10.2 - Early environmental and biological impacts on lifelong health Flashcards
What challenges could the foetus have in utero that might have a lasting impact on its health? (6)
- foetal infection in utero
- maternal nutrition (under/over) - impact foetal health and development
- maternal illness
- maternal stress
- maternal medication - can cross placenta and be modified to affect child
- environmental factors/exposures (e.g. exposure to pesticides)
Which hypothesis predicts programming adult health in early life?
Developmental Origins of Health and Disease (DOHaD) hypothesis AKA Barker hypothesis
What did the Barker hypothesis focus on?
Birth weight and growth early in life with vascular disease and coronary events in adulthood
What did the Barker study show?
- on average, adults who had a coronary event had been small at birth and thin at two years of age
- thereafter they put on weight rapidly (compared to peers)
- children that were small until ~2yrs had high rate of catchup growth, accelerating outside the curve and increasing weight –> increased risk of CVD and CV events
- people that stayed within their birth weight and gradually increased were at lower risk of developing CVD
What was the hypothesis made following the Barker study?
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
How can the DOHaD/Barker hypothesis be applied to child health specifically?
Undernutrition in utero + overnutrition as a child –> increased risk of metabolic syndrome (e.g. CVD, DM) –> increased risk of cardiovascular events
Describe the mechanisms of DOHaD.
- idea of programming in utero
- leads to changes which influence development and physiology
- these changes might include predictive adaptive responses (PARs)
- PARs are proposed to be developmental adaptations taken to prepare the foetus for its future environment
- PARs do not benefit the foetus immediately, but are taken in anticipation of the environment they will be exposed to (i.e. undernutrition as foetus predicts poor external environment so foetus adapts to increase nutrition in external environment)
What is the difference in CVD risk in child of mother with adequate nutrition vs maternal malnutrition during pregnancy?
- adequate nutrition –> healthy baby –> healthy adult
- maternal malnutrition –> undernourished baby exposed to rich environment + high energy intake (to catch up on missed nutrition) –> overshoot in nutrition –> CV problems as adult
What happens if there is a mismatch between predictive adaptive responses (PARs) and actual environment?
If a foetus 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 risk of ill health in later life (e.g. undernourished foetal env –> rich external env = maladapted = CVD)
How can we link mechanisms of DOHaD to biology?
- foetal environment along with nutritional supply, hormonal exposure (from mother) and vascular blood supply all affect gene expression in foetus
- if these alter gene expression, this will alter foetal endocrinology/metabolism, foetal structure, blood flow/vascular loading and immune responses etc
- when the foetus is born, it will experience other environmental exposures e.g. smoking in adulthood (amplification in infancy for somethings e.g. catch-up growth)
- these can manifest later in life as health disorders e.g. CVD, metabolic, lung and immune-mediated diseases, neurodevelopmental disorders
What diseases can we associate with early environmental exposures? (6)
- cardiovascular disease
- type 2 diabetes
- lung disease
- cancer risk
- neurological, special sense and intellectual development
- allergic and autoimmune diseases
What three major mechanisms as a foetus can cause a lasting impact on health?
- hormonal effects (especially glucocorticoid exposure)
- epigenetic modifications
- irreversible developmental changes in organ size/structure
How does glucocorticoid exposure impact Developmental Origins of Health and Disease (DOHaD)?
- foetal glucocorticoid exposure is usually regulated by placental 11BHSD2 enzyme (shields foetus from GCs by breaking them down)
- reduction in 11BHSD2 expression or increased maternal GCs (e.g. from stress) may lead to greater foetal GC exposure
- this in turn ‘programmes’ (induces changes in) foetal growth, development and metabolism
- also causes wider HPA axis dysregulation and changes in GC receptor expression
- overall sensitivity to GCs changed –> predisposed to CVD
How are epigenetic modifications linked to Developmental Origins of Health and Disease (DOHaD)?
- epigenetic changes modify the expression of genes without modifying DNA sequence
- includes DNA methylation (negative regulator of gene expression, turning them off), post-translational (protein) modification of histones (euchromatin/heterochromatin) and non-coding RNAs
- in utero exposures (e.g. maternal stress) can modify the types/levels of these epigenetic marks, leading to altered/dysregulated gene expression
What can maternal or placental stress cause?
- foetal epigenetic changes –>
- foetal growth restriction, increased capacity to store energy (–> obesity), adaptations in metabolic pathways (–> DM), adaptations in terminally differentiated cell numbers:
- changes to cardiomyocytes/nephrons/vascular myocytes –> hypertension/CV disorders
- altered neurons and other brain cells –> risk of stroke, schizophrenia, cognitive dysfunction, depression, other behavioural disorders
