DOHaD

Question 1

What is Developmental Origins of Health and Disease (DOHaD)?

Answer 1

Early life as a determinant of long-term health

Question 2

What are maternal factors that can influence health of child?

Answer 2

• Malnutrition
• Chemical exposure
• Diabetes
• Obesity
• Hypertension
• Drug exposure
• Smoking

Question 3

Describe key findings that led to the development of FOAD

Answer 3

• Link between low birth weight and later metabolic disease risk
  * Dependent on adverse uterine environment
• e.g. Dutch Winter Famine (Autumn 1944 - Spring 1945)
• Estimated 20K starved to death and over 4.5 million
  affected by famine - 400-800cal/day
• Effects of famine assessed on births during this period
• Mothers malnourished in first trimester = normal weight
  babies (caught up nutrition in later trimesters)
  * Higher risk of CVD and obesity
• Mothers malnourished in 2nd trimester = normal weight
  babies
  * Kidney or breathing disorders
• Mothers malnourished in 3rd trimester = lean and small
  babies that remained lean in adulthood
• All adults whose mothers experienced famine had impaired
  glucose tolerance (correlates with obesity, diabetes, etc.)
• Reduced insulin secretion or insulin resistance

Question 4

Describe key findings that led to the development of DOHaD

Answer 4

• Exposure to suboptimal environment during pregnancy or
  lactation is associated with multiple adverse health effects from
  birth to adulthood
• Reproductive effects
• Infertility
• Low sperm count/quality
• Developmental effects
• Low birth weight
• Childhood behaviour problems
• Metabolic effects
• Obesity
• Type II diabetes
• DOHad studies help to discover the early mechanistic drivers of
  later life diseases e.g. diabetes
• Uncovering mechanism early in life means interventions can be
  commenced at time of origin of disease

Question 5

Describe the findings from animal models of early life exposure and later disease risk

Answer 5

• Intrauterine growth restriction
  
  • Maternal nutrient deprivation
    
    • Protein restriction
    • Total caloric restriction
      * Uterine artery ligation
      * Hypoxia
• Environmental exposures
  * Phthalates
  * Bisphenol A (BPA)
• Pre-term birth
  * Causes and consequences
  * Ex utero exposure
  * Post-natal care
• All lead to defects in multiple organs - placenta, brain, liver,
  heart, muscle, kidneys or pancreas
• All associated with metabolic disorders (hypertension, liver and
  heart diseases, obesity, diabetes)

Question 6

Describe the effect of ddevelopmental exposure to environmental chemicals

Answer 6

• Bisphenol A present in everything we drink, eat and touch
  * Exposure unavoidable because of ubiquitous exposure
• Mouse model: female mouse exposed to BPA via food crossed
  with unexposed male
  * Mice maintained on BPA diet from 2 weeks prior to
  conception, throughout mating, gestation, etc.
  * Control, lower and higher dose BPA diet
• After birth, offspring maintained on a controlled diet and health
  and well-being measured
  
  • Male offspring had effects (sex-specific effect):
    
    • Obesogenic phenotype
    • Pancreatic islet dysfunction
    • Increased diabetes risk

Question 7

What are the limitations of human studies and provide some findings of a recent study?

Answer 7

• Limited to accessible tissues e.g. only post-mortem
• Cannot have long-term follow-up feasibly
• Study of human amniocytes to determine whether early life
  phenotypic changes associated with BPA exposure would alter
  genome (based on methylation)
  
  • Amniocytes
    
    • Pluripotent progenitor cells
    • Primarily derived from foetus (accessible)
    • Stem cell like qualities
    • Express stem cell markers
• Distal interactions of multiple genes - changes in gene expression and methylation pattern