Early life conditions and adulthood disease

Question 1

The 4 Hypothesised mechanisms

Answer 1

• Thrifty Phenotype (survival right here right now)
• Maternal effects (predicting short-term environment)
• Predictive adaptive responses (predicting long-term environment)
• Matching

Question 2

Evidence for importance of early developmental conditions

Answer 2

• Small babies have an increased risk of dying from heart disease in adulthood - Osmond et all 1993 BMJ.
  (Tendency to blame mum for birth condition of baby -smoking, eating badly etc.)
• England, 1920s: Local infant mortality rate predicts risk of death from coronary heart disease years later - Barker & Osmond 1986 Lancet
  (Birth weight also predicts many other adult diseases (high blood pressure, cholesterol, diabetes, obesity, stoke) – ‘metabolic syndrome’ or ‘syndrome x’, of major public health concern, costly to NHS)
• Small baby boys from 1930s had reduced marriage prospects in Finland and England - Phillips et al. 2001 Br. Med. J.

Question 3

Thrifty Phenotype Hypothesis (1992)

Answer 3

“We propose that type 2 diabetes is the outcome of the foetus having to be nutritionally thrifty” - Hales and Barker 1992, Diabetologica
• Foetus changes structure and function of tissues because they help it to cope with a reduced nutrient supply there and then
• Cutting corners allows the offspring to survive right here, right now
• Developing slowly and being small at birth better than dying

Question 4

Thrifty phenotype as an adaptive maternal effect (2001)

Answer 4

“The poorly nourished mother gives the foetus a forecast of its post-birth nutritional environment. The adaptations only become detrimental when the postnatal environment and mother’s forecast differ” - Hales and Barker 2001, British Medical Bulletin
• i.e. Foetus changes structure and function of tissues because they help it to cope with a reduced nutrient supply in the short-term future
• Restraint of foetus in developmental stage to ensure it’ll survive outside of the womb (during suckling period)

Question 5

Predictive adaptive response (PAR) (2004/5)

Answer 5

“PARs are induced by environmental factors acting in early life, not as an immediate physiological adaptation, but as a predictive response to expected future environment” “The induction of PARs will confer a survival advantage in the predicted reproductive environment” - Gluckman et al. 2005 TREE Gluckman & Hanson 2004, The Fetal Matrix
• i.e. fetus changes structure and function of tissues because they help it to cope with a reduced nutrient supply in the long-term future
• The reason you don’t take as much nutrition now, is that you will be in better shape when you need to reproduce yourself (when the poor environment is likely to still be the same), if you don’t invest everything now in growth

Question 6

Matching between maternal and offspring phenotype (2007)

Answer 6

“The thrifty phenotype has been favoured due to its capacity to improve the fit between offspring and maternal phenotypes, and represents a mechanism to maximise maternal, rather than offspring, fitness.” Wells 2007, Biological Reviews
- i.e. fetus changes structure and function of tissues so that its metabolic demands will match that which its mother can provide from utero to childhood

Question 7

Big question

Answer 7

Are there real short/long-term benefits of changes (small size/insuline resistance etc.) associated with poor early environment compared to not making those changes - or are small size etc. just consequences of constrained maternal environment?
Costs of reproductive success, costs of getting the ‘prediction’ about environment wrong?

Question 8

Catch-up Growth

Answer 8

• If you are born small, and stay small from birth onwards – not so bad
• If you are born small then improve/grow from extra nutrition, problems start occurring.
• Born healthy then environment worsens? Effects unknown.
• Heart disease risk in relation to birth size and size at 12 - Eriksson et al. 2001 BMJ
• Baby girls whose mum was starving produce themselves offspring with increased mortality risk (Dutch famine 1944-45) - Lumey & Stein 1997 Am J Publ Health.
• Most damage if mother was exposed to famine in her 1st & 3rd trimester as foetus. Fathers exposure to famine had no effect.

Question 9

Why does birth weight vary among women?

Answer 9

• Genetic explanation is unlikely, as birthweight related to maternal size, not to paternal size
• Proved by crossing Shetlands and shire horses - Walton & Hammond 1938 Proc. R. Soc. Lond. B
  (o Sheltie father, shire mother = offspring are big
  o Shire father, sheltie mother = offspring are small)
• Biggest morphological predictor of birth weight: maternal pelvic size
  • Low nutrition of mother determines smaller pelvic size, hence smaller children in her turn?

Question 10

Why is early environment associated with adult disease?

Answer 10

Cohort effects or maternal effects on intrauterine growth, with downstream effects on adult phenotype
• Animal experiments help give answers – e.g. Bertram & Hanson 2001 Br. Med. Bull.
• It is the long-term effects that are the most important.
- Foetal gene expression → nutrient availability effects hormonal control → influences long-term changes in body structure, physiology and metabolism → consequences for adulthood health
- long-term effects most significant, rather than genetic or correlations between birth/adult environment