Module 2 - part 1 developmental origins of health and disease (DOHaD) Flashcards
time when nazi germany restricted food to the netherlands
The hunger winter (94/95)
the hunger winter
- well fed at conception, malnourished during final months
- born small
- stayed small whole lives
- below average obesity
*effects passed to grandchildren
the hunger winter
- malnourished first few months, well fed after
- large baby (fetus caught up)
- higher obesity rates
- numerous other health problems (mental health)
The Barker hypothesis
- aka DOHaD hypothesis
England and Whales study
“adverse influences early in development, and particularly during intrauterine life, can result in permanent changes in physiology and metabolism, which result in increased disease risk in adulthood”
- positive correlations between HD and infant mortality
- both sexes, all ages, different geographical regions
- adverse effects of poverty on maternal nutrition and lactation
- also seen in nodular goitre (iodine)
Nutritional perturbations during pregnancy
- trimester 1
- embryonic growth influenced by nutrients
- hyperglycemia (maternal diabetes) delays embryonic growth
Nutritional perturbations during pregnancy
- trimester 2
- complex relationship between fetus, placenta and mother
- nutrient deficiency affects placental function
Nutritional perturbations during pregnancy
- trimester 3
- undernutrition slows fetal growth to maintain placental function
- effects on fetus depend on duration
intrauterine environment influences
nutrient and O2 supply to fetus
undernutrition lowers which hormones
- affect
- treatment
fetal and placental hormones
- insulin, insulin-like growth factors (IGFs)
- affects pancreatic development
- glucose infusion fixes problem
relationship between placental weight and birth weight
- babies who develop diabetes have small placentas in relation to birthweight
causes of increased risk of developing adult disease
- how?
undernutrition
- hypoglycaemia
over nutrition
- hyperglycaemia
Others
- maternal contraint
- disease
- placental function
- imprinted genes
how
- changes in metabolism, hormone production and tissue sensitivity to hormones
Hypothesized mechanisms of increasing adult disease risk
- altered fetal nutrition
- exposure to stress / high levels of glucocorticoids
- thrifty phenotype hypothesis
- genetic / epigenetic influence
altered fetal nutrition
- under/over nutrition
- effects depend on
undernutrition
- reduced birth weight
- increased BP
- impaired glucose tollerance
over nutrition (high fat or high kcal)
- impaired glucose homeostasis
- hypertension
effects depend on
- offspring sex
- estrogen levels
- diet composition
- exposure to postnatal factors
exposure to stress / high levels of glucocorticoids
glucocorticoids
- dexamethasone (exogenous) and cortisol (endogenous - stress)
- high levels = low body weights, and high BP
normal function
- cortisol deactivated by 11beta-hydroxysteriod dehydrogenase 2 (11B-HSD2)
- doesnt block dexamethasone
- low levels, more active cortisol get in
thrift phenotype hypothesis
malnurished
- fetus lowers insulin levels so more glucose in blood for brain and heart
- reversible, but will make permanent changes if persist
- leads to T2D when in real world
genetic / epigenetic influence
- amount of methyl donors (choline, folate)
- changes in proper methylation
- epigenetic influences may not show until later in life, environmental cues (eg. high fat diet)
- changes extend to F2 generation
epigenetic landscape
Conrad Waddington 1940
- interaction of genes with their environment, which bring the phenotypes into being
- “little nudges”
- pleuripotent cells -> cell differentiation -> acetylation + methylation
epigenetics
- methods
inheritable changes in genes that are not encoded by DNA sequence
- DNA methylation
- histone modification (acetylation, methylation, etc.)
histone code
collection of all modifications to histones, including acetylation, methylation, phosphorylation, and ubiquitination
epigenetic events affect
cell differentiation
x-chromosome inactivation
genetic imprinting
CpG islands
CG content - 42%
- linear relation b/w # genes and # CpG islands per Mb
- 19, 22, 17, 16 more
- islands 60-70% CG content (*only 1/5th of what expected)
- under-represented bc ‘deamination’ of cytosine
methods of deaminate cytosine
depends on methylation state
- removal of amine group (NH2)
unmethylated -> uracil
- changes detected by DNA repair mechanisms (because not a nucleotide in DNA)
methylated -> thymine
- not corrected bc repair mechanisms dont recognize error
how histones effect modification
active gene
- unmethylated cytosines
- acetylated histone tails blocks DNA wrapping around histones
inactive gene
- methylated cytosines (DNA methyltransferase DNMT)
- deacetylated histone tails
adding and removing acetyl groups
HAT -> histone acetylase (active gene)
HDAC -> histone deacetylase (inactive gene
how food alters epigenome
- contains inhibitors and activators of chromatin remodelling enzymes
- dna methyltransferases, histone acetylases etc
- used to “program” epigenome
dietary compounds that influence methylation
folate and B12 (choline another methyl donor)
- folate passes methyl group to vit B12
- methyl group used by DNA methyltransferase onto genome
epigenetic variation wrt mother and offspring
inherited through mitosis and meiosis
- nutr status, diet composition, xenobiotics, reproductive factors, radiation etc. of prenatal + early postnatal
sensitive regions to epi change
- promotor regions
- “metastable epialleles” -> regions modified in an variable and reversible manner
epigenetic changes during development
“global demethylation events”
- occur during gamate development
- primordial germ cells (PGCs)
- re methylation during development
- sperm and oocyte still methylated
- global demethylation during zygote formation
- embryo re methylation, placenta remains lower methylation
how methylation affects gene expression
- gene promotors
effect gene promotors
a) silences DNA regions
b) insertions into sensitive methylation regions alters final gene product (DNA spliced into exon - new product)
c) promotors normally silence that become active influences gene product (promotors can work against each other)
Epialleles
- genomic regions which epigenetic status “varies” amongst individuals in a population
- methylation and histone acetylation most common
3 types of epialleles
1. obligatory cis - within a gene trans - somewhere else besides the gene 2. facilitated epiallele 3. pure epiallele
obligatory epiallele
result of ‘mutation’ or change in DNA (SNP, insertion, deletion)
cis - epigenetic change at gene
trans - epi change somewhere else
ex. loss function of DNMT1
facilitated epiallele
mutation epigenetic change depends on environmental factor present (strocastic factor)
- low/high amounts of methyl done in diet
ex. agouti mouse
pure epiallele
no DNA change required
- DNA already capable of methylation
- depends on environmental factors only (strochastic factor)
ex. imprinted genes
methylation patterns between tissues
- aging?
great variability
- important consequences on gene expression
aging (twin study)
- similar methylation/acetylation patterns at 3yrs old
- huge differences at 50yrs of age
*shows environmental influence exists
The Axin Fused mouse
murine axin gene
- expressed in embryo and adult
- high range of methylation (shown in kinkyness of tail)
- transposable element in intron 6 influences downstream promotor
- ex. of facilitated epiallele
- more methylation, the straighter the tail
Agouti mouse
encodes signalling molecule that promotes yellow follicular pigment
- transposable element 100kb upstream
- hypo- to hyper- methylated
- facilitated epiallele
- supplementing folate, choline, B12 alters phenotypes of offspring
bariatric surgery effect on offsrping
human example
- 6000 genes differentially methylated (gluc homeostasis and inflammation)
- offspring lower obesity, improved cardiovascular
