Our Fetal Legacy: Developmental Origins of Health

1
Our Fetal Legacy Developmental Origins of Health
Disease (DOHAD)

• Brendan J. Waddell
• School of Anatomy Human Biology
• The University of Western Australia

2
The Metabolic Syndrome hypertension
insulin resistance dyslipidemia
abdominal obesity
Developmental Origins of Adult Disease
3
Geographic Patterns of Disease A Clue?
4
Developmental Origins of Adult Disease
Low birthweight associated with.

• High blood pressure
• Obesity
• Diabetes
• Impaired Reproduction?

All of these effects due to.
Developmental Programming
5
The Fetal Period Why So Special?
6
Growth
Length
Rate
Peak growth rate at midpregnancy
7
Severe consequences of a poor fetal environment

• Fetal growth restriction
• Malformations
• Programming of adult health disease

8
Developmental Programming Models
Adult offspring
Phenotypic outcomes - hypertension -
insulin resistance - hyperleptinemia -
increased adiposity - delayed puberty
Undernutrition
Endocrine disturbances - Adrenal axis -
Insulin action - Leptin - Inflammatory
cytokines - Gonadal axes
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Glucocorticoids in Pregnancy

• Glucocorticoids provide potent
  differentiation signals for late fetal
  maturation
• Excess glucocorticoids reduce fetal growth
• Glucocorticoid programming of the adult
  phenotype (DOHAD Hypothesis)

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Postnatal modification of programming outcomes
Exacerbation of programmed effects -
Hypercaloric postnatal nutrition exacerbates
effects of fetal undernutrition (Vickers et al,
2000)

• Attenuation of programmed effects -
  Postnatal pharmacological treatments
  IGF-1 or leptin (Vickers et al, 2001, 2005)
  - Dietary manipulation ??

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Developmental Programming of Adult Leptin
20

16
12
Plasma leptin (ng/ml)
8
4
0
Con
Prog
Con
Prog
Meat-meal
Fish-meal
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Experimental Design
Postnatal diet
In utero environment
Control (Con)
Dexamethasone exposure (Dex)
Birth
Crossfostering resulted in 4 groups Con/Std,
Con/Hn3, Dex/Std, Dex/Hn3
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Rat Model
Maternal Glucocorticoid Treatment (0.75 ?g/ml
Dexamethasone acetate in drinking water, Days
13-23)
Day 23 (term)
Day 0
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Fetal Glucocorticoid Excess Programs Adult
Blood pressure
Values without common notation differ
significantly (P lt 0.05, LSD test)
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Amplification of glucocorticoid signalling in key
target tissues liver, adipose and kidney?
Corticosterone
Corticosterone
11b-HSD1
GR
? cell function
11-DHC
11-DHC
16
Renal GR mRNA expression
Female
Male
35
35
b
30
30
b
25
25
b
b
20
20
Relative expression
15
15
a
a
a
a
10
10
5
5
0
0
Values without common notation differ (P lt 0.01,
ANOVA)
Wyrwoll et al (2007) Hypertension 50579
17
How does DEX permanently change expression of
specific genes in various tissues ? (eg, GR in
kidney, Glut4 in muscle, TNFa in adipose)

• Epigenetics Heritable variations in
  gene expression that are independent of
  nucleotide sequence
• Key mechanisms include histone modifications
  (eg, acetylation) and DNA methylation
• DNA methylation ? gene silencing (usually)

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Chromatin / DNA Structure
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(No Transcript)
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Methylation status of renal GR promoter?
Genomic DNA extracted
methylation-sensitive
Hypomethylated
Hypermethylated
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Renal glucocorticoid receptor (GR)
GR mRNA
GR methylation
a
b
35
7
30
b
6
a
25
5
20
4
Relative expression
Relative methylation
15
a
a
3
b
10
2
b
5
1
0
0
Values without common notation differ (P lt 0.01,
ANOVA)
Wyrwoll et al (2007) Hypertension 50579
22
Acknowledgments
Caitlin Wyrwoll School of Anatomy Human
Biology, UWA Peter Mark School of Anatomy Human
Biology, UWA Trevor Mori School of Medicine
Pharmacology, UWA Warren Potts Glen Forest Feeds
Grant support from the National Health
and Medical Research Council (NHMRC) of Australia