter fetal growth and development for some time.20 At present, rodent models investigating the mechanistic links between maternal undernutrition and adult disease generally utilise one...

Hypertension during Pregnancy

Another condition common during pregnancy is hypertension.46 It has been predicted that the incidence of chronic hypertension will increase from 1 to 5 in 100 pregnancies over the next decade.47 This is due to the shift to an older child bearing age in women and the increased risk of hypertension in this older population.48 However, few studies have followed the children of mothers with hypertension into adulthood,4951 though both low-birth weight and macrosomic babies have been linked with...

Normal Glucocorticoid Levels in Late Gestation

Normally, glucocorticoid production by the fetal adrenal gland is high in early gestation and becomes reduced during mid-late gestation.6,7 Maintenance of these normal low levels of glucocorticoids is essential for normal fetal growth and development. The fetus is usually 'protected' from exposure to circulating maternal Cortisol by the presence of the enzyme 1 lPhydroxysteroid dehydrogenase type 2 (11(3HSD2) in the placenta, which converts active Cortisol to inactive cortisone. *Corresponding...

Possible Mechanisms Leading to Adult Hypertension

The cardiovascular system regulates blood pressure to maintain an adequate perfusion to meet the needs of each tissue (Figs. 1,4). Normal blood pressure is regulated by a number of organs and physiological systems, exerting both short (reflex) and long-term effects. Mechanisms integrating the control of arterial blood pressure are oudined and possible adaptations in the development of components of the cardiovascular system resulting in alterations in function and the programming of...

Plasticity of Embryo Development

Zygotes and early embryos are not bound to an absolute set of physiochemical or nutritional conditions for successful development. For example, there are several commercial manufacturers of culture media systems for human embryo development in clinical infertility treatment, all of which differ in concentrations of key constituents. The ability of embryos to develop adequately under varying conditions has been referred to the 'plasticity' of embryo development. Nevertheless, we now recognise...

Epigenetic Reprogramming Occurs in Early Development

Early development is a critical time for epigenetic reprogramming, with clearing and re-estalishment of epigenetic marks taking place throughout the genome. There is increasing evidence that cytosine methylation plays a crucial role in differentiation and development. After fertilization there is a rapid demethylation of the genome. Fluorescent antibody studies have demonstrated that the paternal genome undergoes a rapid, active demethylation complete within 4 hours of fertilization, while the...

Neuropathological Evidence for Neural Injury before Birth in Schizophrenia

The key neuropathological data for an in utero origin to schizophrenia centre around neuronal migration, and, increasingly, glial proliferation. The presence of neuronal disarray, heterotopias and malpositioning are very suggestive since cytoarchitecture is largely determined during early fetal life, well before the last trimester.5'35. Among the cellular findings are abnormal cytoarchitecture of the entorhinal cortex characterized by poorly formed layer II neuron clusters and laminar...

Perspective

This chapter has examined the hypothesis that schizophrenia and other mental illnesses may have at least in part their origin in preceding fetal neurodevelopmental injury. Although the combined epidemiological, neuroanatomical, behavioural, and imaging evidence is highly suggestive, the data cannot yet definitively distinguish the roles of inherited predisposition and environmental triggers. Considerable work remains to properly understand the impact of timing and the nature of different...

Conclusions

Strong evidence in both human and in animal studies supports the hypothesis that hypertension can be programmed in utero. Future studies should encompass the following (1) Prehypertensive animals should be studied to differentiate between the primary initiating programming events and events secondary to the consequent development of hypertension. (2) Best practice methods should be employed to determine arterial blood pressure single time-point measures are open to misinterpretation...

References

Altered retinal function and structure after chronic placental insufficiency. Invest Ophthalmol Vis Sei 2002 43(3) 805-812. 2. Zubrick SR, Kurinczuk JJ, McDermott BM et al. Fetal growth and subsequent mental health problems in children aged 4 to 13 years. Dev Med Child Neurol 2000 42(l) 14-20. 3. Spinillo A, Stronati M, Ometto A et al. Infant neurodevelopmental outcome in pregnancies complicated by gestational hypertension and intra-uterine growth retardation....

Nephron Glomerular Number

The kidney has been implicated in the programming of adult disease predominandy through studies in which a low reduced nephron number resulting from maternal intervention is associated with elevated blood pressure in the adult offspring. Much interest has focused on the so called Brenner hypothesis which states that a reduction in nephron endowment at birth contributes to the development of hypertension.11 However, is it really that simple The normal range of glomeruli in a human kidney is...

Is Low Birth Weight a Risk for Kidney Disease

Much of the evidence for programming of adult disease comes from human epidemiological studies and animal models where the offspring is of low birth weight due to maternal undernutrition or placental insufficiency.3'4 Infants born of low birth weight, that is small for gestational age (SGA) are at increased risk of developing adult diseases particularly hypertension and noninsulin dependent diabetes mellitus (NIDDM). A link between low birth weight and renal disease is not as firmly established...

Children and Adolescents Neurodevelopmental Milestones

The literature regarding neuromotor outcomes in school-age children born IUGR is sparse and somewhat variable, both methodologically and in outcomes. This is partly because no two studies appear to have used the same assessment instrument, and the findings have been inconsistent. They range from little or no increase in the likelihood of suboptimal motor performance to significant decrements in a wide range of fine and gross motor skills. Again, none have included neurophysiological assessments...

Maternal Diet Altering Fetal Phenotype

Given the impact that diet can have on DNA methylation in an adult individual, several studies have now been undertaken to see if these effects occur during embryonic development. Rees et al demonstrated that a maternal protein-deficient diet (supplemented with threonine) led to global hypermethylation of DNA in the livers of fetal rats. The authors propose that the hypermethylation seen in the offspring is a result of threonine metabolism competing for enzymes involved in methionine...

Is It Just Nephron Number Thats Important

Arguments against the Brenner hypothesis primarily come from human and animal experiences where removal of a kidney from an adult, thereby halving the nephron number, does not generally result in hypertension. Long term follow up studies of patients who have had a kidney removed due to a tumour or donated a kidney for transplantation have not shown an increased incidence of hypertension.25 Other studies in the rat where the glucocorticoid treatment occurred earlier in gestation also show that...

Epigenetic Lability at Genomically Imprinted Genes

Genomic imprinting is an epigenetic phenomenon by which certain mammalian genes are expressed preferentially from either the paternally-inherited or maternally-inherited allele. Monoallelic expression of imprinted genes is regulated by allele-specific methylation of specific CpGs.14 Most imprinted genes are found in clusters, and these imprinted domains are regulated in coordinate fashion via long range mechanisms including antisense RNA interference and methylation-sensitive boundary...

Kidney Development

Kidney Branching Morphogenesis

Renal development in mammals involves the development of three sets of excretory organs, the pronephros, mesonephros (transitory organs) and the metanephros (Fig. 1). The meta-nephros (permanent kidney) develops from two embryonic precursor cell populations, the Figure 1. Development of the permanent mammalian kidney. Schematic diagram illustrating the development of the mammalian excretory system. The pronephros and mesonephros are transitory and degenerate. The metanephros forms when the...

The Couch Potato Syndrome

We have recendy reported experimental evidence suggesting that maternal undernutrition can induce sedentary behaviour, hyperphagia and concomitant obesity in offspring independent of postnatal dietary influences. We had previously shown that maternal undernutrition throughout pregnancy in the rat results in hypertension, hyperinsulinemia and hyperleptinemia in the offspring when they reach adulthood.6 Obesity was not present until after puberty and was associated with hyperphagia. In the course...

Postnatal Nutrition

We can distinguish two conceptually different types of interactions between prenatal influences and postnatal nutrition in the pathogenesis of metabolic disorders and obesity. Diet-induced obesity during postnatal life can amplify pathogenic mechanisms established by adverse prenatal influences. Alternatively, changes caused by prenatal influences can facilitate a disease process that is induced by postnatal environmental factors such as nutrition. An example is the development of obesity and...

Maternal Stress and Motor Development in the Offspring

Apart from sub-optimal nutrition in utero, another source for altered prenatal programming of motor development is maternal stress. Maternal stress during pregnancy has also been shown to impair neuromotor development in rats and non-human primates, although the number of studies is relatively small. The gestational timing at which maternal stress occurs appears to determine the type of adverse affect on neuromotor development and outcomes.102 In rats, acquisition of a range of precocious...

H

Heart 1-3, 5, 8, 14, 20, 33, 88, 103, 113, 114, 125, 127, 158, 159, 187, 189, 191, 192, 200, 220 Hertfordshire 9-12, 14, 15, 19 High altitude 220-223 High blood pressure 90, 103, 104, 109, 113, 131, 132, 138, 159,219 Histone modification 71 Hypertension 3, 8-10, 19, 20, 31, 70, 74-76, 87, 88, 90, 91, 94, 103-114, 121, 123, 126,130-132, 138-140,146, 147, 150, 151, 153, 179-181, 198, 199, 223 Hypertensive pregnancy 107, 108 Hypobaria 220 Hypothalamo-pituitary-adrenal (HPA) axis 2, 3, 5, 16, 146,...

The History of the Neurodevelopmental Hypothesis

The neurodevelopmental hypothesis proposes that adverse environmental events during fetal life impairs and subsequendy alter neural development, leading to mental illness in adulthood.10'14 Like all good theories, it has a long history. As early as 1891, the founding father of adolescent psychiatry, Scottish psychiatrist Thomas Storer Clouston, proposed that there was a developmental component to adolescent or developmental insanity. He considered it a disorder of cortical development the last...

Summary and Conclusions

Numerous epidemiological studies have shown that perturbations in early life can have persistence consequences for health in later life. Both prospective clinical studies and experimental research have clearly shown that the propensity to develop abnormalities of cardiovascular, endocrine and metabolic homeostasis in adulthood is increased when fetal development has been adversely affected. The pathogenesis is not based on genetic defects but on altered genetic expression as a consequence of an...

Prenatal Programming of Human Motor Function

Henderson-Smart and Jeffrey S. Robinson Abstract In a world in which athletic skill is often valued more highly than intellectual prowess, we know surprisingly litde about the development of the human motor system. Even less is known about how an adverse intrauterine event or environment might program motor learning, memory and function throughout the lifespan. We are only beginning to investigate how events during development of the brain and central nervous system...

Springer Science Business Media Landes Bioscience Eurekahcom

Springer Science Business Media Eurekah.com Landes Bioscience Copyright '2006 Eurekah.com and Springer Science Business Media All rights reserved. No part of this book may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher, with the exception of any material supplied specifically for the purpose of being entered and executed on a...

Programming of the Adipoinsular Axis and Altered Adipogenesis

It is important to note that very few animal studies have addressed interactions between pre and postnatal nutrition. However, other studies that have investigated diet-induced obesity point to a link between peripheral leptin resistance and insulin resistance in the development of obesity. The physiological role of hyperleptinemia associated with caloric excess has been proposed to relate to the protection of nonadipocytes from lipid oversupply that would lead to steatosis and lipotoxicity.68...

Developmental Origins of Cardiovascular Disease Type 2 Diabetes and Obesity in Humans

Fetal Origins Adult Disease

Fetal growth restriction and low weight gain in infancy are associated with an increased risk of adult cardiovascular disease, type 2 diabetes and the Metabolic Syndrome. The fetal origins of adult disease hypothesis proposes that these associations reflect permanent changes in metabolism, body composition and tissue structure caused by undernutrition during critical periods of early development. An alternative hypothesis is that both small size at birth and later disease have a common genetic...

Epigenetic Lability at Transposable Elements

Except for a brief period of global demethylation in the early mammalian embryo, transposable elements in the genome are generally silenced by hypermethylation.15 However, these parasitic elements comprise over 45 of the mammalian genome, and their aberrant transcriptional activity can interfere with the expression of neighboring genes.32 Dysregulation of even a small fraction of human transposable elements could therefore cause substantial genomic instability.15'29 Notably, transposable...