To develop the hypothesis further, Baker et al 3 reviewed how fetal undernutrition at different stages of gestation can be linked to different birth phenotypes, each linked to adaptations associated with changes in concentrations of placental and fetal hormone and later with different metabolic abnormalities in adulthood. The DOHaD society has sponsored meetings in Toronto, Ontario, Canada , Utrecht, The Netherlands , Perth, Western Australia , and Santiago, Chile , and these international congresses provided an important forum for exchange of ideas and progress in this rapidly expanding field www.
Here we review some of the expanded themes, including: The field is now so large that a selective review is necessary. Using data from one of these cohorts, Roseboom et al 8 investigated effects of timing of fetal undernutrition based on the Dutch cohort exposed to the — famine at the end of World War II and showed that fetal undernutrition may affect different organs of the body depending on different critical phases of development i. Using data from another cohort, Barker et al 9 investigated the trajectory of growth during infancy and childhood in the Helsinki to Birth Cohort see Eriksson et al 10 and showed that adult outcomes were moderated by the tempo of growth in infancy and childhood as well as by fetal growth and birthweight i.
This program of research also initiated a new a cohort study of contemporary births. Initial goals were to directly test some of the assumptions of the DOHaD approach i. The SWS started with interviews of 12, young female residents of Southampton to obtained measures of prepregnancy characteristics, followed by detailed, prospective evaluation of this cohort that was described by Inskip et al. Two examples from this research program are described here to address methodological issues that are critical for the evaluation of some basic assumptions of the DOHaD approach e.
These are crucial measures in the theory of developmental plasticity or predictive adaptive response, which predicts that maternal diet may regulate blood flow to developing organs i. Haugen et al 12 evaluated the effects of maternal adiposity and diet in low-risk pregnancies in the SWS at 36 weeks of gestation using Doppler ultrasound to estimate blood flow in the umbilical cord and ductus venosus, which shunts well-oxygenated placental blood from the liver to the brain and heart. The low-risk group was selected to gain a better understanding of these factors in normal conditions rather than in extreme conditions in a high-risk group.
Two independent effects were documented: Harvey et al 13 reported on parental determinants of neonatal body composition in births in the SWS, with dual-energy x-ray absorptiometry scan assessment of fat and muscle mass components of body composition in the offspring within 2 weeks of birth. With this rigorous measurement of neonatal body composition, this study documented that total fat mass was related to maternal lifestyle factors smoking and physical activity as well as maternal height, parity, and triceps skinfold thickness.
One conclusion was that if these influences on fat mass have persisting effects, this information could point the way to early life interventions that may prevent later obesity. These examples of rigorous and prospective early evaluations in the SWS protocol show how modern methods can be used to assess fetal adaptations and their effects on structures and functions that may alter body composition rather than just weight at birth.
Developmental Origins of Health and Disease
This may provide improved estimates of the underlying DOHaD-related factors that contribute to risk for common adult disorders e. Collaboration between centers see www.
Applications of the predictive adaptive response concept, presented and discussed in additional detail in a book by Gluckman and Hanson, 15 suggest that the fetus forecasts the future by sensing the current environment in utero and develops adaptively to match capabilities with expected demands. Gluckman et al 16 emphasized one of the premises of this hypothesis that the association of outcomes with birthweight is an epiphenomenon of the relationship between nutrient availability to the fetus and the predictive adaptive responses that this elicits.
Gluckman et al 17 extended the concept of developmental plasticity by emphasizing that fetal programming may operate across the range from undernutrition to over-nutrition, with a U-shaped curve relating prenatal nutrition to adult metabolic disease. Gillman 18 noted limitations of undernutrition and low birthweight as markers of prenatal etiological pathways related to postnatal health outcomes.
This led to consideration of fetal, infant, and child body composition as a phenotype and abnormalities anywhere in the maternal-fetal supply line of nutrients as a common final pathway that may alter body composition. Oken and Gillman 19 addressed the fetal origins of obesity and noted two different relationships with birthweight: Gillman et al 20 , 21 used the life course approach to focus investigations on general in utero conditions and placental function and physiological processes regulating fetal development across a broad range of birth sizes, rather than on abnormal or pathological processes at one extreme.
Its initial goals were to identify women early in pregnancy and to enter them into a protocol for prospective assessments twice during pregnancy, within 3 days of birth, and at 6 months, and at 1, 2 and 3 years of age. Weight early in life was directly associated with higher BMI at 3 years of age, but the association was larger for standardized weight at 3 years of age than for birth-weight. This suggest that increases in weight in the first 6 months of life may produce additional programming effects that increased risk for obesity in early childhood and thus may influence risk for later obesity more than birthweight alone that is assumed to reflect fetal programming.
An early extension of the DOHaD approach was to go beyond nutrition hypotheses and to relate fetal development to exposure to other factors such as prenatal maternal stress and maternal-placental-fetal biological mediators of stress. Wadhwa 25 reviewed how psychoneuroendocrine processes in human pregnancy influence fetal development and health.
Drake et al 26 reviewed the fetal glucocorticoid overexposure hypothesis as an alternative to the fetal undernutrition hypothesis to account for the relationship of the prenatal environment to adult disorders related to cardiovascular, metabolic, neuroendocrine, and behavioral phenotypes. A multi-investigator research program at the University of California, Irvine, was initiated in , and Wadhwa 25 reviewed the contributions of this program over the initial 12 years, which generated extensive information on the short-term effects of exposure to maternal psychosocial stress during pregnancy.
This focused research documented that length of gestation and fetal growth are mediated, in part, by maternal-placental-fetal stress physiology, particularly placental corticotrophin-releasing hormone. Because simple birth phenotypes such as birthweight may represent a crude marker of intrauterine conditions that are likely to exert a causal role, this research program was recently extended based on the DOHaD approach to evaluate healthy young adults born with a normal birth-size phenotype i.
Entringer et al 27 — 29 showed that compared with healthy young individuals without this history, these prenatal stress-exposed individuals exhibited primary insulin resistance and a lipid profile consistent with the metabolic syndrome, 27 altered immune function, 28 altered endocrine function, 29 and compromised cognitive function. Also directed by the DOHaD approach, Buss et al 31 evaluated brain morphology in young adults and revealed an association between birthweight and postnatal environment: Lower birth-weight was associated with smaller hippocampal volume a well-established risk factor for depression and psychopathology only in individuals exposed to postnatal adversity low levels of parental bonding.
Swanson and Wadhwa 32 have suggested that the DO-HaD approach also may be relevant to the origins of some child mental health disorders. They provide an excellent description of the potentially unique contributions of epigenetics, a glossary of terms, and a thorough description of methods used to detect genome-wide variation in DNA methylation and chromatin modification.
Outstanding reviews were published in that provide background on how the principles and concepts of epigenetics have been applied to the DOHaD approach. In their review of the DOHaD approach, Gluckman et al 17 provided an excellent summary of epigenetic modification of histones or of DNA itself in a figure p.
This figure summarizes the important epigenetic processes of DNA methylation and histone acetylation and methylation that have been discussed and reviewed elsewhere 31 — 34 in detail and thus are not repeated here. Regulation of gene expression through epigenetic processes. Transcriptionally active chromatin top characterized by the presence of acetyl groups Ac on specific lysine residues of core histones in the nucleosome, which decreases their binding to DNA and results in a more open chromatin structure that permits access of transcription factors.
In addition, cytidine-guanosine CpG sequences in the promoter regions P of actively transcribed genes are generally unmethylated, allowing for the binding of transcription factors. Transcriptionally inactive chromatin bottom is characterized by histone deacetylation, promoter CpG methylation as indicated by methyl groups [Me] , and decreased binding of transcription factors.
For simplicity, other histone modifications [such as methylation] and additional regulatory factors [such as methyl-CpG binding proteins] are not shown. Effect of in utero and early-life conditions on adult health and disease. N Engl J Med ; 1: Two types of genes are modified epigenetically i.
Imprinted genes are those in which specifically either the maternally derived or the paternally derived allele is suppressed, thereby rendering them functionally haploid i. In other nonimprinted genes, one or both alleles are regulated epigenetically, and these metastable epialleles result in varying levels of gene expression. The modification of DNA from conception forward occurs to establish the epigenetic influence of gene expression, which is clearly presented in an article by Reik et al 37 that is often cited in reviews of imprinting. This article provided a figure outlining the processes of methylation reprogramming in the germ line and in preimplantation embryos that is reproduced here Fig.
As Leudi et al 38 discuss, many undiscovered genes are predicted to be imprinted, and this set of genes is likely to have special importance for reproductive medicine and fetal growth. However, as pointed out by Gluckman and Hanson, 15 there is a strong epigenetic basis for the DOHaD model of disease pathogenesis based on animal studies, which for example show that minor alterations in the maternal diet during pregnancy can produce lasting changes in the physiology and metabolism of offspring. We summarize here classic findings from two research programs that have provided evidence about possible epigenetic mechanisms involved in this type of phenotypic plasticity in the DOHaD approach.
More detailed description and review was provided as background for a meeting on Genes, Environments and Human Development, Health and Disease. A Methylation reprogramming in the germ line. Primordial germ cells PGCs in the mouse become demethylated early in development. Remethylation begins in prospermatogonia on E16 in male germ cells and after birth in growing oocytes. Some stages of germ cell development are shown modified from B Methylation reprogramming in preimplantation embryos.
The paternal genome blue is demethylated by an active mechanism immediately after fertilization. The maternal genome red is demethylated by a passive mechanism that depends on DNA replication. Both are remethylated around the time of implantation to different extents in embryonic EM and extraembryonic EX lineages. Methylated-imprinted genes and some repeat sequences dashed line do not become demethylated. Unmethylated imprinted genes dashed line do not become methylated. Epigenetic reprogramming in mammalian development.
A group at Duke University has used a mouse model to investigate the effects of maternal diet during pregnancy on the phenotype manifested in the offspring www. The viable yellow agouti A vy mouse has a mutation that causes yellow hair pigmentation. Waterland and Jirtle 40 investigated methyl supplementation of the diet of mothers during pregnancy and showed when a standard diet is supplemented by methyl donors, methylation of the A vy gene increases and the coat-color distribution shifts toward the brown phenotype.
A group at McGill University has used a rodent model to investigate epigenetic effects of maternal care. In rats, an important component of maternal care consists of licking and grooming, which varies widely across individuals. Meaney and Szyf 42 showed that increased licking and grooming increased hippocampal expression of the glucocorticoid receptor GR mRNA and protein, decreased hypothalamic corticotrophin-release factor, and reduced hypothalamic-pituitary-adrenal response to stress.
This work showed a direct relationship between maternal behavior and DNA methylation in the rat hippocampal GR gene specifically in the exon 1 7 promoter.
FROM EPIDEMIOLOGICAL OBSERVATIONS TO THE FETAL ORIGINS HYPOTHESIS
Weaver et al 43 demonstrated further that the stress responses in adult rats that are programmed early in life by maternal care can be reversed by central infusion of methionine a methyl donor , suggesting that the inherently stable epigenomic marks established by behavioral programming at a critical period early in life are potentially reversible later in life. This provides a biological basis for speculations about the effects of poverty on early experience, and how exposure to abuse, family strife, emotional neglect, and harsh discipline may have epigenetic effects that produce individual differences in neural and endocrine response to stress and may increase the susceptibility to common adult disorders such as depression and anxiety, drug abuse, and diabetes, heart disease, and obesity.
Aaggard-Tillery et al 44 used a nonhuman primate model to investigate the effects of maternal diet on alternations to the epigenome that may be related to obesity. In the first stage of investigation, Aagaard-Tillery et al 44 identified an epigenetic change in the liver of these offspring hyperacetylation of fetal hepatic tissue that was associated with the high-fat diet and the resulting obesity.
Developmental Origins of Health and Disease
Even though obesity was maintained, the epigenetic changes in offspring were no longer present. This finding suggests that obesity may, in part, be due to the effects of maternal diet rather than maternal obesity on the fetal environment. Tyckol 45 addressed the special nature of imprinted genes in placental growth. The placenta is the principal metabolic, respiratory, excretory, and endocrine organ of the fetus, which has substantial molecular variation across the fetal and maternal compartment see Sood et al 46 and affects birthweight even after adjustment for placental weight see Salafia et al In a study of intrauterine growth restriction IUGR and non-IUGR placenta, an altered expression of imprinted genes in placental response to maternal vascular underperfusion was investigated by McMinn et al.
This suggested unbalanced expression of these two oppositely imprinted genes was one component of the adaptive response of placental tissue to chronic maternal vascular underperfusion associated with IUGR, which provides some support for the conflict hypothesis. New methods are emerging for assessing epigenetic marks, such as the MSNP approach for determining allele-specific methylation and allele-specific expression patterns that may be dependent or independent of genome sequence see Kerkel et al Niemtz and Feinberg 52 provide an example of early epigenetic research in reproductive medicine.
A summary of recent studies relevant to reproductive medicine is facilitated by two recent reviews in the series of Seminars in Reproductive Medicine, 55 , 56 which provide detailed background for the application of the DOHaD approach to reproductive medicine and epigenetic processes Fig. Rinaudo and Lamb 55 summarized the literature on in utero stress related to deficient maternal-placental nutrient supply and some adverse childhood and adult outcomes i. They also provided a brief review of perinatal morbidity associated with stress during the preimplantation period related to in vitro culture in assisted reproduction.
They concluded that the evidence linking stress in utero to risk for adult disorders is convincing, and that the preimplantation embryo development is particularly sensitive to epigenetic regulation and dysregulation. Kalra and Molinaro 56 summarized the literature on association of in vitro fertilization with perinatal morbidity and the risk for congenital abnormalities, preterm birth, low birthweight, and other pregnancy-related complications. Other reviews of reproductive outcomes after IVF 57 and ICSI 58 also are available and add to the growing recognition that alteration of biochemical and biophysical conditions at conception and during early embryonic life associated with ARTs may result in changes in epigenetic processes and produce short- and long-term effects on development and health.
There are many recent developments in the field of epigenetics. Recent workshops Epigenomics of Addiction and conferences Epigenomics of Human Health and Disease have summarized these new developments in the understanding of mechanisms and methods that are being applied in the current investigations. The basic processes that describe how cells with the same molecular instructions the DNA code become differentiated during development through differential expression of genes have been reviewed in detail, with information available on the NIH Web site see www.
The next phase of research to address epigenetic mechanisms in humans would benefit substantially from large birth cohort studies with prospective measures of broad domains of exposures and outcomes. Recently, the Avon Longitudinal Study of Parents and Children ALSPAC study, 60 the Danish National Birth Cohort, 61 and the SWS 11 have taken initial steps to identify critical developmental processes that underlie fetal growth and development 13 , 62 , 63 and later outcomes in childhood related to the overnutrition hypothesis, 64 preterm birth, 61 and body composition.
Broad exposures and outcome domains will be assessed at multiple times across stages of development before conception, during pregnancy, and at birth; in infancy, childhood, adolescence; and into adulthood. A recent summary of the background, controversies, and status of the NCS was provided by Landrigan et al. However, with such a large and representative birth cohort characterized by broad exposure and outcome domains, many more hypotheses will be tested and will emerge as the NCS progresses.
Modified Text from [15] Note the commment made by Emeritus Professor P Pharaoh "One caveat that should be borne in mind, concerns the tests that are used to assess cognitive function.
What do these tests actually measure? Ideally they measure innate mental ability, whatever that is, at a point in time. In contrast, a recent study of only postnatal growth to 3 years of age identified "Slower infant weight gain was not associated with poorer neurodevelopmental outcomes in healthy, term-born 3-year-old children.
Fetal origins of adult disease. Early influences on cardiovascular and renal development. Fetal origins of adult diabetes. The developmental origins of health and disease hypothesis. Pediatr Nurs , 36 , Perinatal environment and its influences on metabolic programming of offspring.
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Developmental origins of adult disease. Med Princ Pract , 19 , Developmental origins of health and disease: Risk factors and outcomes associated with first-trimester fetal growth restriction. JAMA , , External Links Notice - The dynamic nature of the internet may mean that some of these listed links may no longer function. If the link no longer works search the web with the link text or name. Links to any external commercial sites are provided for information purposes only and should never be considered an endorsement.
UNSW Embryology is provided as an educational resource with no clinical information or commercial affiliation. Discussion View source History. Delivery of a small for gestational age infant and greater maternal risk of ischemic heart disease. Perinatal risk factors for diabetes in later life. Diabetes , 58 , Persistent epigenetic differences associated with prenatal exposure to famine in humans. The fetal origins hypothesis years on.
BMJ , , The fetal and infant origins of adult disease. The maternal and fetal origins of cardiovascular disease. J Epidemiol Community Health , 46 , Fetal nutrition and cardiovascular disease in later life. Fetal origins of adult disease-the hypothesis revisited. Nature , , David Barker --a giant in reproductive epidemiology. Acta Obstet Gynecol Scand , 93 , Glomeruli and blood pressure. Less of one, more the other?. Birth weight and cognitive function at age 11 years: