L3: Developmental Origins of Disease

Question 1

Describe the aim of the Dutch Famine Birth Cohort Study

Answer 1

• Investigate impact of In Utero exposure to famine on health and wellbeing of Dutch population

Question 2

Describe Barker’s early origins hypothesis:

Answer 2

‘Chronic, degenerative conditions of adult health, including heart disease and type II diabetes, may be triggered by circumstances decades earlier, in utero nutrition in particular’
(Posited after study into effect of weight in infancy on ischaemic HD)

Question 3

Define DOHAD:

Answer 3

Developmental origins of health and disease

Question 4

What is a developmental indicator for development of coronary heart disease?

Answer 4

Size at birth

Question 5

Key findings of Dutch Cohort Study (by famine-exposure point during pregnancy):

Answer 5

• From conception: Higher risk of CHD
• From first trimester: Increased prevalence of obstructive airways disease
• From second trimester: Higher blood pressure at adulthood and mental diseases

Question 6

List 5 diseases associated with small body size at birth:

Answer 6

• Adult cardiovascular disease
• Type II diabetes
• Osteoporosis
• Schizophrenia
• Depression

Question 7

Name a disease associated with large body size at birth:

Answer 7

• Cancer

Question 8

Evidence for epigenetic regulation of development (x2):

Answer 8

• Agouti mice (supplemented vs unsupplemented diet altered proportions of different coat colourings -> transposable elements are a target for nutritional effects)
• Copy cat (cloned individual displayed both phenotypical and behavioural differences) -> anecdotal not significant

Question 9

List 6 factors in the embryo environment that can be epigenetically modulated and thus affect development:

Answer 9

• Glucose/energy substrates
• Amino acids
• GFs
• Steroid hormones
• Cytokines
• Metabolic regulators

Question 10

List 6 potential short-term impacts of embryo environment with ability to impact development:

Answer 10

• Epigenetic modifications
• Altered intracellular signalling
• Metabolic stress
• Gene expression changes
• Apoptosis
• Cell proliferation disturbed

Question 11

Define epigenetic:

Answer 11

• Stably maintained mitotically (and potentially meiotically) heritable patterns of gene expression that occur without changes in the DNA sequence
• Reversible

Question 12

Fluctuations in genome-wide methylation level throughout development:

Answer 12

• Fetal germ cells: Low
• Mature gametes: High
• Zygote: High
• Embryo-blastocyst: Low
• Developing fetus: Increasing
• At two points (formation of primordial germ cell, and in the early embryo), the slate is wiped clean to achieve an ‘epigenetic ground state’ allowing controlled differentiation into gamete or tissue-specific lineages, respectively -> global demethylation

Question 13

What is the theory of developmental plasticity?

Answer 13

• Epigenetic reprogramming allow adaptation to environment (i.e. the embryo-uterine dialogue)
• This allows selection of the right phenotype to fit the anticipated future environment

Question 14

Potential epigenetic consequences of ART: (explanantion and 2 pieces of evidence)

Answer 14

• ART cause stress to gametes and early embryo, with more extreme ART intervention having more severe impact on the animals potential and predisposition to metabolic disease after birth
• Mechanism not fully described or understood
• Imprinting disorders (increased incidence of Beckwith-Wiedemann and AS in IVF babies)
• Altered glucose parameters in mice

Question 15

Limitations to the study of epigenetic effect of ART: (x3)

Answer 15

• Non-conserved mechanisms between species (model organisms not representative of human responses)
• Lack of historical data (first IVF child born 1978) -> impossible to carry out cohort study on incidence of late-onset diseases

Question 16

Key types of epigenetic modifications:

Answer 16

• Histone PTMs
• Chromosome remodelling
• Nucleosome positioning
• DNA/RNA methylation and demethylation
• ncRNAs

Question 17

Consequence of maternal low protein diet:

Answer 17

• Fed from fertilisation stage to blastocyst
• Caused offspring to exhibit cardiovascular disease
• Increased blood pressure throughout adult life
• Smaller heart mass (females)
• Increased lung ACE activity -> increased blood vessel contraction
• Reduced capacity to dilate arterial vessels

Question 18

Evidence for differences between in vivo and in vitro fertilised individuals (cattle and mice):

Answer 18

• Large offspring syndrome in calves (congenital condition associated with cloning in cattle)
• Glucose parameters are altered in mouse offspring produced by ART and SCNT

Question 19

Why is the use of animal models particularly important in the study of DOHaD?

Answer 19

• Able to finely control environmental exposures
• Can access and thus analyse metabolically relevant tissues like pancreatic islets and the liver

Question 20

What are the 3 overarching types of findings from studies of the dutch famine cohort:

Answer 20

• Prenatal famine exposure seems to have permanent effects on human health (CHD, obesity, schizophrenia)
• The effects of undernutrition depend on timing during gestation and the organs/systems developing during that critical time window (most chronic disease associated with early gestational exposure during organogenesis whereas glucose intolerance was associated with mid to late gestational exposure during rapid proliferation of the endocrine pancreas)
• Effects of famine found to be independent of size at birth
• N.B.: Potential behavioural impact of famine on likelihood to ‘coddle’ and overfeed children

Question 21

What studies corroborate the findings of the Dutch Cohort Famine Study?

Answer 21

• Dutch Hunger Winter Family Study -> used unexposed siblings as controls rather than unrelated time controls
• Nigerian famine, 1967 - 1970 (increased rates of hypertension and T2DM)
• Great Leap forward famine, China (diabetes, hypertension, schizophrenia)

Question 22

Key limitations of Dutch Famine Birth Cohort Study: (x2 related)

Answer 22

• Selective conception (fertility decreased by around 50% in this period due largely to amenorrhoea in women)
• Selective perinatal survival