1 Lecture 3: Origins of Animals Developmental, molecular and paleontological perspectives.
Biological Determinants: Developmental Origins · Biological Determinants: Developmental Origins 1....
Transcript of Biological Determinants: Developmental Origins · Biological Determinants: Developmental Origins 1....
Biological Determinants:
Developmental Origins
Peter Nathanielsz, Peter Nathanielsz,
Center for Pregnancy and Center for Pregnancy and
Newborn Research,Newborn Research,
University of Texas Health University of Texas Health
Sciences Center.Sciences Center.
San AntonioSan Antonio
Biological Determinants:
Developmental Origins
1. Overview of developmental programming and evidence for the importance of the developmental environment in determining offspring – particularly female offspring phenotype.
2. Mechanisms whereby a female offspring’s phenotype is changed by her developmental environment thus putting her own later pregnancy at risk.
3. Transgenerational effects.
4. Action.
ProgrammingThe process through which a stimulus or
insult establishes a persistent response.
Developmental programming
hypothesisExposure during a critical period in
development may influence phenotype -
life time function and health.
Developmental ProgrammingDevelopmental Programming
The idea that our lifeThe idea that our life--time health is as much time health is as much
impacted by the conditions under which we impacted by the conditions under which we
develop in the womb and early life as by our develop in the womb and early life as by our
genes is a paradigm shift in our thinking of genes is a paradigm shift in our thinking of
what needs to be done to improve the health of what needs to be done to improve the health of
the nation. We need to think in terms of genethe nation. We need to think in terms of gene--
environment interactions. environment interactions.
We pass more biological milestones
before we are born and in the early
months as a baby than at any other
time in our lives.
How we pass these milestones will
be greatly affected by our very first
environments, the womb and
immediately after birth.
Biological Determinants:
Developmental Origins
1. Overview of developmental programming and evidence Overview of developmental programming and evidence for the importance of the developmental environment for the importance of the developmental environment in determining offspring in determining offspring –– particularly female offspring particularly female offspring phenotype.phenotype.
2. Mechanisms whereby a female offspring’s phenotype is changed by her developmental environment thus putting her own later pregnancy at risk.
3. Transgenerational effects.
4. Action.
Blood cholesterol in men and women at the age
of 50 can be related to the extent to which they
had to protect their brain when they were fetuses
How do we know that
nutrition in pregnancy
is important?
A
young
Pima
woman
High Type 2
Diabetes
Low Type 2
Diabetes
Biological Determinants:
Developmental Origins1. Overview of developmental programming and evidence
for the importance of the developmental environment in determining offspring – particularly female offspring phenotype.
2. Mechanisms whereby offspring’s phenotype is changed 2. Mechanisms whereby offspring’s phenotype is changed by her developmental environment thus putting her by her developmental environment thus putting her own later pregnancy at risk.own later pregnancy at risk.
3. Transgenerational effects.
4. Action.
The couch potato rat.The couch potato rat.
Severe maternal undernutrition (30% normal diet) induces
increased fat mass and reduces offspring locomotor activity. Vickers MH et al., 2000;2001; 2003
Voluntary locomotor activity
Cardiovascular variables allometry and plasma
analytes in six month old offspring of fat mice.Samuelsson, A.-M. et al. Hypertension 2008;51:383-392
Immunohistochemistry in 0.9 G fetal baboon
pancreas CTR (A-C) and MNR (D-F). IGF-1 (A,D);
IGF-2 (B,E) and insulin (C,F).
A B C
D E F
0
0.5
1
1.5
2
2.5
3
CTR MNR
% o
f are
a s
tain
ed
0
4000000
8000000
12000000
16000000
CTR MNRD
en
sit
y
Fetal pancreatic Insulin fraction and density from ad lib fed controls baboons (CTR, n=7) or nutrient
restricted (MNR; fed 70% CTR; n=7 ) from 0.16 to 0.9G. Data M ± SEM. *p< 0.05.
Insulin Protein in 0.9G Baboon Fetal Pancreas
*
*
Effects of maternal obesity on fetal Effects of maternal obesity on fetal
development in the sheep.development in the sheep.
The sheep is widely used as a
biomedical model for human
pregnancy, and is the only model
large enough to study the challenged fetus directly combined
with an evaluation of post-natal effects.
Methods
• Multiparous Western Whiteface ewes carrying singleton fetuses were fed a high energy diet at 100% (controls) or 150% (Obese) of NRC recommendations from 60 days before conception to day 75 of gestation.
• A subset of ewes were subjected to a GTT on day 75.
• A second set of ewes were necropsied on day 75 of gestation and the fetus recovered.
• A third set of ewes were allowed to deliver.
The first half of gestation is critical for:
1) Placental growth and vascularization
2) Fetal organogenesis: fetal organs shown
to be most affected by early gestational under nutrition include the pancreas.
0.00%
1.00%
2.00%
3.00%
4.00%
5.00%
6.00%
Cot Car
Va
sc
ula
r a
rea
de
ns
ity
Con OB
*
*
Vascularity in both CAR and COT tissues of OB and C ewes at d 75 of gestation
Relative Content of FATP1,FATP4 and CD36 protein in COT of Relative Content of FATP1,FATP4 and CD36 protein in COT of
Control and OB Ewes on Day 75 of GestationControl and OB Ewes on Day 75 of Gestation
FATP1
FATP4
Tubulin
C C OB OB
CD36
:control fed ewes; obese over-nourished ewes:
Mean ± SEM; **: p<0.01; n=5 in each group.
Placental macrophages in obese women. A: placental sections from a lean (pre-gravid BMI: 22.5) woman
-rare Macrophage staining; an obese (pre-gravid BMI: 31.7) woman with increased numbers of
macrophages (C) and (D). Right : Placental macrophage number. M ± SE. *: p < 0.001 obese vs lean.
Lower panel: macrophages (thick arrows) in the villous stroma Thin arrow: syncytiotrophoblast nuclei,
#: fetal blood space, *: maternal blood space. Scale 20 µm. J.C. Challier et al Placenta 29 274-281
Concentration of Glucose and Insulin in
Maternal Blood on 0.5 Gestation in the obese
sheep model.
0
50
100
150
200
250
-20 0 20 40 60 80 100 120 140
Time (min)
glu
co
se (
mg
/dL
)
OB
C
Area Under the Curve differs by dietary treatment (P<0.05)
0.00
0.50
1.00
1.50
2.00
2.50
3.00
-20 0 20 40 60 80 100 120 140
Time (min)
Insu
lin
(n
g/m
L)
OB
C
C OB C OB0
10
20
30
40
50
60
70
Maternal Fetal
*
*
Glu
co
se (
mg
/dl)
Glucose Content in Both Maternal and Fetal Blood
on D75 of Gestation
*Means ± SEM differ (P<0.05)
Fetal beta-cells in
- obese mother
Fetal beta-cells in
control mother
Beta cells in the pancreas
of the fetal sheep
Insulin Content in Both Maternal and Fetal Blood
on D75 of Gestation
*Means ± SEM differ (P<0.05)
C OB C OB0.0
0.5
1.0
1.5
Maternal Fetal
*
*Insu
lin
(n
g/m
L)
Con fetal muscle OB fetal muscle
Effect of obesogenic diet on fetal muscle Effect of obesogenic diet on fetal muscle
histologyhistology
AA B
Cort
isol (n
g/m
l)
0
5
10
15
20
Cort
isol (n
g/m
l)
0
5
10
15
20
CTR NR Fat CTR NR Fat
*
Cortisol in Control (CTR, n=6) maternal nutrient restricted (NR, n=6)and overfed (Fat, N=6) ewes and fetuses at 78 days of gestation.
* p< 0.05 compared to CTR group.
*
*
MATERNAL FETAL
Fetal plasma cortisol at 0.5 G
* *
Post natal data
We have evaluated glucose We have evaluated glucose
handling at two months of age.handling at two months of age.
Concentration of Glucose and
Insulin in Lambs at 2 Months of Age
Time (min)
BL 2 5 10 15 30 60
Glu
co
se
(m
g/d
L)
0
50
100
150
200
250
Compared to Control group (C): *P<0.05; + p=0.07.
0
50
100
150
COB
C OB
AU
C (
mg/d
l/h)
*
Time (min)
BL 2 5 10 15 30 60
Insulin
(µ U
/mL)
0
10
20
30
0
10
20
30
40
COB
*
AU
C (
mg/d
l/h)
C OB
+
Gillman MW et al, JAMA 2001 285, 2461-2467
Risk of Overweight in Adolescence By Duration of
Breastfeeding in Infancy
What are the possible
mechanisms
for the programming of a
predisposition to obesity?
Yura et al Cell
Metab. 2005
Jun;1(6):371-8.
Effects of maternal dietary protein restriction and folic acid
supplementation during pregnancy in rats on gene promoter methylation
and RNA expression in the offspring 34 d after birth
Diets: C 18% protein, 1mg/kg folic acid ( ); R – 9% protein, 1 mg/kg folic acid ( );
RF – 9% protein, 5mg/kg folic acid ( ). Values are mean ± SD, n=10 offspring/
maternal dietary group. P< 0.05: a) vs C; b) vs RF.
0
20
40
60
80
100
120
% C
ontr
ol
0
200
400
1000
1200
1400
GR PPARα PPARγ GR PPARα PPARγ ACOX
ab ab
ab
ab
ab
DNA methylation mRNA concentration
Lillycrop K et al.
Biological Determinants:
Developmental Origins1. Overview of developmental programming and evidence for
the importance of the developmental environment in determining offspring – particularly female offspring phenotype.
2. Mechanisms whereby a female offspring’s phenotype is changed by her developmental environment thus putting her own later pregnancy at risk.
3. 3. TransgenerationalTransgenerational effects.effects.
4. Action.
Windows of Development
CC RR CR RC
At birth litters were adjusted to 12 pups/litter
Zambrano et al. (2005) Journal of Physiology 566: 225-236
GrowthGestation Lactationday0 22 0 21 ~130
Control ControlCC
RR Restricted
CR
RC
~270
Time line
~90
Control
Control
Control
Restricted
Restricted
Restricted
Control
Control
Control
Puberty
Mothers Pups
Adult life
Programming of Obesity
Zambrano et al. (2005) Journal of Physiology 566: 225-236
CC
RC
CC RC
22 month old female offspring from dams fed control (CC) and
restricted (RC) diets
IRI
0
2
4
6
8
a,b
a
b
CC RR CR RC
a*
*
IRI
0
5
10
15
20
CC RR CR RC
aa
a
b
*
*
Insulin Resistance Index (IRI) in grand daughters and
grandsons of rats fed either control (C - 20%)protein or restricted (R – 10%) protein diet during
pregnancy (first letter) or lactation (second letter); mean + SEM; n=12 -16.
Granddaughters Grandsons
Transgenerational effects of maternal under nutritionon insulin resistance in granddaughters and grandsons.
Biological Determinants:
Developmental Origins1. Overview of developmental programming and evidence for
the importance of the developmental environment in determining offspring – particularly female offspring phenotype.
2. Mechanisms whereby a female offspring’s phenotype is changed by her developmental environment thus putting her own later pregnancy at risk.
3. Transgenerational effects.
4. Action.
ACKNOWLEDGEMENTSACKNOWLEDGEMENTSTo all members of the Center for Pregnancy and To all members of the Center for Pregnancy and
Newborn Research, University of Texas Health Newborn Research, University of Texas Health
Science Center, San Antonio.Science Center, San Antonio.
• Steve Ford
• Elena Zambrano
• Natalia Schlabritz
• Cun Li
• Thomas McDonald