Developmental Origins of Health and Disease Flashcards
What is DOHAD?
• Events during development ‘program’ the risk of disease in adulthood. Adverse environments disrupt normal fetal growth and development, and this leads to increased susceptibility as adult to CV and metabolic disease.
What is the Barker Hypothesis, and what evidence supported it
• DOHAD idea first suggested in 1989s by Barker
• Study of men and women born in Hertfordshire → correlation between LBW and incidence of deaths from CVD
− Almost 50% higher risk 4kg
What are the more recent developments that resulted in Fetal Programming being changed to DOHAD?
• Not limited to LBW, HBW is also a factor
• BW doesn’t actually seem to be the important factor, it is a surrogate marker for suboptimal environment
• Evidence that pre-term birth is risk factor (more time in incubator)
• Not limited to the fetal period → preconceptual, early pregnancy, throughout pregnancy, postnatal (2-4 years)
→ thus coined the term DOHAD
What diseases and conditions are linked with birthweight?
- Cardiovascular → stroke, coronary artery disease
- Metabolic → glucose tolerance, obesity *
- CNS → IQ, depression, neurodevelopment
- Autoimmune → thyroiditis, rheumatoid disease*
- Respiratory → chronic lung disease, asthma
- Cancers → Breast, testicular, prostate, leukemia
- Musculoskeletal → osteoporosis
- Genitourinary → PCOD*
What is the idea around ‘mismatch’ of environments?
• One of the leading theories is a mismatch between the pre-natal and post-natal environment.
• Eg) Fetus receiving low pre-natal nutrition → low BW. Fetus makes adaptations so it can survive in the low nutrition environment
− Physiological adaptations to adverse environment → benefit fetus in short term, harmful in the long term.
− Preparation for sub-optimal environment after birth → altered HPA axis (more glucocorticoids), altered metabolism, promote fat gain, elevated insulin levels.
• If post-natal environment does match anticipated environment (eg, food is abundant) they will have a rapid catch up of growth
− Obesity, insulin resistance, high BP, CVD, exaggerated stress response
• Combination of low prenatal nutrition and abundant post natal nutrition is the worst combination.
What would be the effect of a suboptimal environment during different developmental windows?
Evidence to suggest effect of supoptimal environment depends upon the time of the insult (ie, during what developmental window)
− Kidneys → fewer nephrons developing linked to high blood pressure and kidney disease
− Pacnreas → could affect beta cell production leading to diabetes
− Brain → psychological and behavioural problems (particularly a problem in pre-term birth as a lot of brain development happens in the third trimester).
− Placental development → could affect all organs in the future
What is the effect of stress pre-pregnancy on the fetus?
Khashan et al, 2009
• Study looked at effect of death or illness of close relative during pregnancy
• 16% increased risk of pre-term delivery with pre-pregnancy stress (6 months prior to pregnancy)
What is the effect of peri-conceptual undernourishment on the fetus?
Blooomfield et al, 2003
• Study used a sheep model of protein restriction – sheep fed 50% reduced protein diet from 60 days before pregnancy → 30 days of pregnancy
• Babies were an appropriate size, but born prematurely, resulting in neonatal death
• Labour was triggered prematurely due to premature activation of fetal HPA axis
• Fetal stress was caused by undernutrition, and this lead to activation of the HPA axis.
Is the same thing true in humans? Hard to study because cant put them on a known severe diet but
• Women with low pre-pregnancy BMI have:
− Increased risk of pre-term delivery
− Insulin resistance and high BP in offspring
• Women from the Dutch Hunger Winter (1944-45) with calorie restriction to 800 showed evidence of earlier delivery
What is the effect of undernutrition during the pre-implantation period on the fetus?
Maternal Undernutrition during the Preimplantation period
Kwong et al, 2000:
• Female rats fed low protein diet (95) during pre-implanation period then return to control die
• Blastocysts found to have reduced cell numbers
• Offspring had:
− Reduced BW (female only)
− Accelerated postnatal growth
− Hypertension
- Seems preimplantation embryos are very vulnerable to environmental factors
- This can be an issue for IVF as fetus in culture up to blastocyst stage
What are the effects of IVF and embryo culture on embryonic development?
Effects of IVF & Culture on Embryo Formation
Giritharan et al, 2007
Comparing mouse embryos from
• In vivo fertilization → normal
• In vivo fertilization and embryo culture (IVC) → fertilized in vivo, then collected and cultured to blastocyst
• In vitro fertilization and embryo culture (IVF)
Results
• IVC had reduced cells in the ICM and TE
• IVF had reduced cells in the TE
• Don’t really know what affect this has on the fetus → still able to form embryo and placenta, but does suggest culture conditions have a strong effect on fundamental processes eg) proliferation, apoptosis, allocation to specific lineages.
Effects of Embryo Culture on Gene Expression
• Embryo culture alters placental gene expression
− Reduced mRNA of GLUT genes
− Reduced mRNA of system A genes
− Reduced mRNA of 11B-HSD2
− Reduced mRNA of IGF-2
• Imprinted genes especially susceptible
• Gene imprinting
− Normally genes expressed bi-allelically
− Imprinting – inactivation of allele from mother or father
− Only one allele expressed – monoallelic
− Imprinted genes important for fetal growth
➢ Maternal genome contributes to development of fetus
➢ Paternal genome contributes to development of extra-embryonic tissue
Rivera et al, 2008
• Loss of genomic imprinting with suboptimal culture conditions
− H19 normally monoallelic
− After mouse embryo culture it is bi-allelic
− H19 is a negative regulator of IGF-2
− IGF-2 promotes placental development and transporter activity
− 2x expression of H19 = reduced IGF-2 expression → can therefore effect placental function
Loss of imprinting also has effects on behavior
• Angelman, Prader-Willi, Beckwith-Wiedermann syndromes
• Associated with behavioural abnormalities
• Higher incidene in ART → is it due to culture of embryos?
What are the long-term effects of IVF and embryo culture?
Long term effects of embryo culture:
Ecker et al,
• Compared in vivo embryos with those cultured in 2 different culture media
• Transferred to recipient mother
• Examined effect on the behavior of offspring as adults
− Mice subject to elevated zero maze
− Relies on the fact mice are apprehensive in open spaces and elevated areas and prefer to spend time in enclosed areas
− Normal animals did this, but those from culture spent more time in open spaces
➢ Cultured embryos had decreased anxiety, or failure to lean (decreased memory)
What are the effects of undernutrition during pregnancy on the offspring?
Effects of Diet on Tissue Structure
• Insults can disturb cell growth and proliferation
• Change in balance of cell number seen in response to altered maternal diet
• Reduction in nephron number observed in response to pre-natal low protein diet in rat → renal disease and hypertension
• Low protein diet also linked to reduced beta cells → diabetes
• Reduced secondary muscle fibres
Effects on Epigenetic Programming
• Early life nutrition may impact histone methylation
• Hypomethylation of genes encodring PPAR and glucocorticoid receptors following a low protein diet resulting in increased expression of these genes
• Hypothethylation of angiotensin receptor seen
Vickers et al, 2000 • Rats fed low protein diet during pregnancy. Offspring had − LBW − Obesity later on − Impaired glucose tolerance − Hypertension
Also effects seen with nutrient rich diet:
• Cafeteria feeding → rats given human food
− Slows fetal growth
− Predispose offspring to adiposity
− Altered feding behavior
− → however, this protocol may have led to nutrient imbalance, establishing commonality with the undernutrition models.
Is the same true for humans?
• Dutch Hunger Winter
− Low BW
− Reduced glucose tolerance in adults
− Evidence of insulin resistance in adults
• Imbalance of protein and carbs during pregnancy results in LBW
• Micronutrients also important → low folate and iron linked with LBW
• Project Viva has reported that blood pressure of 6 month old babies inversely related to maternal calcium intake via supplements
What are the effects of stress during pregnancy on fetal growth?
• 9/11 and natural disasters
− Elevated cortisol levels in babies
− Reduced fetal growth
• Clinical uses of glucocorticoids
− During threatened pre-term labour to promote lung maturation
− However, if these babies aren’t born and continue to term, they have LBW
• Placental 11B-HSD-2 protects against cortisol
− FGR babies have reduced 11B-HSD2
− Fetus exposed to excessive cortisol, giving low birth weight
Are nutrition and stress linked in terms of effect on fetus/offspring?
Langley-Evans et al, 1996
• Pregnancy control rats fed 18% casein, pregnant restricted rats fed 9% casein for 2 weeks prior to mating and throughout pregnancy
• 11B-HSD2 activity measured in placental
➢ Undernutrition in the rat reduces the level of 11B-HSD-2
➢ Therefore, undernutrtion leads to elevated glucocorticoids
Are glucocorticoids the cause of fetal programming?
Raikkonen et al, 2009
Study performed on liquorice consumption in pregnancy
• Liquorice contains glycyrrhiza → an 11B-HSD2 inhibitor
• Consumption common in Scandinavia
• In those with high liquorice consumption ( >500mg/week)
➢ Earlier labour
➢ Cognitive behavioural problems in children → speech, memory, ADHD
➢ Increased cortisol exposure therefore affects brain development
Effects of stress in pregnancy have also been studied in rats
• Rats treated with dexamethasone → reduced BW and reduced placental weight
• Offspring have metabolic syndromes, obesity and hypertension
• High fat diet after weaning exacerbates these effects
Can dietary interventions fix the effects of stress and undernourishment on the offspring?
Wyroll et al, 2006:
Omega 3 fatty acids
• Rats + dexamethosome during pregnancy to induce stress
• Fed on diet high in omega 3’s
• Negative effects on blood pressure blocked by a high omega 3 diet
Vickers et al, 2006
Leptin
• Rats undernourished during pregnancy
• Offspring treated with leptin in neonatal period
• Prevents all aspects of the induced phenotype
− Leptin reduces body fat, increases activity and reduces food intake by increased satiation → resents pathways involved in energy homeostasis
→ None of these have effects on normal rats
