Transcript Fetal Origins of Adult Disease Asymmetric Growth Restriction From

Intergenerational Nutritional Effects
&
Developmental Origins of Health
and Disease
2011
Intergenerational Effects
• Cohort studies
– Maternal birthweight and fetal grown
– Dutch famine studies
• Experimental Study
– Supplementation in Guatemala
Godfrey KM, Barker DJP, Robinson S, Osmond C. Mother's birthweight and
diet in pregnancy in relation to the baby's thinness at birth. Br J Obstet
Gynaecol 1997;104:663–7
Illinois Study
Coutinho et al. Am J Epi, 1997 146:804-809
• N=15,287 Black and
117,708 white matched
pairs of infants and
mothers.
• Mothers were born
between 1956-75,
infants between 19891991
Mean infant
birthweight
Mean parental
birthweight
% low birthweight
infants
% lbw born to
women with lbw
% lbw born to
women not lbw
Black
White
3139 g
3434
3133
3377
12%
5%
18%
9%
11%
5%
Results
• Father’s birthweight had effect on infant
birthweight but not as strong as mothers.
• Each 100 g increase in maternal
birthweight was associated with 24-27 g
increase in infant birthweight
FIGURE 3 Mean offspring birth weight (g) for categories of paternal birth weight in selected
strata of maternal birth weight
Bouchard, C. Am J Clin Nutr 2009;89:1494S-1501S
Copyright ©2009 The American Society for Nutrition
Dutch Famine Studies
Susser and Stein, Nutrition Reviews, 1994
• Dutch famine winter lasted 6 months, from
November 1944- when nazis imposed
transport embargo on west Holland until• May 7, 1945 when Holland was liberated
from the occupation
• Strong evidence for critical stages of
development in several physiological
systems
Dutch Hunger Winter: Calories
Affects of Famine
• Fertility decreased
• Maternal weight fell during pregnancy with
famine exposure
• Third trimester famine exposure had
strong effect on birthweight
• Third trimester famine exposure was
associated with infant mortality at 30-90
days
Birth Cohorts
Obesity in Young Men after Famine
Exposure in Utero and early Infancy
(Ravelli et al NEJM, 1976)
• N=300, 000 Dutch military inductees at age 19
• Famine exposure in first 2 trimesters lead to
80% higher prevalence of overweight (p<0.0005)
• Famine exposure in last trimester or famine
exposure in first 5 months of life associated with
40% lower prevalence of overweight (p<0.005)
Adult Obesity
Interpretation?
• Cohort B1
– Conceived and gestated at time of moderate
caloric restriction
– Born into time of famine
– Low rates of adult obesity
• Cohort D1
– Conceived and gestated at a time of famine
– Born into food sufficiency
– High rates of adult obesity
Other Impacts of Famine
Exposure
• Excess central nervous system disorders (such as NTD)
• Schizophrenia (Hulshoff et al. J Psychiatry. 2000)
– Famine exposure associated with twofold risk of schizophrenia in
50 year old women.
– Prenatal famine exposure in patients with schizophrenia was
associated with decreased intracranial volume.
– Prenatal Hunger Winter exposure alone was related to an
increase in brain abnormalities, predominantly white matter
hyperintensities.
• Major Affective Disorder (Brown et al. J Psychiatry, 2000)
– Risk of developing major affective disorder requiring
hospitalization increased significantly for subjects with exposure
in the third trimester, relative to unexposed subjects.
Intergenerational Impacts
A mother's exposure to famine prior Stein et al.
to conception of her offspring was
Epidemiology. 2009
associated with lower self-reported Nov;20(6):909-15
measures of mental health and
quality of life in her adult offspring.
Children born to women who
themselves were exposed to the
famine while they were in utero
have increased neonatal adiposity
and poor health 1.8 (95% CI 1.12.7) times more frequently in later
life (due to miscellaneous causes)
Painter et al. BJOG,
2008
Sep;115(10):12431249.
Reproductive performance
and nutrition during childhood
Nutrition Reviews; Washington;
Apr 1996; Martorell, Reynaldo;
Ramakrishnan, Usha; Schroeder,
Dirk G; Ruel, Marie;
Longitudinal Supplementation
Trial (1969-1977)
• Guatemala, 4 Villages, one pair of villages
had about 900 people each and the other
about 500 each.
• 2 each randomized to:
• Atole (Incaparina, a vegetable protein mix
developed by INCAP*, dry skim milk, sugar, and
flavoring, 163 kcal/cup, 11/5 g protein)
• Fresco (flavored drink with sugar, vitamins and
minerals, 59 kcal/cup)
*Institute of Nutrition of Central America and Panama
• Feeding center was open daily for over 7 years, from
1969 to 1977.
• Anyone in the village could attend, but careful
recording of consumption, including of additional
servings as well as of leftovers, was done only for
women who were pregnant or breastfeeding and for
children 7 years or younger.
• Supplements were available twice daily, in
midmorning and midafternoon, so as not to interfere
with meal times.
Conceptual framework
“Malnutrition in early childhood constrains
the future capacity of women to bear
healthy newborns and their ability to feed
and care for them, and through these
mechanisms the growth and development
of the next generation.”
Follow-Up data - 1990s
• The prevalence of low birthweight is
currently 12% in Atole villages (n = 65)
and 28% in Fresco villages (n = 58)
among women exposed to the
supplements during the intrauterine period
and the first 3 years of life.
• Mean birthweights are 2.90 kg in Atole
villages and 2.73 in Fresco villages.
Role of intergenerational
effects on linear growth
U Ramakrishnan; R Martorell; D G
Schroeder; R Flores; The Journal
of Nutrition; Bethesda; Feb 1999;
Methods
• The sample was restricted to singleton, term
(>37 wk of gestation) births that occurred in the
four study villages between 1991 and 1996, to
women who were born during the original
longitudinal study (1969-1977)
• Complete data were available for 215 motherchild pairs, and 60% of the mothers (n = 140)
Results
• For every 100 g increase in maternal birth
weight, her infant's birth weight increased by 29
g after adjusting for the effects of maternal age,
gestational age and sex of the infant. This
relationship was highly significant (P < 0.001)
• For every centimeter increase in maternal birth
length, her child's birth weight increased by 53 g.
Fetal Nutrition and Chronic
Diseases of Adulthood
Developmental Origins of Health
& Disease
UN Standing Committee on
Nutrition, 2006
While undernutrition kills in early life, it also leads to a high
risk of disease and death later in life. This double burden of
malnutrition has common causes, inadequate foetal and
infant and young child nutrition followed by exposure
(including through marketing practices) to unhealthy energy
dense nutrient poor foods and lack of physical activity.
The window of opportunity lies from pre-pregnancy to around
24 months of a child’s age.
Developmental programming of type 2 diabetes and cardiovascular disease.
Martin-Gronert M S , Ozanne S E J. Nutr. 2010;140:662-666
©2010 by American Society for Nutrition
Barker’s Fetal Origins Theory
• Coronary heart disease, stroke, type 2
diabetes, hypertension and osteoporosis,
originate through developmental plasticity,
in response to malnutrition during fetal life
and infancy. Certain cancers, including
breast cancer, also originate in fetal life.
Barker DJP. The origins of the developmental origins theory. J Intern
Med. 2007.
Fetal Origins Concepts
Barker et al
• Nutrition in early life has permanent
effects.
• Undernutrition has different effects at
different times of life.
• Rapidly growing fetuses and neonates are
vulnerable to undernutrition.
• Undernutrition results from inadequate
maternal intake, transport, or transfer of
nutrients.
The Barker Hypothesis
Fetal Origins of Adult Disease
Adverse intrauterine events
permanently “program” postnatal
structure/function/homeostasis
“Adapted Birth Phenotype”
* Better chance of fetal survival
* Increased risk of adult disease
Susan P. Bagby, MD, Professor of Medicine & Physiology/Pharmacology
Division of Nephrology & Hypertension OHSU, Portland, OR
FETAL ORIGINS OF ADULT CVASC DISEASE
In Utero
Birth
Adverse Intrauterine
Events
Low Birthweight/IUGR
MODIFIERS
Childhood
Adulthood
COFACTORS
Adult “Metabolic Syndrome”
Abd’l Obesity
CAD
HTN
Diabetes
 TG/ HDL
Renal Failure
Coronary heart disease death rates,
expressed as standardized mortality
ratios, in 10,141 men and 5585 women
born in Hertfordshire, United Kingdom,
from 1911 to 1930, according to birth
weight.
(Osmond C, Barker DJP, Winter PD, Fall
CHD, Simmonds SJ. Early growth and
death from cardiovascular disease in
women. BMJ 1993;307:1519–24)
Age-adjusted Relative Risk of Non- fatal
Coronary Heart Disease and Stroke
1.50
Relative Risk
Mean ± 95% CL
1.25
1.00
0.75
0.50
5.0
7.5
10.0
Birthweight
121,700 American Nurses, self report study BMJ 315:396,1997
Catch-up growth in childhood and death
from coronary heart disease: longitudinal
study
(Eriksson et al, BMJ, 1999)
• Subjects: 3641 men born in Helsinki
between 1924-1933
• Followed with school data for weight and
height
• Deaths from coronary heart disease from
1971-95 (standardized mortality ratios)
were endpoints.
Catch-up growth in childhood and death
from coronary heart disease: longitudinal
study (Eriksson et al, BMJ, 1999
• Men who had low birth weight or were thin at
birth have high death rates from coronary heart
disease
• Death rates are even higher if weight "catches
up" in early childhood
• Death from coronary heart disease may be a
consequence of prenatal undernutrition followed
by improved postnatal nutrition
• Programs to reduce obesity among boys may
need to focus on those who had low birth weight
or who were thin at birth
David J.P. Barker, F.R.S., Clive Osmond, Ph.D., Tom J. Forsén, M.D.,
Eero Kajantie, M.D., and Johan G. Eriksson, M.D. Trajectories of Growth among Children Who
Have Coronary Events as Adults. N Engl J Med 2005;353:1802-9.
Diabetes in Low-Birth-Weight Men
370 men
Age 64 yrs
8
30
6
20
4
10
2
0
0
<5.5
6.5 7.5
8.5 9.5
Birth Weight (lbs)
>9.5
Odds Ratio/Adj for BMI
% Impaired Gluc Tol or DM
40
Gestat’l
DM
Hales et al. BMJ 303: 1019, 1991
Fetal Milieu Affects Obesity Risk
Trouble at Both Ends of the Birth Weight Spectrum
Odds
Ratio 2.5
For
2
Obesity
3-D
Colum
n1
1.5
1
0.5
0
<2.5
2.5-3.0
3.0-3.5
3.5-4.0
Birth Weight (kg)
3-D Column 1
>4.0
Eriksson J et al Internatl J Obesity 2001
Birth Weight Predicts Blood Pressure at Age 31
Sys BP (mmHg)
1966 Northern Finland Birth Cohort
+/- adjust for current BMI
n = 5960 offspring
130
128
126
124
122
<2500 -2999 -3499 -3999 -4499 >4500
Birth Weight (gm)
Jarvelin M et al. Hypertension 2004
Variables:
Birth Weight
Ponderal Index
Sex
Gestational age
Mat’l Ht, Wt
Parity
Socioeconomic
Current BMI
Birthweight and Adult HTN in US Women
HTN Prevalence (%)
Nurses Health Study I
40
Age
46-71
8.4%
30
15
10
3.1%
Age
30-55
< 5.0
5.0-5.5
5.6-7.0
7.1-8.5
8.6-10.0
Birthweight Category (lbs)
Early Growth Patterns Predict Adult HTN
Growth Patterns in 1404 Children
who later developed Hypertension
BMI
Weight
Height
0.2
Z Score
0.1
Cohort
_______________________________
0.0
Average
}
(n=8760)
-0.1
-0.2
0
2
4
6
8
10
12
14
Age (Yrs)
Barker et al. J HTN 20:1951, 2002.
Animal Models (Waterland and Garza)
“Overall the data from animal models of
metabolic imprinting support the observed
epidemiological associations.”
Effect of Gestational Type 2 Diabetes on
Body Weight in Adult Offspring
Framework for understanding the
maternal regulation of fetal
development and programming
Godfrey & Barker. Fetal nutrition and adult
disease. Am J Clin Nutr 2000 71: 1344-1352.
Adverse Intrauterine
Events
Asymmetric Growth Restriction
* Low Birth Weight for Gestational Age
* Low Wt: Height Ratio (thinness)
* Relative sparing of heart, brain, adrenal
* Disproportionate reduction of kidney,
liver, pancreas, skeletal muscle mass
* Reduced abdominal girth
Fetal Origins of Adult Disease
* Thin
* Small abdominal
girth ( liver size)
* Low arm circumference
( muscle mass)
* Preserved
From Barker, 1998
central fat mass
Asymmetric Growth Restriction
“More powerful predictor than other risk factors”
? % Growth-Restricted Phenotype in Lower
Birth Weight Categories
Conceptual Graph
% Term Births
Growth-Restricted Phenotype
35
% of Term Births
30
25
20
15
10
5
0
<5
5.0-5.5
5.5-6.0
6.0-6.5
6.5-7.0
7.0-7.5
BirthWeight Category (lbs)
>7.5
Potential Mechanisms of
Developmental Programming
Structural Deficits  Reduced
Functional Units in Organs
Kidney
 Nephron #
Pancreas  Islet Cell #
HTN
 Insulin secretion
 Glucose
Muscle
 muscle mass
 Basal met rate
 Exercise capacity
Heart
 myocyte #
 Risk CHF
Liver
 cells #
?  lipid metabolism
What Conveys Risk of HTN in
Lower Birth-weight Offspring ?
Brenner et al. 1988,1994
Low Birth Wt, Low Nephron Number and HTN
“… retardation of renal development as occurs
in individuals of low birth weight gives rise to
increased postnatal risks for systemic and
glomerular hypertension as well as enhanced risk
of expression of renal disease.”2
1Am
J HTN 1988 1:335-47; 2Am J Kid Dis 1994 23: 171
New Nephrons Form in Concentric Layers
during Gestation
Condensing Mesenchyme
Comma Shaped Bodies
Glomeruli
Outer Nephrogenic Layer
Branching Morphogenesis  Nephrogenesis
Ages 1-17 yrs
In Term Births:
Birth Weight
Predicts
Nephron Number
All Ages
 230,000 nephrons
per kg increase
in birth weight
Hughson et al,
Kid Internat (2003) 63, 2113
Also:
Merlet-Benichou et al, 1999
Manalich et al, 2000
Maternal Protein Deficiency
Asymmetric Growth Restriction in Utero
“The Thrifty
Phenotype”
Impaired Kidney
Development
# Nephrons
(permanent)
FOOD
CATCH-UP
GROWTH
#
Nephrons
BODY
MASS
BP
Rethinking “FOAD”
Programming events may act:

Periconceptually

Prenatally

Postnatally: infancy, childhood
Cardiovascular outcomes may appear:

In childhood, adolescence

In midlife

In elderly
Rapid Infant Growth
and Risk of Childhood Adiposity
Prevalence of
Overweight
at Age 7 Yrs
Birthweight
Rate of Wt Gain
In first 4 mo
Stettler et al, Ped.
109, 2002.
DEVELOPMENTAL ORIGINS OF
HEALTH & DISEASE
In Utero
Low Birthweight/IUGR
Infant Undernutrition 0-1 yr
Childhood
Food:
Access
Palatability
+
Accelerated
Growth
“Metabolic Syndrome”
Adulthood
Abd’l Obesity
HTN
CAD
Diabetes
 TG/ HDL
Renal Failure
Inter-Generational Transmission
Birth
Fetal
Undernutrition
Are Nutrition-Induced Epigenetic Changes the Link
Between Socioeconomic Pathology and Cardiovascular
Diseases?
Lopez-Jaramillo et al. Am J Ther. 2008 Jul-Aug;15(4):362-72.
Epigenetics
• Epigenetics = the study of stable alterations in gene
expression that arise during development and cell
proliferation.
• Epigenetic phenomena do NOT change the actual,
primary genetic sequence.
• Epigenetic phenomena modulate when and at what level
genes are expressed.
• The protein context of a cell can be understood as an
epigenetic phenomena.
• Examples include: DNA methylation, histone hypoacetylation, chromatin modifications, X-inactivation, and
imprinting.
http://cnx.rice.edu/content/m11532/latest/
Epigenetic Mechanisms for Nutrition
Determinants of Later Health Outcomes
(Zeisel, Am J Clin Nutr, 2009)
• “Epigenetic code is a series of marks added
to DNA or to proteins (histones) around which
DNA is wrapped.”
• Methylation, covalent modifications of histones and
chromatin and RNA
• Some “marks” can be inherited
• Examples of the impact of this inheritance:
• Grandmother’s smoking in pregnancy & risk of asthma
in grandchildren
• Brains from suicide victims, methylation of 5’ regulatory
region of genes encoding ribosomal RNA associated
with early childhood abuse & neglect
FIGURE 1 Epigenetic marks alter gene expression
Zeisel, S. H Am J Clin Nutr 2009;89:1488S-1493S
Copyright ©2009 The American Society for Nutrition
Fig. 2. General example of epigenetic regulation of gene transcription
General example of epigenetic regulation of gene transcription. Epigenetic regulation of
gene expression is characterized by stable changes to DNA and chromatin structure that
alter gene expression independent of gene sequence. The primary forms of epigenetic
control involve DNA methylation by DNA methyl-transferase (DNMTs), and histone tail
modifications, such as acetylation/deacetylation, by histone acetyl-transferase (HAT) and
histone deacetylase (HDAC) activities, respectively. Additionally, microRNAs have recently
been shown to regulate DNA methylation as well. Histone tail acetylation promotes an
open-chromatin conformation, and is associated with regions of active gene expression,
while histone tail deacetylation promotes a closed-chromatin conformation and is
associated with gene silencing. DNA methylation of cytosine guanine (CpG) dinucleotides
in the 5' promoter region of genes generally induces transcriptional silencing, both by
blocking transcription factor binding and by promoting the recruitment of transcriptional
corepressors or histone-modifying complexes. MeBP, methyl-CpG binding protein; TF,
transcription factor; Pol II, DNA polymerase II.
Heerwagen, M. J. R. et al. Am J Physiol Regul Integr Comp Physiol 299: R711-R722 2010;
Copyright ©2010 American Physiological Society
Mechanisms Emerging…
Sandovici et al. Proc Natl Acad Sci. 2011
• transcription factor Hnf4a, implicated in
the etiology of type 2 diabetes (T2D)
• Transcriptional activity of Hnf4a in islets is
restricted to the distal P2 promoter through
its open chromatin configuration and an
islet-specific interaction between the P2
promoter and a downstream enhancer.
• Exposure to suboptimal nutrition during
early development leads to epigenetic
silencing at the enhancer region, which
weakens the P2 promoter–enhancer
interaction and results in a permanent
reduction in Hnf4a expression.
• Aging leads to progressive epigenetic
silencing of the entire Hnf4a locus in islets,
an effect that is more pronounced in rats
exposed to a poor maternal diet.
DNA methylation differences after exposure to
prenatal famine are common and timing- and sexspecific. Tobi et al, Hum Mol Genet. 2009 Nov 1;18(21):4046-53
• Methylation of INSIGF was lower among
individuals who were periconceptionally exposed
to the famine (n = 60) compared with their
unexposed same-sex siblings
• Methylation of IL10, LEP, ABCA1, GNASAS and
MEG3 was higher
• “persistent changes in DNA methylation may
be a common consequence of prenatal
famine”
Early Risk Determinants and Later Health
Outcomes: Research Priorities
(Field, Am J Clin Nutr, 2009)
• ID biological mechanisms responsible for lasting
and later health effects
• ID genes; research on genomics, metabolomics
and epigenetics
• Understand imbalanced nutrition; focus on
overnutrition during critical periods
• Understand social/environmental factors that
influence critical windows
• ID how and when to intervene to prevent later
disease