Lecture 19 -- Developmental programming of adult health & disease Flashcards
Barker hypothesis
Early life environmental manipulation impacts on later physiological changes and disease risk
Birth weight as an indicator
Indicator of future health. higher birth weight - lower chance of developing non-communicable diseases (NCD)
Low birth weight is linked to development of
INCREASES RISK OF NON-COMMUNICABLE DISEASES
(1) hypertension
(2) Type 2 diabetes (NIDDM)
(3) Hyperlipidaemia
(4) Metabolic syndrome
(5) Ischameic heart disease
(6) Osteoporosis
(7) Depression
…..in adults
What is a powerful proxy for adult disease?
Birth weight
What is involved with developmental programming?
Environment that the developing foetus is exposed to can affect how the foetus develops
what were the main finding of the Barker studies?
(1) Found a strong correlation between CVD risk and difficult pregnancies 60-70 years earlier.
(2) Lower the birth weight, higher the odds ratio of this individual having type 2 diabetes. The same applies for developing metabolic syndrome.
Does the timing of gestational malnutrition affect the phenotype of the offspring? How? How was this found out?
Yes –
»EARLY increases adult HYPERTENSION, and
»LATE increases adult ADIPOSITY & GLUCOSE INTOLERANCE.
Study of the DUTCH HUNGER WINTER
Infant death rate is a powerful indicator of…
overall quality of gestational environment/the health of the population (reflective of maternal health)
Outline epidemiological study of the DUTCH HUNGER WINTER (winter 1944/45)
- Stresser
- Post-natal environment
- Effect on baby?
STRESSER: MATERNAL MALNUTRITION (did not span entire pregnancy)
PN-ENVIRON: Nutrient RICH
EFFECT: timing of gestational malnutrition impacted on adult phenotype…
EARLY = ++ hypertension
LATE = ++ adult adiposity & glucose intolerance
What effect does timing of gestational malnutrition have on developmental programming? How was this found?
Epidemiological studies of the Dutch Hunger winter (1944/45)
Timing of gestational malnutrition impacted on adult phenotype…
EARLY = ++ hypertension
LATE = ++ adult adiposity & glucose intolerance
Outline epidemiological study of the SIEGE OF LENINGRAD (1941-1943)
- Stresser
- Post-natal environment
- Effect on baby?
STRESSER: MATERNAL MALNUTRITION (SPANNING THE ENTIRE PREGNANCY)
PN-ENVIRON: Nutrient POOR
EFFECT: No relationship between birth weight & later metabolic phenotype of offspring.
What differences in findings were found in the epidemiological studies conducted on the SEIGE OF LENINGRAD and the DUTCH HUNGER WINTER?
Discrepancy in results is reflective of the ‘thrifty adaption’ in response to gestational malnutrition which produces difference effects depending on the conditions of the post-natal environment
>For the children of the siege of leningrad = thrifty adaptation = ADVANTAGEOUS b/c nutrient deprived environment persisted following siege
>For children of the DUTCH HUNGER WINTER = causes metabolic diseases b/c post 1945 = nutrient rich environment
THRIFTY ADAPTATION
in the face of nutrient restriction during pregnancy= alterations lead to ‘thrifty adaptation’
B/c internal environment is a good indicator for the state of the external environment (into which it will be born) = adaptation leading to optimise survival in a nutrient poor environment (like capacity to lay down more fat to conserve as much energy as possible)
The observed phenotype of thrifty adaptation depends on …
POSTNATAL ENVIRONMENT;
nutrient poor = advantage
nutrient rich = leads to ++ obesity & metabolic disorders
PREDICTIVE ADAPTIVE RESPONSE?
Attempt to explain why adaptations to foetal development would occur. Restrictions of nutrients during gestation causes a THIFTY ADAPTION in the baby
What are the programming models to investigate developmental programming?
- Epidemiological studies
- Primates
- Sheep
- Rodents (rats, mice, guinea pigs)
What happens if there is low maternal protein EARLY in the pregnancy?
- Hypertension
* Renal failure
What happens if there is low maternal protein LATE in the pregnancy?
- Obesity
- High-fat food preference
- Decreased activity
- Glucose intolerance
What is the adult phenotype in HSD2 knockout rodents & rodents with HSD2 inhibitors (Carbenoxolone)
Reduction birth weight relative to control
Impaired glycemic control
due to changes inPEPCK expression (rate limiting enzyme in glucose synthesis)
PEPCK
Rate limiting enzyme in glucose synthesis
Exposure to synthetic glucocorticoids in foetus leads to _____?
Changes in PEPCK expression (rate limiting enzyme in glucose synthesis)
Exposure to synthetic glucocorticoids leads to increased PEPCK activity (influencing glucose synthesis and therefore cause impaired glycaemic control in the adult phenotype)
What are the 3 types of testing protocols used in studies on developmental programming in rodents?
(1) DEXAMETHASONE: synthetic glucocorticoids
(2) CARBENOXOLONE: HSD2 enzyme inhibitor
(3) GENETIC MODIFICATION: 11B-HSD@ knockout (removal of 11b-HSD2 from genome)
What is the phenotype of an 11B-HSD2 knockout?
> > low birth weight
alterations in behaviour
> > > > Anxiety like behaviours
(how explore mazes)
Depressive-like behaviours
(tail suspension test, forced swim test, willingness to engage in pleasurable activities)
What is the role of glucocorticoirds in foetal development?
Essential role in foetal MATURATION IN LATE GESTATION
- change tissues from proliferating state –> mature differentiated state
