developmental programming: effects of diet, exercise, and … … · · 2014-10-01developmental...
TRANSCRIPT
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Developmental Programming: Effects of Diet, Exercise, and Polychlorinated Biphenyl Exposure during Pregnancy
on Long-term Health in Offspring
Kevin J. PearsonAssistant Professor
Pharmacology and Nutritional SciencesUniversity of Kentucky College of Medicine
April 2, 2014
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Outline• Developmental origins of health and disease
• Maternal exercise during healthy pregnancy
• Maternal obesity and high fat diet consumption
• Polychlorinated biphenyl exposure
• Translational approach
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Known for decades
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Adapted from Barker and Osmond, 1986
Coronary Heart Disease (1968-1978)
David BarkerNeonatal and CVD mortality link
Infant Mortality (1901-1910)
Slide credit: Barbara Alexander
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Low birth weight
•Low birth weight is
defined as less than
5 ½ pounds.
•About 1 in every 13
babies in the US is
born with LBW.
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• Alcohol, illicit drugs, smoking
• Environmental exposure (PCBs)
• Placental problems
• Chronic health problems in the mother
• Inadequate maternal weight gain
• Socioeconomic factors
• Poor nutrition
• Age: teen mothers or women over 40
Causes
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> 8.5
7.5-8.5
< 7.5
> 9.1% LBW
7.0-9.1% LBW
< 7.0% LBW
Percent of live births, 2007
Low birth weight
Source: Centers for Disease ControlNational Vital Statistics System
National average= 8.3% LBW
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Source: Centers for Disease Control and Prevention
Obesity—BMI ≥ 30
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Source: Centers for Disease Control and Prevention
2008
Diabetes
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Stroke
Source: Centers for Disease ControlNational Vital Statistics System
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Hypertension
Source: Centers for Disease ControlNational Vital Statistics System
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Western diet fed-dam data
Samuelsson et al., Hypertension 2008
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Offspring data
•Body weight differences•Increased fat mass•Hypertensive•Impaired glucose tolerance
Samuelsson et al., Hypertension 2008
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Paternal influence
Ng et al., Nature 2010
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Developmental origins• Barker hypothesis
– Maternal malnutrition leads to obesity, diabetes, and heart disease in offspring.
– Fetal/developmental programming– Developmental origins of health and disease
(DOHaD)
– High Initial Damage Load Hypothesis• Early development produces an exceptionally high load of initial damage,
which is comparable with the amount of subsequent aging-related deterioration accumulating during the rest of the entire adult life.
• Predicts that even small progress in optimizing the early-developmental processes can potentially result in a remarkable prevention of many diseases in later life.
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DOHaD“You live in two worlds;the world of your mother and the world into which
you are born.”
Slide credit: Barbara Alexander
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But how is this occurring?
Epigenetic Mechanisms
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DNA to protein
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DNA to protein
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Chromatin• Made up of
– DNA and proteins• Histones.• Non-histone chromatin proteins.
• Fundamental packaging of DNA.– Need to highly condense DNA to
fit in cell.– Yet – must be accessible when
needed.
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Chromatin Structure –Successive Coiling
http://www.cbs.dtu.dk/staff/dave/roanoke/genetics980218.html
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Chromatin is Dynamic
• Structure of chromatin is remodeled– ATP-dependent process– Important to allow
• Replication• Transcription• Repair• Packaging
– Histone code informs chromatin structure• Histone modifications serve to recruit other
proteins by specific recognition of the modified histone
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Epigenetics
• ‘Epi’ means over or above– ‘epi’genetics
• Conrad Waddington coined the term in his description of cellular fate. – Epigenetic landscape
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Epigenetics• “Epigenetics is the study of heritable changes
in phenotype (appearance) or gene expression caused by mechanisms other than changes in the underlying DNA sequence.”– DNA methylation– Histone modification
• Acetylation, phosphorylation, and ubiquitination– Non-coding RNA
• Short interfering RNA, microRNA, etc.– Genomic imprinting
• Epigenetic regulation is critical for mammalian development and cellular differentiation.
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Epigenetic overview
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Block transcription
DIRECTLYDNA methyl-binding protein•Recruit co-repressors
MBP binding can slow elongationDNMT binding recruit histone modulators
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Histones
• Highly conserved• Basic proteins with a
globular structure• ‘Poor’ tail
– Up to 30% of mass of histones
– Relatively unstructured and flexible
– Not part of globular domain– Quite important in
epigenetics
Marks et al. Nature Reviews Cancer 2001
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Histone modifications
• Small covalent modifications
Methylation Acetylation
Phosphorylation
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Epigenetics 2006
Lots to study—histone code
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Example : Acetylation• Reduces affinity for
histone to DNA (DNA is negatively charged)
• Leads to more open chromatin conformation
• Recruits complexes to allow for transcription
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Acetylation
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Multiple methyl groups
Nature Reviews Molecular Cell Biology 8, 307-318 (April 2007)
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Histone modifying enzymes
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Epigenome
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Outline• Developmental origins of health and disease
• Maternal exercise during healthy pregnancy
• Maternal obesity and high fat diet consumption
• Polychlorinated biphenyl exposure
• Translational approach
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Lab overview
Developmental origins of health and disease
Maternal obesityPCB exposure Maternal exercise
OFFSPRINGDiabetesObesityCancer
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Aging intervention—Short-termHigh health return on early investments
Pregnancy ~3 weeksLifespan ~150 weeks
Pregnancy ~40 weeksLifespan ~4160 weeks
Mice Humans
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Maternal exercise
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Exercise during pregnancy
• Many known maternal benefits– Cardiovascular health– Body composition and weight maintenance – Muscle discomfort and cramps– Glucose regulation– Labor complications
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Offspring effects
• Maternal exercise improves learning and memory in the offspring.
• Unclear metabolic effects.
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HypothesisVoluntary exercise during pregnancy and
nursing improves health in offspring.
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ICR (CD1) mouse
• Outbred strain• Good breeders• Maternal care• ~21 day gestation
period• Litter size is 11-12
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Maternal intervention
Carter et al, AJP 2012
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Maternal running data
Time (days)0 10 20 30 40
Run
ning
dis
tanc
e (k
m/d
ay)
0
2
4
6
8
10
12
14
♂ pups born
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No negative effects
Body weight was completely normal throughout life.
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Female glucose disposal
Time (min)0 30 60 90 120
Glu
cose
(mg/
dl)
0
50
100
150
200
250
300
350
Sedentary; n = 20Exercise; n = 18
**
Sedentary Exercise
AU
C (g
/dl m
in)
0
20
24
28
**
** P < 0.01 compared to Sedentary
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Male glucose disposal
Sedentary ExerciseA
UC
(g/d
l m
in)
0
20
24
28
32
36
Time (min)0 30 60 90 120
Glu
cose
(mg/
dl)
0
50
100
150
200
250
300
350
Sedentary; n = 19Exercise; n = 18
*
* P < 0.05 compared to Sedentary
* *
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Body composition
• No change in female offspring born to sedentary or exercised dams.
• Male offspring born to exercised dams– Increased lean mass– Decreased fat mass
• Sex specific differences.
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Is the effect species specific?
Time (day)0 5 10 15 20 25 30 35 40 45
Run
ning
dis
tanc
e (k
m d
ay-1)
0
1
2
3
4
5
6
7
8
9
♂Pups born
Sprague-Dawley Rats
Carter et al, MSSE 2013
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Future directions for project
• Test controlled exercise rather than voluntary• Timing of exercise important?• Mechanism
– Epigenetics• High fat diet consumption in offspring• Gestational diabetes
– offspring outcomes
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Lab overview
Developmental origins of health and disease
Maternal obesityPCB exposure Maternal exercise
OFFSPRINGObesityDiabetes
Cardiovascular disease
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Goal: To identify a maternal diet in ICR mice that negatively influences
offspring body composition and glucose tolerance.
Easy!!!
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Lard‐based diet
10%fat 60%fat
45%fat
Butter‐based diet
60%fat
32%fat
11%fat
Maternal obesity
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Normal offspring
• Offspring were completely normal even if they are born to obese moms consuming extremely high fat diets.– Body weight– Body composition– Glucose tolerance– Heart function
• Does this mean that these mice cannot be negatively programmed?
NO!!!!
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Lab overview
Developmental origins of health and disease
Maternal obesityPCB exposure Maternal exercise
OFFSPRINGObesityDiabetes
Cardiovascular disease
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Superfund Research Program
• Joint program sponsored by the National Institute of Environmental Health Sciences and the Environmental Protection Agency.
• Network of university grants that are designed to seek solutions to the complex health and environmental issues associated with the nation's hazardous waste sites.
• 3 biomedical projects • 2 nonbiomedical projects
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•Chemicals widely used as coolants.•Banned in 1977 •More than one million capacitors and 14,000 transformers containing PCBs are still in use in the U.S. •Primary sources of PCB exposure
• Ground water or soil contamination• Food contamination from food
storage in silos with PCB-coated interiors
• Consumption of fish from contaminated waterways
•Additional sources of PCB exposure are still being identified…
Polychlorinated Biphenyls (PCBs)
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LESS PCBs
MORE PCBs
PCBs: origins and environmental fate
Slide credit: Nicki Baker
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PCB 126—Coplanar PCB• 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126)
• Dioxin-like– Characteristic dioxin toxicity
• Dioxin (TCDD)—contaminant in Agent Orange– Manufacturing by-product, extremely toxic– FDA: “Almost every living creature has been exposed to dioxins”
• Toxic Equivalency Factor (TEF)– A potency index/health risk value where other compounds are
compared to TCDD
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Concerns
• Persistent organic pollutants– Fat soluble, prone to accumulation– World-wide ban
• Health– Cancer– Cognitive impairment– Inflammation– Obesity/diabetes– Reproductive failure
• Fertility• Miscarriage• Low birth weight
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Pup survival, body weight, inflammation
Control
No PCB exposure No PCB exposure
Maternal exposure1 mole/kg PCB 126 5 mole/kg PCB 126
Prior to mating
Pregnancy
Nursing
Prior to mating
Pregnancy
Nursing
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Pregnancy weight gain is decreased
Time (days)0 5 10 15 20 25 30
Food
inta
ke (g
/wee
k)
0
10
20
30
40ControlPCB
Time (days)0 5 10 15 20 25 30
Bod
y w
eigh
t (g)
0
25
30
35
40
45
50
55ControlPCB
*****
A
B
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Maternal PCB and LBW
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-7 mating
gestation
-28 -14 0 7 -21 14 21
Wean
Day
Less Frequent Dosing
Time (days)-20 -10 0 10 20
Mat
erna
l bod
y w
eigh
t (g)
0
40
45
50
55
60
65ControlPCB126
Age (days)P3 P7 P14 P21
Offs
prin
g bo
dy w
eigh
t (g)
02468
1012141618
ControlPCB126
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Time (min)0 20 40 60 80 100 120
Glu
cose
(mg/
dL)
0
100
200
300
400
500
ControlPCB
***
Lean Fat
Tiss
ue (g
)
0
5
10
15
20
25
30
ControlPCB
*
Unhealthy offspring
Male Offspring Male OffspringFemale Offspring
Lean Fat
Tiss
ue (%
)
0
20
40
60
80ControlPCB
*
**
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Hypothesis
MaternalInflammation
Glucose Intolerance
Fetal Programming
Obesity and Glucose Intolerance
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In utero or milk
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Funded AimsPerinatal PCB Exposure
Adult DiseaseDiabetesObesity
MaternalExercise
AhR
Inflammation
OffspringProgramming
Aim 3
Aim 2
Aim 2
Aim 1
Nrf2
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Outline• Developmental origins of health and disease
• Maternal exercise during healthy pregnancy
• Maternal obesity and high fat diet consumption
• Polychlorinated biphenyl exposure
• Translational approach
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Aging intervention—Short-termHigh health return on early investments
Pregnancy ~3 weeksLifespan ~150 weeks
Pregnancy ~40 weeksLifespan ~4160 weeks
Mice Humans
$$
$$
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Translation
• Neonatal foreskin– Can we link gene expression, protein
levels, or markers of oxidative stress with maternal or fetal characteristics?
• Maternal and birth weight• Smoking• Alcohol use• Exercise• Environmental contaminants
Your developing baby; Conception to birth. Doubilet, Benson and Weisman
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Foreskin as a model for other disease states
• Great tissue model because there are multiple cell types within the tissue
• Readily available where circumcisions are performed, and the tissue is routinely discarded
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NanoString nCounter• Isolated RNA• Design a codeset for
genes of interest– Stress response– Transporters/receptors– Adipokines– Cytokines
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Smoking during pregnancy
• 30% of women delivering at UK Hospital
Control Smoker
Birt
h Le
ngth
(cm
)
0
40
45
50
55
Control Smoker
Birt
h W
eigh
t (g)
0
2750
3000
3250
3500
3750
Control Smoker
Ges
tatio
n Le
ngth
(wee
ks)
0
34
36
38
40A
B
C
*
P = 0.077
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Gene expression data
Control Smoker
SOD
3 m
RN
A (c
ount
s)
0
375
450
525
600
Control Smoker
Prdx
1 m
RN
A (c
ount
s)
0
1800
1900
2000
2100
2200
2300
Control Smoker
CYP
1B1
mR
NA
(cou
nts)
0750
1000
1250
1500A
B
C*
**
P = 0.058
Control Smoker
Apo
D m
RN
A (c
ount
s)
05000
5500
6000
6500
7000
7500
8000
Control SmokerIR
mR
NA
(cou
nts)
0
150
200
250
300
Control Smoker
PTP1
B m
RN
A (c
ount
s)
0
900
950
1000
1050
1100
A
B
C
*
*
*
Control Smoker
CR
EB1
mR
NA
(cou
nts)
0
1500
1750
2000
Control SmokerFA
TP4
mR
NA
(cou
nts)
0
800
900
1000
1100
1200
Control Smoker
Che
mer
in m
RN
A (c
ount
s)
0
17502000
2250
2500
2750
3000
3250A
B
C
*
*
**
StressGlucose
Transport Adipose
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Neonatal Biomarkers of In Utero Tobacco Exposure
Smoking in Pregnancy
FunctionalAnalyses
Stress ResponseGlucose Transport
Adipogenesis
BiomarkersRNA
EpigeneticsOxidative Stress
Aim 1 Aim 2
Neonatal Foreskin
Developing Embryo,Fetus, Neonate • Collaborators
• Kristin Ashford, PhD• John O’Brien, MD• Rich Charnigo, PhD• Carmen Marsit, PhD—
Dartmouth
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Where do we go from here?• Obviously very preliminary.• We are looking to see if protein levels
match RNA data. • New tissue for programming studies.
– How does it compare to placenta, cord blood?
• Risk assessment for environmental exposures???
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Summary
• Maternal exercise protects improves offspring health.
• Are maternal “exposures” more important than maternal obesity? – Our data in a mouse model suggest PCBs
are worse. • Much, much, much more work needs to
be done.
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Our goal is to figure out if there are epigenetic changes in the offspring that are induced by
maternal behavior/environment.
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AcknowledgementsUK
Bernie HennigLisa Cassis
Andrew MorrisWendy Katz
Preetha ShridasKaryn Esser
Richard CharnigoJohn O’BrienUK SRP folks
My lab
FundingCOBRE-NIH NCRR
R01-NIH NIDDKR03-NIH NCI
Superfund Research Program
Rebecca Epstein-PollackSara Tenlep Lindsay Carter
Christy Tobia
Kristen PlattAlyssa Jarrell
ExternalRafael de Cabo
Katie LewisJosephine EganSean NewcomerLaura Woollett
Nathan QiJohn Thyfault
Cetewayo Rashid Mice
Brett Dickens Toria Fischer Christa Childers