W8L3 Fri DOHaD

Question 1

what is DOHaD

Answer 1

Developmental Origins of Health & Disease: perturbations to developing organism that program later disease in adulthood

Question 2

cause of DOHaD

Answer 2

§ Natural perturbations: maternal size affects placenta size which affects oxygen + nutrients foetus receives
§ Non-natural perturbations: maternal diet, infections, smoking/alcohol/drugs/chemicals (EDCs)

Question 3

Barker hypothesis

Answer 3

early infant conditions can have permanent conditioning effect on metabolism + chronic conditions later in life (areas of high infant mortality correlated with areas of high heart disease incidence)

Question 4

Critical period of DOHaD

Answer 4

• Adult health can be influenced by exposure to
  perturbations during
   fetal life
   infancy
   early childhood
  -the first 1000s day of life

Question 5

Hertfordshire Study

Answer 5

-15,000 men and women born between 1911-1930
-Risk of death from heart disease doubled when born <2.5kg

Question 6

‘The Dutch hunger winter (1944-45)’

Answer 6

-Limited food availability toward the end of the war
-400-800 calories/person/day = ↑rates of glucose intolerance (diabetes), blood pressure (hypertension), blood lipids (stroke), breast cancer + obesity in women

Question 7

famine and catchup growth

Answer 7

Ø Exposure to famine within first 9 weeks = normal birth weight, after 9 weeks = reduced birth weight
§ Both had ↑risk of obesity + metabolic syndrome
Ø Catch-up growth: perturbation (within 9 weeks pregnant), nutrition restored = foetus catches up to normal BW
Ø Catch-up growth postnatally: perturbation (after 9 weeks pregnant), nutrition restored after birth, postnatal catch up
§ Restricted to those prematurity >37 weeks, <37 weeks don’t catch up to estimated BMI
§ Fat mass catch-up + no lean body mass = risk of obesity + metabolic syndrome

Question 8

Thrifty phenotype hypothesis

Answer 8

conditions in utero are predictive of conditions that will be experienced in post-natal life
Ø Environmental clues (calorie restriction) = growth restricted = prepare for survival in environment short in resources

Question 9

developmental plasticity: predictive adaptive response hypothesis

Answer 9

Ø Environmental cues determine phenotype; environment may not be same as what environmental cues predicted
Ø Lifestyle mismatch: growth restriction → thrifty phenotype (↓calories, metabolism, energy expenditure) →
higher risk of metabolic disorders (diabetes II, obesity)

Question 10

effect of high BW and large for getational age

Answer 10

§ Hertfordshire study: ↑risk of death when birth weight >4.5kg
§ Large for gestational age (LGA) babies >4.1kg had ↑risk of obesity, heart disease, diabetes + cancer

Question 11

Gestational diabetes (GDM)

Answer 11

placenta produces hormones that ↓insulin resistance (mother may be overweight, high blood sugar or predisposed to diabetes) = ↑circulatory blood glucose = ↑growth of baby = obesity + metabolic syndrome
Ø LGA babies from mothers with GDM have ↑risk of metabolic syndrome + obesity during childhood

Question 12

what is a strong predictor for obesity in adult

Answer 12

Rapid catch-up growth + accelerated growth are strong predictors of obesity in adults

Question 13

Metabolic Syndrome

Answer 13

-a cluster of metabolic abnormalities that result in an increased risk for type 2 diabetes mellitus, obesity and cardiovascular disease in adult
- include: distorted appetite signalling, abnormal kidney signalling , insulin resistance, adipocyte size + no., ↓beta-cell no., expression/production of adipokines, cardiomyocyte no., hypertension, ↓incretin production

Question 14

Type 2 diabetes

Answer 14

loss of beta-cell = ↓insulin production, insulin resistance (liver + muscle cells) = glucose not absorbed + ↑blood = ↑obesity as body storing excess glucose as fat
Ø Healthy: pancreas secretes insulin which binds to insulin receptor + regulates glucose absorption

Question 15

Developmental Programming Hypothesis

Answer 15

§ Early-life environment influences offspring characteristics in later life, including susceptibility to development of obesity
+ related metabolic disorders
§ Effects of developmental programming may be transmitted to future generations without further environmental stress

Question 16

Multi-generational epigenetic inheritance

Answer 16

: somatic epimutations are non-heritable; germline epimutations are heritable

Question 17

Epigenetic modification

Answer 17

Structural changes to DNA or DNA-associated proteins which regulate gene expression without altering the nucleotide sequence
Ø ↑methylation = ↓expression: methyl groups help keep DNA wrapped on histones (DNA inaccessible, gene inactive)
Ø ↓methylation = ↑expression: DNA accessible, gene active

Question 18

Trans-generational nutritional restriction effects experiment

Answer 18

§ F0 population uterine ligation during pregnancy = ↓nutrients in foetus
Ø F1 population: growth restricted; higher risk of obesity + metabolic syndrome
Ø F2 population: same phenotype as F1 (even if only 1 parent)
Ø Blastocyst maternal/paternal line ↓gene expression in a major growth pathway (cell proliferation, protein translation, apoptosis)

Question 19

Maternal diet and oocyte

Answer 19

-lipids + sugar alter mitochondrial activity; micronutrients impact DNA modifications
-altered growth in zygote + impaired embryo growth + health in offspring

Question 20

Paternal lifestyle affect oocytes

Answer 20

environmental/lifestyle insult
→ affects sperm during development (testes) or maturation (epididymis)
→ epigenetic modifications + changes in histone-bound DNA
→ altered gene expression in zygote
→ impaired embryo growth + health of offspring + germ-line epigenetic modification

Question 21

Maternal lifestyle affect offspring

Answer 21

maternal overnutrition, diabetes + obesity
→ germline modifications of foetal gametes
→ epigenetic modifications or mitochondrial modifications/dysfunction
→ altered gene expression in zygote

Question 22

ART effects

Answer 22

• The time around conception is considered one of the most vulnerable periods to adverse influences (perturbations)
• Embryo culture involves potentially inappropriate environmental factors
• e.g. use of different culture media can significantly affect birth weight
• Furthermore, obese parents undergoing IVF also have reduced blastocyst development and live birth rates
• Long term outcomes include increased risk of cardiometabolic, immunological & neurological disorders.
• 2nd generation effects unknown but likely affected

Question 23

Non Traditional
Animal Models

Answer 23

§ Traditional models: both mother + father affect growth + development of foetus which can lead to metabolic disorders
§ Marsupial models: short gestation, long lactation
Ø Milk composition: initially high in carbohydrates, then high in lipids + protein
Ø Foster forward: 60 day old pouch young transferred to 120 day teat = ↑body weight, growth + developmental
milestones accelerated, pouch exit accelerated, obese
Ø Mammary gland index positively correlates with milk production (primiparous females ↓milk production = ↓growth)