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Physiology 3003 > Lecture 19 -- Developmental programming of adult health & disease > Flashcards

Lecture 19 -- Developmental programming of adult health & disease Flashcards

1
Q

Barker hypothesis

A

Early life environmental manipulation impacts on later physiological changes and disease risk

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2
Q

Birth weight as an indicator

A

Indicator of future health. higher birth weight - lower chance of developing non-communicable diseases (NCD)

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3
Q

Low birth weight is linked to development of

A

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

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4
Q

What is a powerful proxy for adult disease?

A

Birth weight

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5
Q

What is involved with developmental programming?

A

Environment that the developing foetus is exposed to can affect how the foetus develops

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6
Q

what were the main finding of the Barker studies?

A

(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.

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7
Q

Does the timing of gestational malnutrition affect the phenotype of the offspring? How? How was this found out?

A

Yes –
»EARLY increases adult HYPERTENSION, and
»LATE increases adult ADIPOSITY & GLUCOSE INTOLERANCE.

Study of the DUTCH HUNGER WINTER

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8
Q

Infant death rate is a powerful indicator of…

A

overall quality of gestational environment/the health of the population (reflective of maternal health)

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9
Q

Outline epidemiological study of the DUTCH HUNGER WINTER (winter 1944/45)

  1. Stresser
  2. Post-natal environment
  3. Effect on baby?
A

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

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10
Q

What effect does timing of gestational malnutrition have on developmental programming? How was this found?

A

Epidemiological studies of the Dutch Hunger winter (1944/45)

Timing of gestational malnutrition impacted on adult phenotype…
EARLY = ++ hypertension
LATE = ++ adult adiposity & glucose intolerance

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11
Q

Outline epidemiological study of the SIEGE OF LENINGRAD (1941-1943)

  1. Stresser
  2. Post-natal environment
  3. Effect on baby?
A

STRESSER: MATERNAL MALNUTRITION (SPANNING THE ENTIRE PREGNANCY)

PN-ENVIRON: Nutrient POOR

EFFECT: No relationship between birth weight & later metabolic phenotype of offspring.

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12
Q

What differences in findings were found in the epidemiological studies conducted on the SEIGE OF LENINGRAD and the DUTCH HUNGER WINTER?

A

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

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13
Q

THRIFTY ADAPTATION

A

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)

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14
Q

The observed phenotype of thrifty adaptation depends on …

A

POSTNATAL ENVIRONMENT;

nutrient poor = advantage
nutrient rich = leads to ++ obesity & metabolic disorders

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15
Q

PREDICTIVE ADAPTIVE RESPONSE?

A

Attempt to explain why adaptations to foetal development would occur. Restrictions of nutrients during gestation causes a THIFTY ADAPTION in the baby

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16
Q

What are the programming models to investigate developmental programming?

A
  • Epidemiological studies
  • Primates
  • Sheep
  • Rodents (rats, mice, guinea pigs)
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17
Q

What happens if there is low maternal protein EARLY in the pregnancy?

A
  • Hypertension

* Renal failure

18
Q

What happens if there is low maternal protein LATE in the pregnancy?

A
  • Obesity
  • High-fat food preference
  • Decreased activity
  • Glucose intolerance
19
Q

What is the adult phenotype in HSD2 knockout rodents & rodents with HSD2 inhibitors (Carbenoxolone)

A

Reduction birth weight relative to control

Impaired glycemic control

due to changes inPEPCK expression (rate limiting enzyme in glucose synthesis)

20
Q

PEPCK

A

Rate limiting enzyme in glucose synthesis

21
Q

Exposure to synthetic glucocorticoids in foetus leads to _____?

A

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)

22
Q

What are the 3 types of testing protocols used in studies on developmental programming in rodents?

A

(1) DEXAMETHASONE: synthetic glucocorticoids
(2) CARBENOXOLONE: HSD2 enzyme inhibitor
(3) GENETIC MODIFICATION: 11B-HSD@ knockout (removal of 11b-HSD2 from genome)

23
Q

What is the phenotype of an 11B-HSD2 knockout?

A

> > 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)

24
Q

What is the role of glucocorticoirds in foetal development?

A

Essential role in foetal MATURATION IN LATE GESTATION

- change tissues from proliferating state –> mature differentiated state

25
Q

What is the clinical application of administering glucocorticoids in women threatening pre-term birth?

A

Premature babies would be born with under developed lungs. By administering glucocorticoids lung maturation is facilitated (changing tissues from proliferative–> differentiated state) .: enhancing survival of the baby

26
Q

Where are glucocorticoids released from and why?

A

> > Stress/circadian rhythm=> hypothalamus
Hypothalamus => CRH
Anterior pituitary => ACTH
Adrenal Cortex => Glucocorticoids
Glucocorticoids => negative feedback hypothalamus/anterior pituitary

27
Q

What is the protein that regulates the entry of glucocorticoids into the cell?

A

11ß-HSD (11ß-hydroxysteroid dehydrogenase)

28
Q

Where is 11ß-HSD2 expressed (and why?)

A

In the placenta and the developing brain

Acts as a barrier to corticosteroids (protects foetus from inappropriate levels of glucocorticoids)

29
Q

What does 11ß-HSD2 do?

A

converts ACTIVE corticosterone -> INACTIVE form

11 dehydrocorticosterone =11ß-HSD2=> corticosterone

30
Q

Effects of maternal low protein diet EARLY in gestation

A

Hypertension

Renal failure

31
Q

Effects of maternal low protein diet LATE in gestation

A

Obesity
High-fat food preference
Decreased activity
Glucose intolerance

32
Q

What is the effect of maternal low protein diets on the foetus?

A

Reduction in 11ß-HSD2 expression in foetus/placent –> poor nutrition reducing protect barrier –> increasing glucocorticoid exposure –> affecting organ development

33
Q

low 11ß-HSD2 is associated with ______

A

Low birth weight

34
Q

Excess glucocorticoids = ___ foetal growth.

HOW?

A

(1) Alters cell number (shifts from proliferating –> differentiated state)
==> kidney; reduced nephrone # = hypertensive adults
==>Apoptosis; ++ programmed cell death

(2) Altered gene transcription (PEPCK)
==>Transcription factors altered
==> Chromatin effects (underlying epigenetic mechanism) –methylation marks on DNA, histones (acetylation/deacytelation), nucleosome spacing

=======>Programs foetus for poor health outcomes.

35
Q

How does maternal low protein diet affect 11ß-HSD2 levels?

A

Decrease 11ß-HSD2 levels, which reduces the protective effects of this against glucocortiocoids

36
Q

What happens to rodent offspiring who are exposed to synthetic glucocortiocoids during gestation?

A

Post-natal elevation in PEPCK, which affects how the liver creates glucose. mRNA for PEPCK is also increased.

37
Q

What happens in 11ß-HSD2 knockout mice?

A

Low birth weight, anxiety like behaviours in adults, increased depressive-like behaviour.

38
Q

How does exposure of the fetus to altered glucocorticoids affect the fetus?

A
  • Altered cell number, division and apoptosis
  • Altered gene expression (transcription), including chromatin effects, histones, nucleosome spacing and methylation
  • Transcription factors.
39
Q

Why did the siege of Leningrad individuals not having any problems?

A

Because their post-natal environment matched their natal environment

40
Q

What is the main idea behind PAR?

A

Thrifty adaptation – the baby adapts it’s metabolism etc, to suit the post-natal environment. This is a survival advantage. This is because the maternal environment is a potential indicator of the external environment.

41
Q

Does maternal obesity result in obese babies? What then?

A

Not obese babies, but poor implantation of the fetal placenta and .: impeded development of placenta in terms of blood supply
Frequently associated with low birth weight babies.

Physiology 3003 (15 decks)

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