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DEVELOPMENTAL (FETAL) ORIGINS OF ADULT DISEASES

(DOHaD)

MAJID MOHAMMADIZADEH MD ISFAHAN UNIVERSITY OF MEDICAL SCIENCES

DEPARTMENT OF PEDIATRICS DIVISION OF NEONATOLOGY

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• Chronic diseases are the greatest public health problem, because of:– direct cost to society and government– disability lasting for years

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

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• 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 trends

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CONCEPT OF DOHaD

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• The 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 famine

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• These 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"

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• The 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

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• IUGR 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

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• The 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 illness

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Public health implications of DOHaD

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• DOHaD 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"

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• This 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

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Return to:

CONCEPT OF DOHaD

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• Malnutrition during gestation that include macronutrients or micronutrients can potentially set the stage for adult-onset chronic diseases

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Thrifty phenotype

• Adaptive 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

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• The 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 years

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• The 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 adulthood

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• Optimal 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

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• Programming 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

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• Developmental 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

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Prenatal and postnatal factors contributing to the development of diabetes mellitus

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

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

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

generations

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An overview of the developmental origins of adult health and disease

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• Although 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

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• 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 etiologies

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Form 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

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Factors that adversely affect the gestational and early postnata l

environment

• Maternal diseases and their treatments:• Psychiatric neurologic disorders• Diabetes• Asthma• Sleep related breathing disorders• Anemia

• Maternal lifestyle and environment:• Maternal behavior, interpersonal stress and psychosocial

trauma• Smoking in pregnancy• Home• Environmental pollutions• Maternal nutrition and micronutrients

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Factors that adversely affect the gestational and early postnata l

environment

• Perhaps 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 hyperinsulinism

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• Many 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 teratogenesis

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The 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 factors

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POSTNATAL AND EARLY CHILDHOOD

GROWTH

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• Findings 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 mellitus

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• These 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 presentations

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SGA infants

• Metabolic and endocrine changes in infants who are SGA include:

• reduced insulin sensitivity, lipid profile aberrations, metabolic syndrome, premature adrenarche, and polycystic ovarian syndrome

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SGA infants

• Most 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 ß-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 adult

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Premature infants

• Premature 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 life

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• After 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 children

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• This 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

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CATCH- UP GROWTH

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Definition

• It is a normal tendency by the body to compensate after a nutritionally restricted period, showing rapid growth

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Consequences

• Short-term benefits:

• Survival

• protecting the reproductive capacity

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Consequences

• It tends to favor:

– nutrient deposition in white adipose tissue resulting in adiposity, particularly visceral adiposity

– a rearrangement of skeletal muscle mitochondria– increased 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

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Consequences

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

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• Rapid postnatal growth, whether superimposed on LBW or normal birthweight, seems to have a similar effect in producing adult chronic diseases

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Should postnatal catch-up growth not be fostered?

If postnatal nutrition matches intrauterine nutrition,can adult chronic diseases be curbed and result in longevity?

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• The 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 brain

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LGA infants

• In 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 work

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LGA infants

• Further 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 cancer

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MISMATCH CONCEPT

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• The 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

• both

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

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• Such 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

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• Most 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 course

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• The concept of catch-up growth should be reevaluated to determine what is optimal for every subset of the population

• At both ends of the spectrum—infants who are LGA and infants with IUGR, who are SGA, or who are premature—there is a period of deprivation followed by exposure to excess

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• As 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 diseases

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PATHOPHYSIOLOGY

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• To 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 LBW

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• The 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

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• This 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

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

• This phenomenon exemplifies the gene-environment interaction

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

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Chronic Diseases Attributed to Developmental Origins

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• All 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 mechanisms

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CANCER

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• The 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 origins

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Some of the main factors in breast cancer development

• Estrogen: high levels in pregnancy

– Higher levels in:• Advanced maternal age• twin gestations• LGA status

• Higher birthweight, birth length, and placental weight

• Rapid childhood growth in combination with a higher birthweight

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• Similar associations have been noted with respect to ovarian cancer

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PSYCHOSOCIAL ASPECTS

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Examples

• Anxiety and depression

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

• Bipolar and schizophrenic disorders

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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 raised

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• 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 role

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• Fast 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 origin

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• There 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

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• Although a developmental structural basis may contribute to subsequent psychoses, other functional perturbations also play a role

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TOXINS, ENDOCRINE DISRUPTERS,AND MICRONUTRIENT

METABOLISM

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• Certain 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 exposed

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• 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

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• In certain cases, micronutrients that play the role of methyl donors have been protective against adult-onset diseases if introduced at the right time

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TRANSGENERATIONAL PERSISTENCE

OF PHENOTYPIC CHANGES

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• Exposure 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 changes

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• A 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

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

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• The 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

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• Maternal 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 adulthood

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EPIGENETICS

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• Epigenetics 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 presentation

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• The main epigenetic mediators are histon modification DNA methylation, and non-coding RNAs