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Lifestyle Genomics nutr 3360 > Module 2 - part 1 developmental origins of health and disease (DOHaD) > Flashcards

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

1
Q

time when nazi germany restricted food to the netherlands

A

The hunger winter (94/95)

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2
Q

the hunger winter

- well fed at conception, malnourished during final months

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

*effects passed to grandchildren

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3
Q

the hunger winter

- malnourished first few months, well fed after

A
  • large baby (fetus caught up)
  • higher obesity rates
  • numerous other health problems (mental health)
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4
Q

The Barker hypothesis

- aka DOHaD hypothesis

A

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)
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5
Q

Nutritional perturbations during pregnancy

- trimester 1

A
  • embryonic growth influenced by nutrients

- hyperglycemia (maternal diabetes) delays embryonic growth

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6
Q

Nutritional perturbations during pregnancy

- trimester 2

A
  • complex relationship between fetus, placenta and mother

- nutrient deficiency affects placental function

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7
Q

Nutritional perturbations during pregnancy

- trimester 3

A
  • undernutrition slows fetal growth to maintain placental function
  • effects on fetus depend on duration
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8
Q

intrauterine environment influences

A

nutrient and O2 supply to fetus

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9
Q

undernutrition lowers which hormones

  • affect
  • treatment
A

fetal and placental hormones

  • insulin, insulin-like growth factors (IGFs)
  • affects pancreatic development
  • glucose infusion fixes problem
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10
Q

relationship between placental weight and birth weight

A
  • babies who develop diabetes have small placentas in relation to birthweight
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11
Q

causes of increased risk of developing adult disease

- how?

A

undernutrition
- hypoglycaemia
over nutrition
- hyperglycaemia

Others

  • maternal contraint
  • disease
  • placental function
  • imprinted genes

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

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12
Q

Hypothesized mechanisms of increasing adult disease risk

A
  1. altered fetal nutrition
  2. exposure to stress / high levels of glucocorticoids
  3. thrifty phenotype hypothesis
  4. genetic / epigenetic influence
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13
Q

altered fetal nutrition

  • under/over nutrition
  • effects depend on
A

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
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14
Q

exposure to stress / high levels of glucocorticoids

A

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
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15
Q

thrift phenotype hypothesis

A

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
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16
Q

genetic / epigenetic influence

A
  • 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
17
Q

epigenetic landscape

A

Conrad Waddington 1940

  • interaction of genes with their environment, which bring the phenotypes into being
  • “little nudges”
  • pleuripotent cells -> cell differentiation -> acetylation + methylation
18
Q

epigenetics

- methods

A

inheritable changes in genes that are not encoded by DNA sequence

  • DNA methylation
  • histone modification (acetylation, methylation, etc.)
19
Q

histone code

A

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

20
Q

epigenetic events affect

A

cell differentiation
x-chromosome inactivation
genetic imprinting

21
Q

CpG islands

A

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
22
Q

methods of deaminate cytosine

A

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

23
Q

how histones effect modification

A

active gene

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

inactive gene

  • methylated cytosines (DNA methyltransferase DNMT)
  • deacetylated histone tails
24
Q

adding and removing acetyl groups

A

HAT -> histone acetylase (active gene)

HDAC -> histone deacetylase (inactive gene

25
Q

how food alters epigenome

A
  • contains inhibitors and activators of chromatin remodelling enzymes
  • dna methyltransferases, histone acetylases etc
  • used to “program” epigenome
26
Q

dietary compounds that influence methylation

A

folate and B12 (choline another methyl donor)

  • folate passes methyl group to vit B12
  • methyl group used by DNA methyltransferase onto genome
27
Q

epigenetic variation wrt mother and offspring

A

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
28
Q

epigenetic changes during development

A

“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
29
Q

how methylation affects gene expression

- gene promotors

A

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)

30
Q

Epialleles

A
  • genomic regions which epigenetic status “varies” amongst individuals in a population
  • methylation and histone acetylation most common
31
Q

3 types of epialleles

A 
1. obligatory
cis - within a gene
trans - somewhere else besides the gene
2. facilitated epiallele
3. pure epiallele
32
Q

obligatory epiallele

A

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

33
Q

facilitated epiallele

A

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

ex. agouti mouse

34
Q

pure epiallele

A

no DNA change required

  • DNA already capable of methylation
  • depends on environmental factors only (strochastic factor)

ex. imprinted genes

35
Q

methylation patterns between tissues

- aging?

A

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

36
Q

The Axin Fused mouse

A

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
37
Q

Agouti mouse

A

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
38
Q

bariatric surgery effect on offsrping

A

human example

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

Lifestyle Genomics nutr 3360 (4 decks)

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