Developmental origins of health and disease

Question 1

What is a reaction norm?

Answer 1

Quantitative variation in a phenotype according to variation in an environmental factor

Question 2

What is an example of a reaction norm? (3)

Answer 2

• Shire horse mother and shetland father produce shire sized offspring (large)
• Shetland mother and shire father produce shetland sized offspring (small)
• Offspring size is dictated by size of the mother

Question 3

What is the open field test? (2)

Answer 3

• Behavioural assay in mice for anxiety in response to being placed in a new environment
• Wall-hugging behaviour (thigmotaxis) is highly correlated with anxiety, inversely correlated with boldness and willingness to explore the new environment

Question 4

What is the difference between B6 and BALB mice in the open field test? (3)

Answer 4

• B6 mice spend more time in the inner area
• BALB mice exhibit higher levels of ‘wall-hugging’ (thigmotaxis)
• B6 mice are less anxious

Question 5

How does prenatal/postnatal exposure of offspring to different genotype foster parents affect offspring behaviour? (4)

Answer 5

• B6 embryos (all same genotype) transferred to B6 female or BALB female for prenatal development
• Offspring from each then brought up by B6 foster mother or BALB foster mother
• Prenatal and postnatal BALB environment B6 mice acquired BALB levels of anxiety shown by spending less time in the inner area of open field test
• B6 environment mice showed B6 anxiety levels

Question 6

How does birth weight affect later life risk of diabetes and hypertension? (2)

Answer 6

• Low birth weight is a strong predicter of increased risk of chronic disease in later life (diabetes, hypertension, heart disease, obesity etc.), graded relationship
• E.g. <2.5kg have 6 fold increased risk of diabetes than >4.3kg

Question 7

What may explain the link between low birthweight and hypertension? (2)

Answer 7

• Low birthweight correlates with lower number of glomeruli in the kidney i.e. reduced kidney function
• Kidneys filter blood and regulate blood pressure

Question 8

What is the thrifty phenotype hypothesis? (3)

Answer 8

• Low nutrition during gestation causes alteration of physiological set points to enhance storage of available energy supplies postnatally which results in increased risk of diabetes/hypertension/metabolic syndrome in later life
• Adaptive if nutrition is limited after birth, maladaptive if the environment changes unexpectedly
• Hales and Barker, 2001

Question 9

What is a PAR? (2)

Answer 9

• Predictive adaptive response
• E.g. thrifty phenotype which illustrates the developmental origins of health and disease (DOHaD) concept

Question 10

What is evidence of the thrifty phenotype? (3)

Answer 10

• Mean birth weight is lowest in India and south east Asia
• These countries have greatest prevalence of diabetes
• Consequence of environmental mismatch in early life and adulthood

Question 11

How did the Dutch famine 1944-1945 affect babies conceived during this time? (2)

Answer 11

• 8 fold increased risk of metabolic disease in adults who were conceived/first trimester during the famine
• Specific DNA methylation differences in adults who were in early gestation during the famine

Question 12

Which genes had specific changes to DNA methylation in famine-exposed embryos? (6)

Answer 12

• CDH23
• RFTN1
• CPT1A
• SMAD7
• INSR
• KLF13

Question 13

How does a selection hypothesis explain the role of DNA methylation in the thrifty phenotype? (5)

Answer 13

• Genome wide DNA demethylation in the zygote followed by DNA remethylation
• Remethylation provides an opportunity for variation in DNA methylation patterns
• Patterns that confer a selective advantage for the developing embryo during nutritional adversity are selected for
• These will promote transcription of genes that promote survival in poor nutrition conditions and promote the thrifty phenotype
• Resulting predisposition to chronic disease in adulthood if energy-dense diet is consumed

Question 14

Why is DNA methylation affected by diet?

Answer 14

SAM derived from methyl donors in the diet e.g. folate

Question 15

What is the methyl donor required for methylation?

Answer 15

S-adenosyl methionine (SAM)

Question 16

How does restricted maternal diet during foetal gestation affect DNA methylation? (2)

Answer 16

• Restricted maternal diet causes reduced DNA methylation and increased transcription of genes involved in fat metabolism (PPARalpha) and gluconeogenesis (GR) in offspring
• Folate supplementation prevents loss of DNA methylation and increased transcription of genes involved in fatty acid metabolism and gluconeogenesis caused by dietary restriction

Question 17

What is the impact of postnatal nutrient-rich diet in offspring after exposure to restricted maternal diet during gestation? (2)

Answer 17

• Nutrient-rich diet amplifies obesity and insulin resistance more after restricted prenatal maternal diet compared to normal prenatal maternal diet
• Nutrient-rich diet is disease-inducing in itself

Question 18

What is an example of a thrifty gene? (4)

Answer 18

• PPAR-gamma2 transcription factor promotes lipid synthesis/formation of lipid droplets in the liver
• Polymorphism at position 12 can code for alanine or proline
• Homozygosity for alanine at position 12 predisposes to type II diabetes (especially in low birth weight individuals) which can be prevented by dietary intervention and exercise
• The allele that predisposes to diabetes is also most responsive to improved diet and exercise