lecture 24: developmental origins of health and disease (DOHaD) Flashcards
1
Q
What are developmental origins of health and disease?
A
- pertubations to the developing organism that programme later disease in adulthood
- coronary heart disease
- hypertension
- type-II diabetes
- stroke
- osteoporosis
- cancer
2
Q
What are examples of pertubations?
A
- natural
- maternal size
- nutrients
- hormones
- oxygen
- non-natural
- smoking
- alcohol
- drugs
- maternal diet
3
Q
What links infant mortality and heart disease?
A
- infant mortality and heart disease are linked geographically
- heart disease is now common in places where death rates among babies had been high at the beginning of the 20th century
4
Q
What was the hertfordshire cohort?
A
- 16,000 men and women born between 1911-1930
- risk of death from heart disease doubled when born less than 2.5kg
- in hertfordshire men weight was still predictive at one year (smaller had greater hazard ratio)
- risk is always a little higher in men compared to women
- increase also occurs at very large body weight
5
Q
What was the Dutch hunger winter?
A
- 1944-45
- 400-800 calories/person/day = less than 35% of daily intake
- compared to population at the time that was well fed
- increased glucose intolerance (diabetes)
- increased blood pressure (hypertension)
- increased blood lipids (stroke)
- increased rates of breast cancer
- increased rates of obesity (women)
6
Q
What is the thrifty phenotype hypothesis?
A
- growth restriction during development
- feotus predicts decreased calories, metabolism and energy expenditure (thrifty phenotype)
- lifestyle match: store calories, grow quickly, reproduce ‘live fast, die young’
- normal growth
- normal calories, metabolism, energy expenditure
- normal phenotype
- burn calories, grow proportionally, live long ‘live long and prosper
7
Q
What is catch-up growth?
A
- babies born below average tend to have more rapidly increasing weight and BMI
- led to coronary heart disease in later life
8
Q
What is happening in western society?
A
- mismatch between foetal prediction and lifestyle
- causing real problems in weight and incidence of diabets globally
9
Q
What happened during paleolithic evolution?
A
- this wasn’t really a problem
- if you were going to experience a pertubation in utero it wasn’t going to be a problem for you in later life because most men died around 26 about 10,000 years ago
- as we’ve gone through history our mean age has gotten much older
- so experience these insults much more
10
Q
What is the potential impact of larger sizes?
A
- big babies: high birthweight may signal later health risks
- bigger than 4.1kg = obesity, diabetes, heart disease, cancer
- 19 pound baby born to mother with gestational diabetes relative to other babies
11
Q
What is gestational diabetes?
A
- overweight and obese women at high risk
- placenta blocks activity of insulin during pregnancy to maintain adequate nutrition to the foetus
- you get positive feedback loop where blood sugar is kept very high
- baby much larger at birth
- risk of being overweight, high blood sugar, predisposition to diabetes
12
Q
What is the growth trajectory of babies that later develop diabetes?
A
- if we look at the growth rate of both small and large babies at birth
- height, weight, bmi
- height not so much affected in low weight babies, weight and BMI sort of normalies to average weight and BMI but take off on this trajectory upwards
- true for large weight babies
- try to normalise relative to average and after 1 year sky rockets in these babies that go on to develop type II diabetes
13
Q
What is a summary of human association studies?
A
- growth restriction (less than 2.5kg)
- catch up growth in infancy and childhood
- increased risk of chronic disease
- health range 2.5kg - 4.1kg
- more than 4.1kg
- e.g. due to gestational diabetes - foetal overgrowth
- weight gain in infancy and childhood
- increased risk of chronic disease
14
Q
What is an overview of the variety of tools used to modulate maternal and foetal status during pregnancy in small and large animals?
A
- no dutch binge eating study to demonstrate obesity association
- animal models
- restricted micronutrients
- ca
- na
- fe
- zn
- uterine ligation
- placental restriction
- natural variation in birth weight
- global restriction
- mild
- moderate
- severe
- restricted micronutrients
- protein
- high levels micronutrients
- fat
- protein
- cafeteria (high fat high sugar)
- restricted micronutrients
15
Q
What happens in animal models with high maternal obesity, high BMI and/or gestational diabetes?
A
- placental abnormalities, disrupted nutrient supply to foetus
- environmental factors, stress, infection
- developmental adaptations: cell number, differentiation, gene expression, hormone levels, cell cycle, CNS function, organogenesis, lipid metabolism, insulin resistance
- affects: liver, adipose, pancrease, muscle, brain, heart, repro tract
19
Q
What are epigenetic effects?
A
- timing of famine:
- early gestation vs mid-late gestation
- birth weight:
- normal vs growth restricted
- % obese as adults
- highest (epigenetic changes) vs lowest
- drove the idea that epigenetic genetic modification was important
20
Q
What did the dutch hunger winter cause?
A
- epigenetic modifications to the developing embryo
- decreased methylation of insulin-like growth factor 2
- persistent epigenetic differences associated with prenatal exposure to famine in humans (PNAS)
21
Q
What are two pathways to disease risk?
A
- we see a pertubation causing restriction or overgrowth thereby restricting/altering the number of cells in the body → catch up growth in infancy and childhood, increased risk of chronic diase
- epigenetic modification → weight gain in infancy and childhood, increased risk of chronic disease
23
Q
How early does parenting start?
A
- from before conception
- in vivo oviductal fluid (e.g. protein, bacterial infection, altered cytokine balance)
- or IVF environments (changed aas, glucose, lipids, cytokines, growth factors, o2, temp, mechanophysical)
- altered metabolism, differentiation
- offspring phenotype
- increased insulin resistance
- increased blood pressure
- increased body weight and fat
24
Q
What is the importance of male gametes?
A
- donated genes
- but also their development is important to health of embryo
- the sperm of obese fathers can influence the development of the embryo and possible health related matters in later life
- paternal lifestyle affects offspring
- environment/lifestyle insult
- toxins
- endocrine disrupters
- smoking
- obesity
- insult affects sperm during development in testes or during maturation in the epididymis
- changed histone-bound DNA, changed microRNA, increased DNA breaks
- altered gene expression in zygote
- impaired embryo growth and health of offspring
- paternal diet-induced obesity retards early mouse embryo development, mitochondrial activity and pregnancy health
28
Q
What are prevalence estimates for diabetes in 2025?
A
- diabetes is going to be a big problem in the future
- can be caused by eating the wrong foods
- effect of previous generation?
30
Q
To what do marsupials give birth?
A
- marsupials give birth to immature young that develop outside the mother
- spend next 9-10 months in the pouch developing
- what is the effect of changing different things - easily studies
31
Q
What happens in the pouch?
A
- long development in the pouch
32
Q
Does growth rate affect later physiology?
A
- yes
- can achieve massive differences in growth trajectory by changing the nutrition
