Epidemiological studies in humans have shown thatimpaired intrauterine growth is associated with anincreased incidence of cardiovascular, metabolic, andother diseases in later life (4). Low birth weight, in par-ticular, has been linked to hypertension, ischemicheart disease, glucose intolerance, insulin resistance,type 2 diabetes, hyperlipidemia, hypercortisolemia,obesity, obstructive pulmonary disease, and repro-ductive disorders in the adult (Table 1). These associa-tions have been described in populations of differentage, sex, and ethnic origin and occur independently ofthe current level of obesity or exercise (4, 21). Detailedmorphometric analyses of the human epidemiologicaldata have shown that certain patterns of intrauterinegrowth can be related to specific adult diseases. Forinstance, it is the thin infant with the low ponderalindex, rather than the symmetrically small baby, thatis more prone to type 2 diabetes as an adult (42). Theseobservations have led to the concept that adult diseaseoriginates in utero as a result of changes in develop-ment during suboptimal intrauterine conditions oftenassociated with impaired fetal growth (4). The processby which early insults at critical stages of developmentlead to permanent changes in tissue structure andfunction is known as intrauterine programming (33).

Intrauterine programming of postnatal physiologi-cal function has been demonstrated experimentally ina number of species using a range of techniques tocompromise the intrauterine environment and alterfetal development (see Ref. 35). Induction of intrauter-ine growth retardation (IUGR) by maternal stress,hypoxia, glucocorticoid administration, dietarymanipulation, or placental insufficiency leads to post-natal abnormalities in cardiovascular, metabolic, andendocrine function in rats, guinea pigs, sheep, pigs,horses, and primates (16, 35). Similarly, in naturally

occurring IUGR in polytocous species, low birthweight is associated with postnatal hypertension, glu-cose intolerance, and alterations in the functioning ofa number of endocrine axes, including the pancreaticislets, renin-angiotensin system, and hypothalamic-pituitary-adrenal (HPA) axis (16). Animal studies havealso demonstrated that the timing, duration, and exactnature of the insult during pregnancy are important

29

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Intrauterine Programming ofPhysiological Systems: Causes andConsequences

Abigail L. Fowden, Dino A.Giussani, and Alison J. Forhead

Department of Physiology, University of Cambridge,Cambridge, UK

alf1000@cam.ac.uk

The intrauterine conditions in which the mammalian fetus develops have an

important role in regulating the function of its physiological systems later in life.

Changes in the intrauterine availability of nutrients, oxygen, and hormones pro-

gram tissue development and lead to abnormalities in adult cardiovascular and

metabolic function in several species. The timing, duration, severity, and type of

insult during development determines the specific physiological outcome.

Intrauterine programming of physiological systems occurs at the gene, cell, tis-

sue, organ, and system levels and causes permanent structural and functional

changes, which can lead to overt disease, particularly with increasing age.

1548-9213/06 8.00 ©2006 Int. Union Physiol. Sci./Am. Physiol. Soc.

PPHHYYSSIIOOLLOOGGYY 2211:: 2299––3377,, 22000066;; 1100..11115522//pphhyyssiiooll..0000005500..22000055

Table 1. Adult diseases associated with suboptimal intrauterine conditions in humans

Physiological System DiseaseCardiovascular system Hypertension

Coronary Heart diseaseStrokeAtherosclerosisCoagulation disordersPre-eclampsia

Metabolic system Impaired glucose toleranceInsulin resistanceDyslipidemiaObesityType 2 diabetes

Reproductive system Polycystic ovarysyndromeEarly adrenarche/menarcheEarly menopause

Respiratory system Chronic obstructive pulmonary diseaseAsthma

Endocrine system HypercortisolismHypothyroidism

Nervous system Neurological disordersSchizophreniaDementia

Skeletal system Osteoporosis

nutrient and O2 availability invariably affect theendocrine environment, the role of hormones as pro-gramming signals has also been examined in humansand experimental animals (15).

Nutritional programming

Prenatal nutritional programming of postnatal physio-logical functions has been demonstrated experimen-tally in a wide variety of laboratory and farm animalsby manipulating the availability of macronutrients andmicronutrients during development. A range of tech-niques has been used to reduce the fetal availability ofmacronutrients used for tissue accretion (7). Theseinclude calorie restriction, isocalorific protein depri-vation, placental restriction, and reductions in umbil-ical and/or uterine blood flows. All of these proce-dures impair fetal growth and lead to abnormalities incardiovascular, metabolic, and endocrine functionboth before and after birth (see Ref. 35). Altered post-natal physiological function has also been observedafter maternal fat feeding and dietary manipulation ofspecific micronutrients, such as minerals (calcium,iron), cofactors (folic acid, taurine), and vitamins (Aand D) (2). In some instances, the programmingeffects of macronutrient restriction can be ameliorat-

30 PHYSIOLOGY • Volume 21 • February 2006 • www.physiologyonline.org

determinants of the pattern of intrauterine growth andthe specific physiological outcomes (7). Furthermore,these studies have shown that maternal insults withlittle, if any, effect on birth weight can alter subsequentcardiovascular and metabolic function (5). Together,animal experiments and human epidemiological datashow that a wide range of individual tissues and wholeorgan systems can be programmed in utero withadverse consequences for their physiological functionlater in life (FIGURE 1). This programming occursacross the normal range of birth weights with theworst prognoses at the extremes (4, 35).

Causes of Intrauterine Programming

In mammals, programming by internal and externalcues during early postnatal life is well established. It isthe concept that the adult phenotype also depends onenvironmental signals operating during intrauterinedevelopment that has recently received the mostattention. Since fetal growth and development dependprimarily on nutrient and oxygen supply (25), theassociations between low birth weight and adult phe-notype have been linked to poor nutrition and oxy-genation during early life (FIGURE 1). However, since

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Causes Mother

Placenta

Fetus

Adult

Programming

Consequences

Placental size, blood flow and function

Fetal growth and development

Intrauterine programming

Fetal hormones

Blood vessels Heart Kidneys Hypothalamus Central nervous system Autonomic nervous system Fat Liver Skeletal muscle Pancreas

Cardiovascular disease

Metabolic disease

Fetal O2 and substrate supply

Disease

Pre-eclampsia, diabetes,

bacteria, viruses

Environment

High altitude,

toxins, temperature,

substance abuse,

alcohol, nicotine, drugs,

maternal constraint

Stress

Hormones,

ANS

Diet

Macro- and

micronutrients

FIGURE 1. Causes and consequences of intrauterine programming

ed by supplementation of the altered diet with singlecofactors and amino acids (2). Indeed, it may be thebalance of micro- and macronutrients that is moreimportant in programming than the absolute amountof nutrient per se.

Programming by alterations in oxygenation

Several of the techniques used to induce fetal under-nutrition also reduce fetal O2 delivery. In rats, chronichypoxia during pregnancy causes disproportionateIUGR and leads to abnormalities in cardiovascularfunction in the adult offspring (9, 11). Similarly, inhuman populations, the hypobaric hypoxia of highaltitude is associated with reduced birth weight andasymmetric growth retardation (19, 37). However, thedevelopmental changes induced by hypoxia may alsohave a nutritional component, because high-altitudepopulations are often impoverished and chronichypoxia during pregnancy in experimental animalsreduces maternal food intake (11, 19). The relativecontributions of fetal hypoxemia and undernutritionto programming in these circumstances have beeninvestigated experimentally by pair-feeding pregnantrats at normal PO2 and by using chick embryos. Inavian species, the specific developmental effects of O2

deprivation can be studied in ovo without the con-founding effects of a hypoxic placenta and/or reducedmaternal dietary intake (47). Both of these approachesshow that hypoxia alone during early developmentcan program the cardiovascular system and, morespecifically, the blood vessels. In the chick embryo,hypoxia during the mid to late incubation period exag-gerates responses to periarterial sympathetic nervestimulation and downregulates nitric oxide-depend-ent dilator function in the vessels of the adult birds. Inrats, prenatal hypoxia but not nutrient restrictionimpairs endothelium-dependent relaxation in themesenteric circulation of the adult offspring (56).

Endocrine programming

Hormones have an important role in regulating nor-mal growth and development in utero, and their con-centrations and bioactivity change in response tomany of the environmental challenges known to causeintrauterine programming (15). Undernutrition,hypoxemia, and stress can alter both maternal andfetal concentrations of many hormones includinggrowth hormone (GH), insulin-like growth factors(IGFs), insulin, glucocorticoids, catecholamines, lep-tin, thyroid hormones, and placental hormones suchas the eicosanoids, sex steroids, and placental lacto-gen. Because some of these hormones cross the pla-centa, the fetal endocrine response to adverse condi-tions reflects the activity of both maternal and fetalendocrine glands and depends on the type, duration,severity, and gestational age at onset of the insult. Ingeneral, suboptimal intrauterine conditions loweranabolic hormone levels and increase catabolic hor-

mone concentrations in the fetus (13). Theseendocrine changes then affect fetal growth and devel-opment either directly or indirectly by altering thedelivery, uptake, and metabolic fate of nutrients in thefetoplacental tissues (13). Certainly, direct manipula-tion of glucocorticoid, androgen, and thyroid hor-mone levels in utero alters fetal development and haslong term consequences for cardiovascular, reproduc-tive, and metabolic function (17, 45).

Of the hormones known to regulate fetal develop-ment, it is the glucocorticoids that are most likely tohave widespread programming effects in utero (seeRefs. 8 and 48). They are growth inhibitory and affectdevelopment of all the tissues and organ systems thatare at increased risk of adult pathophysiology whenfetal growth is impaired (17). In rats, guinea pigs, andsheep, fetal overexposure to either endogenous orexogenous glucocorticoids leads to hypertension, glu-cose intolerance, and abnormalities in HPA functionafter birth (8, 36, 48). The specific postnatal effects ofthese treatments depend not only on the gestationalage at onset and the duration of exposure but also onthe sex of the offspring (8, 36). In addition, the pro-gramming effects of undernutrition can be preventedby abolishing maternal glucocorticoid synthesis byadrenalectomy or metyrapone treatment (30).Glucocorticoids can, therefore, program tissues inutero and may also mediate the programming effectsof nutritional and other environmental challengesduring pregnancy (15).

Critical Periods of IntrauterineProgramming

Environmental insults can cause programming atmany stages during development (FIGURE 2). Duringthe periconceptual and preimplantation periods,nutrient, O2, and hormone levels affect developmentof the oocyte and blastocyst, with consequences forthe distribution of cells between the trophoblast andinner cell mass. Exposure to excess progesterone andmetabolites, such as urea, specifically during theseperiods leads to enhanced birth weight in sheep andpigs (34). In addition, dietary restriction during thepericonceptional period has also been shown to short-en gestation and cause hypertension and abnormalHPA function in adult sheep (29). Developmentalchanges arising before implantation are likely to affectmany cell lineages, although adaptations later in ges-tation, such as upregulation of placental nutrient andO2 transport, may compensate for the early defectsand normalize birth weight. Once placentation hasbegun, the programming effects of environmental sig-nals may be mediated via changes in placental devel-opment (22). However, the extent to which earlyinsults program the placenta per se remains unknown.

During organogenesis, environmental insults maycause discrete structural defects that permanently

31PHYSIOLOGY • Volume 21 • February 2006 • www.physiologyonline.org

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reproductive function (40, 46, 55). Consequently,postnatal environmental changes, particularly beforeweaning, may ameliorate or exaggerate the morpho-logical and functional changes programmed in utero(46).

Mechanisms of IntrauterineProgramming

Intrauterine programming can occur at any level with-in the affected physiological system and may involvestructural and functional changes in genes, cells, tis-sues, and even whole organs (Table 2). These changesmay be isolated or widespread events with either dis-crete or cumulative effects on development dependingon the nature and timing of the programming stimulus(see Refs. 21 and 35).

Genes

The associations between birth weight and later risk ofdegenerative disease may be due to a direct geneticlink between intrauterine growth and disease suscep-tibility inherited at conception (57). In part, thisreflects the survival value of genes selected forreduced fetal growth yet rapid postnatal growth andfuel storage during evolution in populations subjectedto periodic undernutrition (6, 46). The observationthat mutations in the pancreatic glucokinase generesult in reduced fetal insulin secretion, lower birthweight, and adult glucose intolerance indicates thatfetal growth and disease susceptibility can be linkedthrough a single gene (26). However, these monogenicdisorders are rare and cannot explain the variation indisease risk across the normal birth weight range. Inpopulations like the Pima Indians who have a highincidence of type 2 diabetes, there is evidence for botha genetic and an intrauterine origin of the relationshipbetween birth weight and adult insulin resistance (18).The discordant disease risks in monozygotic twins ofdiscrepant birth weights compared with the concor-

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reduce the functional capacity of the organ. If theinsult occurs during gametogenesis, reproductivepotential of the next generation may be impaired (45).During the phase of rapid fetal growth, insults, whichalter the supply, uptake, and utilization of nutrients,will influence tissue growth and may switch the cellcycle from proliferation to differentiation with adverseconsequences for total cell number (17, 25). Becausedifferent fetal organs grow at different rates, the timingof the insult is important in determining the tissuespecificity of the programmed effects. In late gestation,there is a period of fetal maturation during whichmany tissues undergo structural and functionalchanges in preparation for extrauterine life (17). Theseprocesses are often glucocorticoid dependent and canbe activated prematurely by early glucocorticoid expo-sure. In addition, birth itself activates physiologicalsystems that have little or no function in utero but areessential for neonatal viability, such as ventilation,thermoregulation, gluconeogenesis, enteral nutrition,and appetite control (17). Changes in prepartum mat-uration in relation to the timing of delivery may, there-fore, have consequences for the set point and sensitiv-ity of key physiological systems during the perinatalperiod, which can then persist, revert, or amplify inlater life.

Although the sequence of developmental changes isbroadly similar in all mammalian species, there aredifferences in their precise timing between animals. Inaltricial species that are immature at birth (e.g.,rodents and rabbits), several of the physiological sys-tems known to be programmed in utero continue todevelop after birth (FIGURE 2). The period of devel-opmental plasticity, therefore, extends after birth inthese species in contrast to precocial species (e.g.,human, sheep, pig) that are more physiologicallymature at birth (17). Certainly, changes in nutrientavailability, hormone concentrations, and maternalbehavior during the immediate neonatal period in ratsalter their subsequent cognitive, neuroendocrine, and

REVIEWS

Prenatal period

Postnatal

period

Suckling

Weaning

Pre-implantation

Peri-conceptual

Organogenesis

Gestational age, %

0%

(conception)

50% 100%

(birth)

Weaning

Implantation and placental development

Birth

Prepartum maturation

Maximum fetal growthFIGURE 2. Critical periods of developmentat which intrauterine programming mayoccurComposite data are from rodents and humans.

33PHYSIOLOGY • Volume 21 • February 2006 • www.physiologyonline.org

REVIEWSTable 2. Consequences of suboptimal intrauterine conditions† on different organs at different levels in rats before and after birth

Endocrine Liver Skeletal Kidney Heart Blood *Pancreas Muscle Vessels

Genes �Ins2 �GLUT1 mRNA �PGC-1 in �c-ret ��1-adrenoceptor mRNA�O2.– generation

�Glucagon �PGC-1 mRNA different muscles ��AT1 and 2 �HIF-1� mRNA �Antioxidant �Genes for RNA/ �Redox pathways mRNA �Caspase 3 mRNA enzymes

DNA metabolism ��Fatty acid- �GR mRNA �Fas mRNA �eNOS�Igf2 mRNA metabolising �11�HSD2 �Antiapoptotic �sGC expression �Ribosomal S4 enzymes �p53 protein 14-3-3

mRNA �Genes related to oxidative stress

�Genes related to cell signalling, communication, defence, proliferation,and survival

Cells �Glucokinase �Glucokinase �GLUT4 protein �GR ��1-adrenoceptor �Ca-sensitive K �Insulin receptor �PKC-� protein �BSC1 and TSC ��2-adrenoceptor channel �PEPCK activity ��Insulin receptor Na transporters �Gs�:Gi� �Angiogenesis�Proliferation rate �Apoptosis �Ventricular eNOS �NOS activity�Glutathione �Teleomere �Cytochrome c �Tetrahydro-

reductase shortening �Fas protein levels biopterinabundance �Bcl-2 proteins pathways

�Glucagon receptor �HIF-1 protein �cGMP levels�HSP 70 protein�Apoptosis

Tissues ��-Cell number �Perivenous cell �Glycogen content �Branching of �Ventricular �Capillary density ��-Cell mass number �Primary/secondary ureteric bud hypertrophy in muscle�Islet proliferation �Periportal cell myofiber numbers Glomerular �Myocyte

number hypertrophy hypertrophy�IGFBP production and sclerosis �Binucleated ��Glycogen content �Renin and AII myocytes

content

Organ �Insulin content �ATP production �Skeletal muscle �Nephron number �Ejection fraction ��1 and ET1 �Vascularity �Glucose output mass �GFR, RBF �Cardiac output sensitivity �Insulin release Fewer, larger �Insulin sensitivity �Urinary PGE2 and �Coronary flow �NO-dependent

lobules �ATP production albumin excretion �Contractility dilatationAbnormal �Cardiac afterload ���1 sensitivity

glucogenic �Arrhythmia �Sensitivity to response to �Susceptibility to thromboxane hormones I/R injury A2 mimetic

and potassium �Responsesiveness

to �-adrenergicstimulation and sensitivity to adenylyl cyclase activation

System Glucose intolerance, Dyslipidemia, Insulin resistance

*Renal, cerebral, carotid, mesenteric, and other peripheral blood vessels. †Reduced maternal dietary intake, manipulation of maternaldietary composition, uteroplacental insufficiency, hypoxemia, and maternal anemia. AT, angiotensin II receptor; GR, glucocorticoidreceptor; 11�HSD2, hydroxysteroid dehydrogenase; AII, angiotensin II; GFR, glomerular filtration rate; RBF, renal blood flow; BSCI,bumetanide-sensitive Na+-K+-Cl– cotransporter; TSC, thiazide-sensitive Na+-Cl– cotransporter; HIF, hypoxia-inducible factor; FADD, Fas-associated death domain protein; HSP, heat shock protein; I/R, ischaemia/reperfusion; sGC, soluble guanalyate cyclase, NOS, nitricoxide synthase; PEPCK, phosphoenolpyruvate carboxykinase; GLUT glucose transporter; PGC-1, peroxisome proliferator-activatedreceptor-� coactivator-1; IGFBP, IGF binding protein; Igf2, insulin-like growth factor-2; Ins2, rat insulin gene. Data are from Refs. 1, 2, 8,12, 14, 15, 16, 20, 27, 30, 35, and 38.

Hypertension

ine artery ligation during late gestation causeshypomethylation of p53, a gene involved in apoptosis(41). When methyl donor availability is altered by alow-protein diet during pregnancy, the pattern ofhepatic DNA methylation is changed in both the fetusand adult offspring (32, 43). Addition of folate ormethyl donors, such as glycine and taurine, to the low-protein diet restores normal patterns of DNA methyla-tion and prevents the abnormalities in adult cardio-vascular function that are programmed by the unsup-plemented diet (2).

Environmental challenges may, therefore, causeprogramming by altering gene expression via severalmechanisms (Table 2). These include loss of imprint-ing, differential promoter usage, and up- or downreg-ulation of expression from the active allele(s) mediat-ed epigenetically or via transcription factors (53).Certainly, in several genes with multiple mRNA tran-scripts, the relative abundance of the different splicevariants is altered by undernutrition and glucocorti-coid exposure in a tissue-specific manner, with poten-tial consequences for protein translation in fetal tis-sues (14).

Cells

Changes in transcription induced by environmentalchallenges lead to altered protein synthesis and per-manent changes in cellular protein abundance (Table2). These proteins include receptors, ion channels,transporters, enzymes, growth factors, cytoarchitec-tural proteins, binding proteins, and components ofseveral intracellular signaling pathways (FIGURE 3).In particular, there are changes in the adenylyl cyclaseand insulin-signaling pathways in cells, such asadipocytes, hepatocytes, and myocytes, in response tonutrient and O2 deprivation, which persist after birthand influence adult metabolic activity (see Refs. 35and 40). Similarly, prenatal undernutrition and hypox-emia induce permanent changes in the abundance ofmembrane and nuclear receptors for several hor-mones including glucocorticoids, catecholamines,insulin, IGFs, GH, leptin, and prolactin (8, 15, 16, 35).Overall, these changes in protein synthesis alter cellmetabolism and growth and modify sensitivity to sub-sequent challenges.

Environmentally induced changes in cell physiolo-gy can occur at any point in development but are morelikely to have long-term consequences during the for-mation of cell lineages and when cells are differentiat-ing during late gestation in preparation for extrauter-ine life (FIGURE 2). In addition, when cells are grow-ing at their maximum rate, undernutrition and hypox-emia may reduce cell proliferation directly by limitingsubstrate availability for tissue accretion and energygeneration. Indeed, restriction of uterine blood flownear term is known to reduce DNA synthesis in fetalcells with a high proliferation rate in utero (3).Suboptimal intrauterine conditions may, therefore,

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dant risks when birth weight is similar also shows thatdifferent adult phenotypes can develop from the samegenotype when intrauterine growth is compromised(42). However, different specific polymorphisms ofgenes involved in growth and metabolism, such Igf1,PPAR�, and the VNTR region of the insulin gene, mayalter susceptibility to environmental signals andaccount for some of the genetic variation inherent inintrauterine programming (see Ref. 38).

During development, DNA can be modified epige-netically to alter gene expression without a change inDNA sequence (see Ref. 52). In mammals, these mod-ifications occur primarily by DNA methylation and/orposttranslational alterations to the histones packagingthe chromatin. In turn, these conformational changesalter the interaction between DNA and its regulatoryproteins at the promoters, with effects on gene activa-tion and repression (53). DNA methylation is particu-larly important in genomic imprinting, the process bywhich one allele of a gene is silenced in a parent-of-origin manner (10). Imprinting has a major role inearly mammalian development, and many of the 80known imprinted genes are involved in controllingplacental and/or fetal growth (10, 44). Epigenetics,therefore, provides a molecular mechanism for pro-gramming that links genes, the prenatal environment,intrauterine growth, and subsequent susceptibility todisease.

There are two main periods of epigenetic modifica-tion: gametogenesis and early embryogenesis (52).These are the times of widespread demethylation andresetting of the epigenetic marks by de novo methyla-tion. They are, therefore, particularly vulnerable tochanges in the availability of methyl donors and cofac-tors essential for one-carbon metabolism, such asfolate and glutathione (see Ref. 53). Once established,the epigenetic marks are stable mitotically and createunique, lineage-specific patterns of gene expressionand/or silencing. Epigenetic modifications can alsooccur later in development, as changes in DNA methy-lation and imprint status have been observed duringthe perinatal period in several species (10, 53). Forexample, in ovine and human liver Igf2 imprintingswitches from monoallelic expression in the fetus tobiallelic expression in the adult, whereas in rodentsIgf2 is completely silenced in all somatic tissues atweaning (see Ref. 14).

Both nutritional and endocrine factors have beenshown to influence the epigenotype (54).Glucocorticoid administration causes DNA demethy-lation associated with increased gene expression of ahepatic aminotransferase in rats during the perinatalperiod (51). In cultured preimplantation sheep andmouse embryos, the amino acid composition of theculture medium alters the methylation state of keyimprinted genes and changes intrauterine growthafter embryo transfer (57). Similarly, in neonatal ratkidney, uteroplacental insufficiency induced by uter-

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induce changes in the function, number, and size ofcells by altering proliferation, clonal selection, andapoptotic remodeling of cell populations.

Tissues and organs

The changes in cell structure and function, in turn,alter the morphology and physiology of tissues andorgans as a whole (Table 2). If the insult occurs at thetime of organogenesis, the changes may be severe andlead to a permanent developmental deficit. Forinstance, glucocorticoid administration to pregnantewes for 2 days when the mesonephric kidney is devel-oping at the end of the first month of gestation causesa permanent reduction in nephron number and leadsto hypertension in the adult offspring (38). More sub-tle changes in cell composition of tissues, induced bysuboptimal conditions in utero, can also influencepostnatal physiological function. For example, thereare changes in the relative proportions of different celltypes in the pancreatic islets, liver, and skeletal mus-cles after IUGR that are associated with adult insulinresistance, glucose intolerance, and hypertension (seeRefs. 27, 35, and 40). In organs like the placenta, earlychanges in development at the gene (imprinting), cell(transporter abundance), and tissue (vascularity) lev-els may impair fetal nutrient and O2 delivery through-

out gestation with implications for tissue program-ming long after the original insult (see Refs. 22 and 44).

Systems

The postnatal physiological abnormalities observedafter suboptimal intrauterine conditions are multifac-torial and involve several organs and endocrine sys-tems (FIGURE 1 and Table 2). The severity of outcomeis, therefore, determined by the number of organs andsystems adversely affected by the intrauterine insult,which, in turn, depends on the nature and duration ofthe insult in relation to the stage of development (4,21). In sheep, for instance, maternal glucocorticoidtreatment early in gestation leads to hypertension butnot glucose intolerance, whereas treatment late in ges-tation has the opposite effects in the adult offspring(see Refs. 15 and 38). In some systems, a specific trig-ger, or a second challenge, is required postnatally tounmask the intrauterine programming. In pancreaticislets, the abnormalities in insulin secretion inducedby mild prenatal undernutrition only become evidentin the adult when the demand for insulin rises duringpregnancy (27). Similarly, in the heart, an ischemicchallenge in adulthood is required to expose theunderlying abnormalities in development induced byprenatal hypoxia or cocaine exposure (31). In several

35PHYSIOLOGY • Volume 21 • February 2006 • www.physiologyonline.org

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Hormone receptors

1

Hormone receptors

1

Enzyme activities (de novo synthesis, phosphorylation through intracellular signaling pathways and/or ion channels)

6

Nucleus

RNA

DNA

Cell

membrane

Heat

Transporters for nutrients (e.g., glucose, amino acids) and minerals

4Ion channels

3

Mitochondrial oxidative phosphorylation and thermogenic activity

7

ATP

Protein synthesis

5

Intracellular signalling pathways

2

Mitochondrion

FIGURE 3. Cellular processes that may be programmed by intrauterine manipulation of the nutrition-al or hormonal environment1) Hormone receptors. 2) Intracellular signaling pathways. 3) Ion channels. 4) Transporters for nutrients (e.g., glucoseor amino acids) or minerals. 5) Protein synthesis. 6) Enzyme activities by de novo synthesis or phosphorylation throughintracellular signaling pathways and/or ion channels. 7) Mitochondrial oxidative phosphorylation and thermogenicactivity.

utero can be transmitted from one generation to thenext by either the mother or father (12, 46). This trans-generational inheritance of programming may be dueto changes in the primordial germ cells from which thenext generation develops or to recapitulation of themetabolic and endocrine conditions that the motherexperienced as a fetus in utero due to the programmedadaptations in her physiology (1, 28). Alternatively, itmay reflect meiotic inheritance of the epigeneticmarks as a result of aberrant demethylation (52, 57).Incomplete erasure of the epigenetic marks may leadto an inheritable “memory” of epigenetic state at spe-cific alleles.

Because nutrition has improved progressively inmost developed and developing countries over thepast 50 years, many people will have developed a phe-notype in utero that is programmed for a significantlylower level of nutrition than currently available. Thismay explain, in part, the epidemic of hypertension,obesity, and type 2 diabetes in populations worldwide.As food intake, lifestyle, and dietary advice duringpregnancy change in response to these trends, thephysiological adaptations now being programmed inutero by Western high-fat/high-calorie diets may leadto adult phenotypes no better suited to the prevailingenvironmental conditions in the next generation thanthose programmed by poor nutrition a generation ago.However, improved knowledge of the pathophysiologyinduced by transgenerational oscillations in dietaryintake and other environmental factors may enablethe development of nutritional and other interven-tions to ensure that intrauterine programming is ben-eficial and not detrimental to adult health. �

References1. Aerts L and Van Assche FA. Intra-uterine transmission of dis-

ease. Placenta 23: 1–7, 2003.

2. Armitage JA, Khan IY, Taylor PD, Nathaniels PW, and PostonL. Developmental programming of the metabolic syndromeby maternal nutritional imbalance: how strong is the evidencefrom experimental models in mammals? J Physiol 561:355–377, 2004.

3. Asano H, Han VK, Homa J, and Richardson BS. Tissue DNAsynthesis in the pre-term ovine fetus following 8 h of sus-tained hypoxemia. J Soc Gynecol Investig 4: 236–240, 1997.

4. Barker DJP. Mothers, babies and disease in later life. London:BMJ Publishing Group, 1994

5. Barker DJP. The malnourished baby and infant. Br Med Bull60: 69–88, 2001.

6. Bateson P, Barker B, Clutton-Brock T, Deb D, D’Udie B, FoleyRA, Gluckman P, Godfrey K, Kirkwood T, Lahr MM,McNamara J, Metcalfe NB, Monaghan P, Spencer HG, andSultan SE. Developmental plasticity and adult health. Nature430: 419–421, 2004.

7. Bertram CE and Hanson MA. Annual models and program-ming of metabolic syndrome. Br Med Bull 60: 103–121, 2001.

8. Bertram CE and Hanson MA. Prenatal programming of post-natal endocrine response by glucocorticoid. Reproduction124: 459–467, 2002.

9. Chang JHT, Rutledge JC, Stoops D, and Abbe R. Hypobarichypoxia-induced growth retardation. Biol Neonate 46: 10–13,1984.

10. Constancia M, Kelsey G, and Reik W. Resourceful imprinting.Nature 432: 53–57, 2004.

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physiological systems, sex-linked differences inintrauterine programming do not appear until puber-ty when the onset of gonadal steroidogenesis uncoversphysiological abnormalities in peripheral tissues or inthe hypothalamic-pituitary-gonadal axis itself (36, 45).However, in the majority of physiological systemsstudied, the adverse consequences of intrauterinecompromise become more evident with increasingage as compensatory adaptations in other tissues andorgan systems fail (35).

Consequences of IntrauterineProgramming

The consequences of intrauterine programmingdepend on whether the developmental deficit is theinadvertent outcome of an insult acting as mutagen ora specific adaptation to an environmental challengedesigned to maximize survival to reproductive age(20). With mutagenesis, the structural and functionaldeficits are permanent and invariably detrimental tolong-term survival. In contrast, the physiologicaladaptations made in response to suboptimalintrauterine conditions may improve viability in theshort to medium term but at the risk of later morbidi-ty (24). The adaptations in functional capacity pro-grammed in utero may, therefore, be a trade-off tomaintain development of essential tissues, such as thebrain and placenta, and/or a mechanism for setting anappropriate phenotype for the environmental condi-tions ex utero (6, 35). When the functional capacity setin utero does not match that required postnatally,homeostasis may be compromised and lead to abnor-mal physiological parameters, which, eventually,result in overt disease. For example, the enhancedsensitivity of the HPA axis programmed by suboptimalconditions in utero is essential for survival in poorconditions but is inappropriate when nutrients and O2

are plentiful and may cause hypertension and meta-bolic disorders in the adult (see Ref. 16). Similarly,intrauterine programming of a thrifty phenotype byprenatal undernutrition will lead to increased growthand fat deposition if postnatal nutrient availability isbetter than predicted in utero (23, 40, 50). In turn, theincreased adiposity will lead to adult insulin resist-ance, glucose intolerance, and finally type 2 diabetes,particularly as the counterregulatory mechanismsdeteriorate with age (23). Certainly in humans, the riskof developing adult type 2 diabetes is greatest whenpoor prenatal growth is coupled with catch-up growthand adiposity rebound during childhood (21). Indeed,the accelerated growth often observed after IUGR maybe more important than the intrauterine changes perse in programming adult-onset degenerative diseases(49).

Intrauterine programming also has consequencesfor the next generation. The physiological perturba-tions programmed by environmental challenges in

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37PHYSIOLOGY • Volume 21 • February 2006 • www.physiologyonline.org