early life impacts

Question 1

What challenges could the fetus face in utero that might have lasting impact on its health?

Answer 1

Fetal infection in utero

Maternal nutrition (under/over)

Maternal illness

Maternal stress

Maternal medication

Environmental factors/exposures

Question 2

what is the name of the hypothesis that discusses the Programming of adult health in early life

Answer 2

Developmental Origins of Health and Disease (DOHaD) hypothesis

Question 3

Key study by Barker & Colleagues conclusion about typical early development of adults that had coronary event?

Answer 3

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 4

based on the key study by barker and colleagues what was factor was the risk of coronary events most strongly associated with?

Answer 4

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 5

DESCRIBE THE DOHaD hypothesis (summary overview)

Answer 5

undernutrition in utero (explains small babies at birth)

followed by
overnutrition as a child (explains the overgrowth they get after age of 2)

leads to increased risk of metabolic syndrome
leads to increased risk of cardiovascular events

Question 6

what is the mechanism suggested by DOHaD for why the change in energy intake from insufficient energy intake to abnormally high energy intake can lead to metabolic syndrome?

Answer 6

1) programming happening in utero leads to
2) - changes in development and physiology
- (specifically the suggestion is:) these might include PREDICTIVE ADAPTIVE RESPONSES (PARs)

Question 7

what are PARs

Answer 7

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

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

Question 8

explain the DOHaD hypothesis now with the concept of PARs in mind

Answer 8

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.

but this mismatch is specific to foetuses with deprived in utero environment then brought up in a rich diet after birth. NOT the opposite/ other way around: so if adequate nutrition in utero, foetus is less sensitive to changes caused by level of nutrition post birth - which lead to disease ect

Question 9

what is metabolic syndrome

Answer 9

when you have a cluster of 3 or more conditions form this list/ realm:

Abdominal obesity

Elevated blood pressure

Elevated fasting blood sugar

Elevated triglycerides

Reduced high-density lipoprotein (HDL) cholesterol

Question 10

what are the main diseases that have been associated with early environmental exposures?

Answer 10

Cardio-vascular disease
Type 2 diabetes
Lung disease
Cancer risk
Neurological, special sense and intellectual development
Allergic and auto-immune diseases

Question 11

explain all the different phases along lifecourse when disease development can be influenced

Answer 11

1) foetal gene expression can be influenced
leads to
2) foetal development responces
3) then in infancy there might be amplification of developmental responces (for ex with the PAR stuff we saw)
4) then adulthood environmental exposures

Question 12

what are the factors that can affect foetal gene expression (which in turn influences foetal development)

Answer 12

1) maternal health and environment (so literally the environment of mother- her work the chemicals shes exposed to in air - smoking drink ect)
and
2) a) foetal nutrient demand> supply
b) endocrine milieu
c) placental vascular supply

affect foetal gene expression

Question 13

what are some examples of foetal development responces to an altered foetal gene expression

Answer 13

altered endocrinology/ metabolism
changes in foetal bone, lean and fat mass
altered blood flow/ vascular loading
altered immune responces

Question 14

what are the categories we use to talk about in utero “challenges” the foetus faces that can have lasting impacts on its health

Answer 14

3 major mechanisms:

hormonal effects (especially glucocorticoid exposure)

epigenetic modifications

irreversible developmental changes -in organ size/ structure

Question 15

what are the two mechanisms in foetal development that can lead to increased fetal glucocorticoid load

Answer 15

1) ENDOGENOUS glucocorticoids:

environmental factors for mother:
undernutrition, stress, infection-> maternal stress
->increased release of glucocorticoids/ stress hormones and decreased 11BHSD2 expression
-> increased foetal glucocorticoid load

or 2) increased exposure to EXOGENOUS glucocorticoids

Question 16

how is foetal glucocorticoid exposure normally regulated

Answer 16

by placental 11BHSD2 enzyme

Question 17

what are some of the potential consequences of increased foetal glucocorticoid load?

Answer 17

changes in foetal growth,
organ structure,
cell numbers,
epigenetics
HPA axis disregulation
changes in GC receptors expresison (metabolic)

Question 18

what are epigenetic changes?

Answer 18

epigenetic changes modify the expression of genes without modifying the DNA sequence

Question 19

examples of epigenetic changes

Answer 19

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

Question 20

why are epigenetics relevant to this topic?

Answer 20

In utero exposures can modify the types or levels of these epigenetic marks, leading to altered/dysregulated gene expression.

Question 21

what are some of the effects that epigenetic changes can have on fetus?

Answer 21

1) fetal growth restriction - (especially symmetries and stuff on previous lecture)
2) increased capacity to store energy- obesity
3) adaptations in metabolic pathways - diabetes
4) adaptations in “terminally differentiated cell” numbers

( the “ “ term refers to cells that have differentiated to max specificity, and the adaptations refer to changes in the distributions amongst these cell types)

Question 22

examples of adaptations in “terminally differentiated cell” numbers caused by epigenetic changes (cell type and disease caused)

Answer 22

cardiomyocytes/ nephron/ vascular myocytes -> hypertension/ cardiovascular disorders

altered neurons and other brain cells -> risk of stroke, schizophrenia, cognitive dysfunction, depression, other behavioral disorders

Question 23

is DNA methylation positive or negative regulator?

Answer 23

negative, keeps stuff switched off

Question 24

what are the key windows of epigenetic reprogramming during development? what factors can influence each of them?

Answer 24

Thought to be three major windows of developmental vulnerability:

Gametogenesis: parent-specific epigenetic marks are established during the development of sperm and oocytes (before foetus has even formed, health of parents affects health of gametes, affects foetus health)

Early development: 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.

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

Question 25

why are key windows of epigenetic reprogramming during development important to consider?

Answer 25

its important to know them because they are points of vulnerability for environment induced epigenetic changes

Question 26

give 2 examples of Environmental stimuli that have been shown to impact the development of key organ systems, pre-disposing to adult disease.

Answer 26

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

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

Question 27

what are primordial germ cells and how do they relate to this topic of early life impacts?

Answer 27

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).

Question 28

what have experiments on animals shown about PGCs’ sensitivity to environmental impacts?

Answer 28

Experimental data from animal models indicates that fetal germ cell development is sensitive to environmental impacts (eg diet, pharmaceuticals)