1b// Early Environmental and Biological Impacts on Lifelong Health

Question 1

What challenges could the foetus face in utero that might have lasting impact on its health? (6)

Answer 1

Fetal infection in utero

Maternal nutrition (under/over)

Maternal illness

Maternal stress

Maternal medication

Environmental factors/exposures

Question 2

What does DoHaD stand for?

Answer 2

Programming adult health in early life

Developmental Origins of Health and Disease hypothesis

Question 3

What did DoHaD hypothesise? (google)

Answer 3

hypothesized that environmental exposures during early life (particularly the in-utero period) can permanently influence health and vulnerability to disease in later life

Question 4

Who conducted the DoHaD hypothesis?

Answer 4

Barker and Colleagues

Question 5

What did Barker and Colleagues conclude from the DoHaD study?

Answer 5

On average, adults who had a coronary event had been small at birth and thin at two years of age

Thereafter put on weight rapidly.

Question 6

What was the risk of coronary events more strongly related to in the DoHaD study?

Answer 6

The risk of coronary events was more strongly related to the rate of change of childhood BMI, rather than to the BMI attained at any particular age of childhood.

Question 7

What is metabolic syndrome? (google)

Answer 7

Metabolic syndrome is a cluster of conditions that occur together, increasing your risk of heart disease, stroke and type 2 diabetes

Question 8

What did the DoHaD find about metabolic syndrome?

Answer 8

undernutrition in utero (thin early in life course)
and
overnutrition as a child (overshoot)

leads to increased risk of metabolic syndrome

Which in tun leads to increased risk of cardiovascular events

Question 9

What is the mechanism of DoHaD based on?

Answer 9

idea of programming in utero

which leads to changes which influence development and physiology

Question 10

What may the changes from the mechanism of DoHaD include?

Answer 10

might include predictive adaptive responses (PARs)

• is a hypothesis

Question 11

What are Predictive adaptive responses (PARs) proposed to be?

Answer 11

PARs are proposed to be developmental adaptations taken to prepare the fetus for its future environment

Question 12

Do PARs benefit the foetus?

Answer 12

PARs don’t benefit the fetus immediately, but are taken in anticipation of the environment they will be exposed to.

physiological changes in womb to prepare for outside of womb (prepare in anticipation)

Question 13

What happens if there is a mismatch between PAR and actual environment? And why?

Answer 13

contributes to disease rik later on in life

If a fetus acquires PARs in anticipation of a particular post-natal environment, but then encounters a different environment to that predicted, it will be mal- adapted, potentially raising the risk of ill-health in later life.

Question 14

What are examples of what early environmental exposures are associated with?

Answer 14

Cardio-vascular disease

Type 2 diabetes

Lung disease

Cancer risk

Neurological, special sense and intellectual development

Allergic and auto-immune diseases

Question 15

Link mechanisms of DoHaD and biology.

Answer 15

endocrine milieu=> os endo appropriate/ adequate for foetus

Question 16

What are the 3 major mechanisms for the challenges that the fetus face in utero that might have lasting impact on its health?

Answer 16

Hormonal effects (especially glucocorticoid exposure)

Epigenetic modifications

Irreversible developmental changes in organ size/ structure

Question 17

What do they mean by epigenetic modifications?

Answer 17

environmental insults don’t change DNA, but can change when they are switched on and off

Question 18

What is foetal glucocorticoid exposure usually regulated by?

Answer 18

placental 11BHSD2
- highly expressed by placenta and breaks down cortisol

Question 19

What may lead to greater foetal glucocorticoid exposure?

Answer 19

Reduction in 11BHSD2 expression or increased maternal GCs

Question 20

What does increased foetal exposure to glucocorticoids lead to?

Answer 20

This, in turn, ‘programmes’ fetal growth, development and metabolism

(+ wider HPA axis dysregulation, changes in GC receptor expression)

Question 21

Describe the link between glucocorticoid exposure and DoHaD.

Answer 21

Fetal glucocorticoid exposure is usually regulated by placental 11BHSD2 enzyme
Reduction in 11BHSD2 expression or increased maternal GCs may lead to greater fetal GC exposure.

This, in turn, ‘programmes’ fetal growth, development and metabolism
(+ wider HPA axis dysregulation, changes in GC receptor expression)
Int

Question 22

What do epigenetic changes do?

Answer 22

Epigenetic changes modify the expression of genes without modifying DNA sequence

Question 23

What does epigenetic changes include?

Answer 23

Includes DNA methylation, post- translational (protein) modification of histones, and non- coding RNAs

Question 24

What does DNA methylation do (basic)?

Answer 24

turn genes off

Question 25

What do in utero exposures do to epigenetic changes?

Answer 25

In utero exposures can modify the types or levels (DNA methylation, post- translational (protein) modification of histones, and non- coding RNAs) of these epigenetic marks, leading to altered/dysregulated gene expression.

Question 26

Describe the epigenetic mechanism of DoHaD. (diagram)

Answer 26

Question 27

Describe the key windows of epigenetic reprogramming during development are points of vulnerability.

Answer 27

Question 28

How many major windows are there for developmental vulnerability in epigenetic reprogramming?

Answer 28

3

Question 29

What are the 3 major windows of developmental vulnerability in epigenetic vulnerability?

Answer 29

Gametogenesis

early development

organogenesis and foetal growth

Question 30

Describe the gametogenesis window?

Answer 30

parent-specific epigenetic marks are established during the development of sperm and oocytes

Question 31

Describe the early development window?

Answer 31

very early embryos undergo widespread erasure and re- patterning of epigenetic marks during which these gamete-specific marks are erased and new epigenetic profiles established.

Question 32

Describe the organogenesis and foetal growth window?

Answer 32

epigenetic marks influence timing and onset of cell-type-specific gene expression, influencing how cells differentiate

Question 33

DoHaD and in utero programming of organ systems?

Answer 33

Environmental stimuli have been shown to impact the development of key organ systems, pre-disposing to adult disease.

Question 34

What are examples of in utero programming of organ systems linked to DoHaD?

Answer 34

foetal hypoxia

foetal undernutrition

Question 35

Why does foetal hypoxia lead to in utero programming of organ systems?

Answer 35

reduced nephron numbers -> increased risk of hypertension/renal disease in adulthood

Question 36

Why does foetal undernutrition lead to in utero programming of organ systems?

Answer 36

reduced beta cell mass/altered muscle insulin sensitivity - > impaired glucose control in adulthood

Question 37

Are there implications for later generations of in utero exposures?

Answer 37

yes

Question 38

Explain why there are implications for later generations of in utero exposures.

Answer 38

Primordial Germ Cells (PGCs) are the embryonic precursor cells of oocytes and spermatozoa

PGCs undergo epigenetic reprogramming during embryogenesis

These cells then give rise to sperm and egg – which transmit these epigenetic marks to the next generation (i.e. the exposed fetus’ offspring). (transgenerational effect)

Question 39

What have experimental data from animal models show about foetal germ cell development?

Answer 39

fetal germ cell development is sensitive to environmental impacts (eg diet, pharmaceuticals)

Question 40

Does this schematic make sense.

Answer 40

Showing the diff things that can affect us (i’m pretty sure)