Module 2 - part 1 developmental origins of health and disease (DOHaD)

Question 1

time when nazi germany restricted food to the netherlands

Answer 1

The hunger winter (94/95)

Question 2

the hunger winter

- well fed at conception, malnourished during final months

Answer 2

• born small
• stayed small whole lives
• below average obesity

*effects passed to grandchildren

Question 3

the hunger winter

- malnourished first few months, well fed after

Answer 3

• large baby (fetus caught up)
• higher obesity rates
• numerous other health problems (mental health)

Question 4

The Barker hypothesis

- aka DOHaD hypothesis

Answer 4

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)

Question 5

Nutritional perturbations during pregnancy

- trimester 1

Answer 5

• embryonic growth influenced by nutrients

- hyperglycemia (maternal diabetes) delays embryonic growth

Question 6

Nutritional perturbations during pregnancy

- trimester 2

Answer 6

• complex relationship between fetus, placenta and mother

- nutrient deficiency affects placental function

Question 7

Nutritional perturbations during pregnancy

- trimester 3

Answer 7

• undernutrition slows fetal growth to maintain placental function
• effects on fetus depend on duration

Question 8

intrauterine environment influences

Answer 8

nutrient and O2 supply to fetus

Question 9

undernutrition lowers which hormones

• affect
• treatment

Answer 9

fetal and placental hormones

• insulin, insulin-like growth factors (IGFs)
• affects pancreatic development
• glucose infusion fixes problem

Question 10

relationship between placental weight and birth weight

Answer 10

• babies who develop diabetes have small placentas in relation to birthweight

Question 11

causes of increased risk of developing adult disease

- how?

Answer 11

undernutrition
- hypoglycaemia
over nutrition
- hyperglycaemia

Others

• maternal contraint
• disease
• placental function
• imprinted genes

how
- changes in metabolism, hormone production and tissue sensitivity to hormones

Question 12

Hypothesized mechanisms of increasing adult disease risk

Answer 12

1. altered fetal nutrition
2. exposure to stress / high levels of glucocorticoids
3. thrifty phenotype hypothesis
4. genetic / epigenetic influence

Question 13

altered fetal nutrition

• under/over nutrition
• effects depend on

Answer 13

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

Question 14

exposure to stress / high levels of glucocorticoids

Answer 14

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

Question 15

thrift phenotype hypothesis

Answer 15

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

Question 16

genetic / epigenetic influence

Answer 16

• 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

Question 17

epigenetic landscape

Answer 17

Conrad Waddington 1940

• interaction of genes with their environment, which bring the phenotypes into being
• “little nudges”
• pleuripotent cells -> cell differentiation -> acetylation + methylation

Question 18

epigenetics

- methods

Answer 18

inheritable changes in genes that are not encoded by DNA sequence

• DNA methylation
• histone modification (acetylation, methylation, etc.)

Question 19

histone code

Answer 19

collection of all modifications to histones, including acetylation, methylation, phosphorylation, and ubiquitination

Question 20

epigenetic events affect

Answer 20

cell differentiation
x-chromosome inactivation
genetic imprinting

Question 21

CpG islands

Answer 21

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

Question 22

methods of deaminate cytosine

Answer 22

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

Question 23

how histones effect modification

Answer 23

active gene

• unmethylated cytosines
• acetylated histone tails blocks DNA wrapping around histones

inactive gene

• methylated cytosines (DNA methyltransferase DNMT)
• deacetylated histone tails

Question 24

adding and removing acetyl groups

Answer 24

HAT -> histone acetylase (active gene)

HDAC -> histone deacetylase (inactive gene

Question 25

how food alters epigenome

Answer 25

- contains inhibitors and activators of chromatin remodelling enzymes - dna methyltransferases, histone acetylases etc - used to "program" epigenome

Question 26

dietary compounds that influence methylation

Answer 26

folate and B12 (choline another methyl donor) - folate passes methyl group to vit B12 - methyl group used by DNA methyltransferase onto genome

Question 27

epigenetic variation wrt mother and offspring

Answer 27

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

Question 28

epigenetic changes during development

Answer 28

"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

Question 29

how methylation affects gene expression | - gene promotors

Answer 29

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)

Question 30

Epialleles

Answer 30

- genomic regions which epigenetic status "varies" amongst individuals in a population - methylation and histone acetylation most common

Question 31

3 types of epialleles

Answer 31

``` 1. obligatory cis - within a gene trans - somewhere else besides the gene 2. facilitated epiallele 3. pure epiallele ```

Question 32

obligatory epiallele

Answer 32

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

Question 33

facilitated epiallele

Answer 33

mutation epigenetic change depends on environmental factor present (strocastic factor) - low/high amounts of methyl done in diet ex. agouti mouse

Question 34

pure epiallele

Answer 34

no DNA change required - DNA already capable of methylation - depends on environmental factors only (strochastic factor) ex. imprinted genes

Question 35

methylation patterns between tissues | - aging?

Answer 35

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

Question 36

The Axin Fused mouse

Answer 36

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

Question 37

Agouti mouse

Answer 37

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

Question 38

bariatric surgery effect on offsrping

Answer 38

human example - 6000 genes differentially methylated (gluc homeostasis and inflammation) - offspring lower obesity, improved cardiovascular