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1DEVELOPMENTAL (FETAL) ORIGINS OF ADULT DISEASES (DOHaD)MAJID MOHAMMADIZADEH MD ISFAHAN UNIVERSITY OF MEDICAL SCIENCES DEPARTMENT OF PEDIATRICS DIVISION OF NEONATOLOGY 2Chronic diseases are the greatest public health problem, because of: direct cost to society and governmentdisability lasting for years

They include cardiovascular diseases, diabetes, cancer, osteoporosis, obesity, etc.

3 The burden of chronic diseases is rapidly increasing worldwide

Almost half of the total chronic disease deaths are attributable to cardiovascular diseases

Obesity and diabetes are also showing worrying trends4CONCEPT OF DOHaD5The concept of fetal origins of adult disease popularized by Barker arose from a robust association between small size at birth and the risk of chronic adult diseases, such as coronary artery disease, hypertension, stroke, type 2 diabetes mellitus, and osteoporosis

Example: 1944-1945 Dutch famine6These original epidemiologic observations have been extensively replicated by multiple groups in varying populations of different ethnicity employing birthweight as a surrogate for the intrauterine state

The culmination of all these epidemiologic associations is referred to as the "Barker hypothesis"

7The concept of the "developmental programming" and DOHaD has become well accepted because of the compelling animal studies that have precisely defined the outcomes of specific exposures

8IUGR has been widely used as a marker of poor fetal nutrition and health, but some antenatal nutritional disturbances can increase the risk of diseases later in life without affecting fetal growth

At the other extreme of weight, an infant of a diabetic mother who is LGA develops obesity and type 2 diabetes during late childhood

9The health of the child and issues that will determine its appetite and metabolism, intelligence and temperament in life depend on:

the type and amount of nutrients that the baby receives in the womb

pollution, drugs and infections which it is exposed to before and after birth

the mental and physical health of the mother and her levels of stress and mental illness10Public health implications of DOHaD11DOHaD are now recognized to have major public health implications worldwide

WHO states: "The global burden of death, disability and loss of human capital as a result of impaired fetal development is huge and affects both developed and developing countries"12This statement advocates for a broader concept of maternal well-being and achieving an optimal environment for the fetus (and newborn) to maximize the potential for a full and healthy life

This concept has widened to include plasticity during childhood

13Return to:

CONCEPT OF DOHaD14Malnutrition during gestation that include macronutrients or micronutrients can potentially set the stage for adult-onset chronic diseases15Thrifty phenotypeAdaptive mechanisms combat an adverse nutritional or metabolic intrauterine environment by developing safeguards for the energy supply sometimes at the expense of growth, ensuring a reduced fetal demand

Additional nutritional or metabolic stressors encountered subsequently tip the finely crafted phenotypic balance toward a disease state

16The conventional belief is that these phenotypic features are expressed mainly in aging adults

Given lifestyle changes toward an increased caloric intake and relative inactivity, some of these features are seen in childhood or during late teenage years17The molecular, cellular, metabolic, endocrine and physiological adaptations to intrauterine nutritional conditions result in permanent alterations of cellular proliferation and differentiation of tissues and organ systems, which in turn can manifest by pathological consequences or increased vulnerability to chronic diseases in adulthood18Optimal fetal growth is essential for perinatal survival and has long-term consequences extending into adulthood

In conditions of severe intrauterine deprivation, there is a capacity to lose structural units such as nephrons, cardiomyocytes, or pancreatic beta-cells within developing organ systems

These responses will result in the programming of a reduced functional capacity for life

19Programming is defined as a permanent or long term change in the physiology, morphology, or metabolism of a fetus in response to a specific insult or stimulus at a critical period in development

Any programming of an organism or tissue may be regarded as the consequence of an adaptation that is necessary to survive an insult 20Developmental epigenetics is believed to establish adaptive phenotypes to meet the demands of the later-life environment

Resulting phenotypes that match predicted later-life demands will promote health, while a high degree of mismatch will impede adaptability to later-life challenges and elevate disease risk

21Prenatal and postnatal factors contributing to the development of diabetes mellitus

22Sleep disorders during pregnancy influence the risk of insulin resistance and impaired glucose tolerance

23A summary of the current mechanisms considered to underlie the developmental origins of adult disease

24Potential consequences of environment-epigenetic interactions for the health of the next and subsequent generations

25An overview of the developmental origins of adult health and disease

26Although fetal growth and birthweight have served as surrogate markers of fetal nutrition and health, these are two distinct processes

Birthweight at both ends of the spectrum is associated with adult chronic diseases, but it is only a presenting feature

The relationship between prenatal nutritional status and metabolic diseases is shaped like a U as the risk increases at both ends of the birth weight curve i.e. in conditions of poor nutrition and excessive dietary intake

27 It is clear that fetuses subjected to nutritional perturbations with no resultant change in size or growth also develop adult chronic diseases

Examples: isolated glucose deficiency, certain essential amino acid deficiencies, and micronutrient deficiencies

On the other hand, growth can suffer in the presence of adequate nutrition because of multifactorial etiologies28Form of compromises to the fetus which can set the stage for the subsequent onset of chronic diseases:Malnutrition

Reduced blood flow

Hypoxia

Other stressors such as drug exposure, toxins, infections, and inflammation which has the propensity of perturbing the fetal hormonal-metabolic milieu

29Factors that adversely affect the gestational and early postnata l environmentMaternal diseases and their treatments:Psychiatric neurologic disordersDiabetes Asthma Sleep related breathing disordersAnemia

Maternal lifestyle and environment:Maternal behavior, interpersonal stress and psychosocial traumaSmoking in pregnancyHomeEnvironmental pollutionsMaternal nutrition and micronutrients30Factors that adversely affect the gestational and early postnata l environmentPerhaps less well appreciated is that some environmental agents like gamma irradiation and thalidomide also can cause functional disorders that persist postnatally and into adult life

This seems to be true also for hormones that when present in non-physiological concentrations during critical periods of perinatal life can act as endogenous functional teratogens

Example: perinatal hyperinsulinism31Many human teratogens elicit their deleterious effects through mechanisms involving the generation of reactive oxygen species and oxidative stress

Since many antioxidant regulation enzymes are not well expressed early in organogenesis, it may explain why embryos, in earlier periods of development, are more susceptible to teratogen-induced dysmorphogenesis and functional teratogenesis32The origin of chronic diseases is considered to be related to four relevant factors in fetal life:Intrauterine growth retardation (IUGR)

Premature delivery of a normal growth for gestational age fetus

Overnutrition in utero

Intergenerational factors33POSTNATAL AND EARLY CHILDHOODGROWTH34Findings such those during the Leningrad Siege suggest that postnatal manipulation of nutrition may have a protective effect on the trajectory of fetal origins of adult disease

More recent investigations have revealed that in girls and boys, low BW with a slow growth pattern between 0 and 2 years followed by exponential growth between 2 and 8 years led to increased mortality secondary to cardiovascular events, and an increase in glucose intolerance and type 2 diabetes mellitus35These findings are of particular interest to neonatology:

There is an ongoing dilemma as to: what is ideal postnatal growth

whether this growth rate should be the same for infants of varying birthweight ranges and differing presentations36SGA infantsMetabolic and endocrine changes in infants who are SGA include:

reduced insulin sensitivity, lipid profile aberrations, metabolic syndrome, premature adrenarche, and polycystic ovarian syndrome37SGA infantsMost of the phenotypic changes seem to be due to insulin resistance, although the site of insulin resistance seems to be an imbalance between hepatic insulin resistance and pancreatic -islet cell production of insulin

The reduction of insulin sensitivity is magnified with fat mass deposition and a faster "catch-up" growth pattern, which is associated with disease attributable to insulin resistance

This early growth during childhood that is sustained through adolescence predetermines who goes on to develop type 2 diabetes mellitus as an adult38Premature infantsPremature infants, particularly those with VLBW, although distinctly different in presentation at birth, tend to mimic infants with IUGR in the final phenotype

This similarity may be related to the nutritional compromise and stressors (that invoke endogenous glucocorticoid surges and intermittent exposure to hypoxia) encountered during the early postnatal phase of life39After the early postnatal period when complete oral feedings are established, a significant catch-up growth phenomenon is realized in most infants with increasing caloric provision

Long term follow-up investigations of infants with VLBW reveal a higher systolic blood pressure, central adiposity by 19 years of age, and emergence of premature pubarche in 24% of these children40This presentation in infants with VLBW is reminiscent of what was encountered in infants with IUGR who faced an adverse in utero environment

In both cases, the postnatal catch-up growth leads to disease presentations secondary to insulin resistance

41CATCH- UP GROWTH42DefinitionIt is a normal tendency by the body to compensate after a nutritionally restricted period, showing rapid growth43ConsequencesShort-term benefits:

Survival

protecting the reproductive capacity

44ConsequencesIt tends to favor:

nutrient deposition in white adipose tissue resulting in adiposity, particularly visceral adipositya rearrangement of skeletal muscle mitochondriaincreased oxidative injury

These changes set the stage for metabolic syndrome, diabetes mellitus, and coronary artery disease as the child matures into an adult

This catch-up growth results in a shortened life span with changes in the telomeric length

45ConsequencesFor "short-term gain ", catch-up growth results in "long-term pain"

46Rapid postnatal growth, whether superimposed on LBW or normal birthweight, seems to have a similar effect in producing adult chronic diseases47Should postnatal catch-up growth not be fostered? If postnatal nutrition matches intrauterine nutrition,can adult chronic diseases be curbed and result in longevity?48The absence of catch-up growth, while resulting in glucose tolerance, lean body composition, and reduced coronary artery disease with longevity, may negatively affect cognition and reproductive capacity

Avoidance of rapid postnatal catch-up growth within a short period may be beneficial if replaced with moderate long-term growth

Postnatal nutrition results in walking a fine line between guarding against "nutritional excess" while ensuring adequate energy for the developing brain49LGA infantsIn infants who are LGA, postnatal intervention consisting of breast feeding versus bottle feeding led to a decline in obesity during childhood

This intervention represents a "catch-down" mechanism at work50At the other end of the spectrum, infants born with aheavier birthweight, resulting from either maternal diabetes orobesity, are also prone to adult chronic diseases. These infantsare obese during childhood and develop insulin resistancewith the associated phenotypic presentations50LGA infantsFurther postnatal escalated growth leads to earlier acquisition of adult chronic diseases and the associated complications

The weight status in the first 6 months of life predicts obesity at 3 years of age

Infants who are LGA also express elevated IGF concentrations predisposing them to dysregulated cell proliferation and the subsequent development of cancer51MISMATCH CONCEPT52The degree of mismatch can be increased by:

deprived environmental conditions during a critical phase of development (prenatal or postnatal): compromised maternal health, nutrition, toxins, stressors, infections, and inflammation

an excess later: energy-dense foods and television watching with reduced physical activity

both53Epigenetic mechanisms and the mismatch concept of the developmental origins of health and disease

54Such a phenomenon has considerable significance:

to developing societies that are undergoing rapid socioeconomic transitions

to immigrant families in Western countries that came from developing countries

55Most important to NICUs are the neonatal health concerns of nutrition, toxins, stressors, hypoxia, infections, and inflammation during the early phase of life that can have similar effects on the life course of a particular individual

Thought should be exercised before introducing interventions during this period of development that have the potential of altering the life course56The concept of catch-up growth should be reevaluated to determine what is optimal for every subset of the population

At both ends of the spectruminfants who are LGA and infants with IUGR, who are SGA, or who are prematurethere is a period of deprivation followed by exposure to excess57In the case of theformer, this deprivation usually occurs during the first trimesterwith rapid catch-up growth observed during the thirdtrimester resulting in an infant who is LGA, whereas in thelatter category, the deprivation is generally in the third trimesterwith rapid catch-up growth postnatally, as in infantswith IUGR and some infants who are SGA. In prematureinfants who have VLBW, the deprivation is in early postnatallife followed by catch-up growth during the postneonatalstage of development

57As mentioned earlier, situations of deprivation or exposure to stressors can occur in the absence of any effect on the growth potential or size, making it difficult sometimes to understand the mismatch concept and its role in the growing incidence of chronic adult diseases58PATHOPHYSIOLOGY59To determine the pathophysiology behind the link of events that spread over a whole lifetime, multiple animal models have been developed including:

acute interruption of uteroplacental-fetal blood flow

global or selective nutrient restriction

prenatal introduction of key hormones such as glucocorticoids or sex steroids

with the end result being LBW60The critical window of development that offers some plasticity (or pluripotency) may vary from organ to organ with differing effects, depending on when the insult occurs and the stage of development for a particular organ

An adverse environment causes an adaptation during this critical window to match the in utero demand to available energy supply 61Investigations have revealed that altered cell proliferationin pancreatic 13-islet cells underlies the burnout ofthese cells, which, along with peripheral tissue adaptations,results in glucose intolerance and diabetes mellitus inadults who had IUGR. 71,89,9 This metabolic change causesdyslipidemia, hepatic cholestasis, and hepatic dysfunction. 28Changes in myocardial function and vasculareactivityinduce changes in blood pressure. 97 Structural aberrationsin the kidney related to a smaller size and a reduced numberof nephrons also contribute toward hypertension and renaldysfunction that develops with aging. 108 Hypertension,myocardial dysfunction, and dyslipidemia set the stage forcoronary artery disease and stroke

61This adaptive process consists of alterations in chromatin, gene expression, and cell cycle, all altering the cellular size or shape contributing to the ultimate phenotype

A compilation of studies has shown aberrations in most organs, including muscle, heart, liver, fat, bone, kidneys, vasculature, lungs, endocrine system, and brain

In addition, there is a perturbed metabolic-hormonal-immune response, which alters insulin secretion and signaling pathway, the IGF system, cytokines, other hormonal and receptor pathways, and the hypothalamic-pituitary-adrenal axis

62These aberrations lend themselves to maladaptation when the adverse environment no longer exists

This phenomenon exemplifies the gene-environment interaction

63A diagrammatic summary of how decreased nephrogenesis in early life may result in adult hypertension

64Chronic Diseases Attributed to Developmental Origins

65All the presenting features related to cellular structure and function, both secondary to altered nutritional or hormonal/metabolic milieu during critical developmental phases of life

Sex-dependent changes in phenotype are observed related to the influence of sex steroids on many of these pathophysiologic mechanisms66CANCER67The incidence of breast cancer is increased in American and European women compared with Asian women

After a couple of generations, the incidence of daughters of Asian immigrants approaches the incidence of women in their adopted Western country

Genetics and environmental triggers cannot completely explain the pathogenesis of cancer

An array of epidemiologic data has accumulated that supports the hypothesis that cancer has in utero origins68Some of the main factors in breast cancer developmentEstrogen: high levels in pregnancy

Higher levels in:Advanced maternal age twin gestationsLGA status

Higher birthweight, birth length, and placental weight

Rapid childhood growth in combination with a higher birthweight

69Similar associations have been noted with respect to ovarian cancer70PSYCHOSOCIAL ASPECTS71Examples Anxiety and depression

Academic performance, professional attainment, sexuality and reproduction, emotionality, personality, and overall quality of life

Bipolar and schizophrenic disorders72

When examining social consequences of preterm birth, the question of why decreasing gestational age is a risk factor for a less successful adult life is raised73 The fetal programming model provides an explanation:

Adults who were SGA or were VLBW have remodeling of their hormones and metabolism in early neonatal life from heightened stress responses

Malnutrition during a critical time in prenatal and postnatal development may also play a vital etiologic role74Fast postnatal growth superimposed on restricted prenatal growth was also shown to influence the development of the trait anxiety in men and women at 63 years of age

This pattern resembled the pattern seen with the development of cardiovascular events, supporting a shared common developmental origin75There is a growing body of evidence supporting an infectious etiology for the subsequent development of schizophrenia and related psychoses

Particularly, fetal or childhood infections with Toxoplasma gondii or cytomegalovirus have been associated with psychoses during adult life

76Although a developmental structural basis may contribute to subsequent psychoses, other functional perturbations also play a role77TOXINS, ENDOCRINE DISRUPTERS,AND MICRONUTRIENT METABOLISM78Certain endocrine disrupters, such as estrogens, antiandrogenic compounds, and specific environmental toxin exposures (plasticizers in bottles), have been observed to have far-reaching effects on the phenotype of animals studied

These changes persist into the third generation, particularly in male offspring, when a pregnant animal is exposed79 The fetus (second generation) and the gametes of the fetus (which give rise to the third generation) face the same exposure

In the case of the female, the gametes develop postnatally, and any insult during this period can have similar consequences into subsequent generations

80In certain cases, micronutrients that play the role of methyl donors have been protective against adult-onset diseases if introduced at the right time81TRANSGENERATIONAL PERSISTENCEOF PHENOTYPIC CHANGES82Exposure of mother to diethylstilbestrol, phytoestrogens, or androgens sets the next generation and the following for a change in phenotype consisting of an increased incidence of cancers or the development of polycystic ovary syndrome

Introduction of micronutrients that serve as methyl donors, such as folic acid, methionine, or betaine, was observed to reverse the transgenerational phenotypic changes83A woman who has given birth to an infant with a neural tube defect is given a higher dose of folic acid during her next pregnancy to reduce the incidence of neural tube defect

84Maternal undernutrition and overnutrition seem to cause similar effects on the offspring, resulting in a perpetuation of severity from generation to generation

85The adult who had IUGR survives the adverse intrauterine environment, but becomes maladaptive, developing type 2 diabetes mellitus as an aging adult

This phenotype is evident particularly in males, whereas females adapt toward a more insulin-sensitive phenotype

When a woman who had IUGR becomes pregnant, glucose intolerance emerges, however, manifesting as gestational diabetes

86Maternal hypercholesterolemia is known to cause hypoaminoacidemia and IUGR

Offspring exposed to maternal hypercholesterolemia in utero express normal cholesterol values, but develop an increased incidence of atherosclerosis in adulthood87EPIGENETICS88Epigenetics consists of covalent changes of the genome that do not alter the DNA sequence, but are inherited through mitosis and meiosis

Epigenetics is essential for gene expression and the cell cycle, and forms the important link between environment and genome

The genome manipulates the ultimate phenotypic presentation89The main epigenetic mediators are histon modification DNA methylation, and non-coding RNAs90