Transcript دكتر محمدي۱

1
DEVELOPMENTAL (FETAL) ORIGINS
OF ADULT DISEASES
(DOHaD)
MAJID MOHAMMADIZADEH MD
ISFAHAN UNIVERSITY OF MEDICAL SCIENCES
DEPARTMENT OF PEDIATRICS
DIVISION OF NEONATOLOGY
2
• 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.
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
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
10
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
16
• 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
18
• 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
19
• 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
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 etiologies
28
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:
•
•
•
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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
35
• 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
36
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
38
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-hormonalimmune response, which alters insulin secretion and
signaling pathway, the IGF system, cytokines, other
hormonal and receptor pathways, and the hypothalamicpituitary-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
73
•
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
75
• 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
79
•
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
80
• In certain cases, micronutrients that play the role of
methyl donors have been protective against adultonset 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
83
• 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
84
• 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 insulinsensitive 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
89
• The main epigenetic mediators are histon
modification DNA methylation, and non-coding
RNAs
90