Module 2: Epigenetics & Gestational Diabetes

Question 1

Birth weights of offspring from mothers affected by the hunger winter

Answer 1

Mother well-fed at conception, malnourished during last trimester = baby small at birth, remained small

Mother malnourished during first trimester only = baby normal at birth, higher rates of obesity, normal and mental health problems

• can carry to grandchildren!

Question 2

The barker hypothesis

Answer 2

“Developmental origins of adult diseases”
-infant mortality can serve as a marker for poverty
-poverty can affect maternal nutrition and breast milk quality
-areas w higher infant mortality rates also have higher rates of heart disease (approx 50 years later)

Question 3

Nutritional perturbations during pregnancy- trimester 1

Answer 3

EMBRYONIC GROWTH slowed by undernutrition, over-nutrition cause hyperglycemia (gestational diabetes)

Question 4

Nutritional perturbations during pregnancy-trimester 2

Answer 4

Undernutrition affects PLACENTAL FUNCTION - alters relationship between fetus, placenta, and mother

Question 5

Nutritional perturbations during pregnancy - trimester 3

Answer 5

Undernutrition slows FETAL GROWTH to maintain PLACENTAL FUNCTION
-effects on fetus depends on deficiency duration

Question 6

Undernutrition on fetal and placental hormones

Answer 6

Lowers hormones (insulin, IGF), affects pancreatic development

Question 7

Relationship between placental weight and birth weight

Answer 7

small placentas (in relation to birthweight) associated with babies who develop diabetes

Question 8

Hypothesized mechanisms for health of fetus (4 answers)

Answer 8

1. Quality and quantity of maternal nutrition

2.Exposure to stress/high levels of glucocorticoids

3. Thrifty phenotype hypothesis

4.Genetic/epigenetic influence

Question 9

1.Quality and quantity of maternal nutrition(under/overnutrition, junk food diet)

Answer 9

Maternal undernutrition = lower birthweight –> increased bl. pr –> impaired glucose homeostasis
Overnutrition (HFD or excess calories) = high circulating glucose

Junk food diet - influences offspring to eat junk food

Question 10

2.Exposure to stress/high levels of glucocorticoids (cortisol)

Answer 10

Occur w high glucocorticoids (cortisol) or problems in placental barrier
-glucocorticoids regulate fetal organ maturation
-high cortisol = accelerated organ maturation at expense of fetal growth –> born w low body weight
-Placental 11β-HSD2 inactivates cortisol - (lower amount of 1β-HSD2 –> more cortisol –> lowe birthweight)

Question 11

3. The thrifty phenotype hypothesis

Answer 11

Poor nutrition in early life causes permanent changes in genes related to glucose-insulin metabolism
-fetus adapt during nutrient restriction - (reduce insulin secretion, increase bl. glucose levels - more for brain and heart)
-reversible, but becomes permanent if persists
-fetus prepared for undernutrition, given food abundance- problem! (disease)

Question 12

Epigenetics

Answer 12

Changes in cell function, do not involve DNA sequence
-ex. DNA methylation impacts how genes are expressed, does not alter sequence

Question 13

4.Genetic/epigenetic influence

Answer 13

-amount of methyl donors in diet influences epigenome
-change in promotor methylation affect gene express. - can extend across generations
-phenotypic affects related to modifications may not be visible until later in life (depend on eviron. factors)

Question 14

Best studied examples of epigenetic changes in genome

Answer 14

-DNA methylation (CH3 groups added to specific bases)
-Histone modification (acetylation,methylation,etc)

Question 15

“Histone code”

Answer 15

Collection of all modifications to histones - acetylation, methylation, phosphorylation, ubiquitination

Question 16

Adding and removing acetyl groups - enzymes

Answer 16

HAT- histone acetylase (adds)
HDAC-histone deacetylase (removes acetyl groups)

Question 18

Methylation and de-methylation - gene expression

Answer 18

Methylation - turns OFF gene expression –> promotes binding of proteins that silence transcription
De-methylation - turns ON gene expression –> favours transcription

Question 19

Diet and epigenome

Answer 19

food contains inhibitors and activators of chromatin remodelling enzymes (DNA methyltransferases, histone acetylases, hisone deacetylases)
-can “program” epigenome

Question 20

Is epigenetic changes inherited through mitosis or meiosis?

Answer 20

Both

Question 21

Epigenetic “sensitive regions”

Answer 21

-Promotor region
-Metastable epialleles
–>regions of genome that can be epigenetically modified in a variable and reversible manner

Question 22

Gene promotor example

Answer 22

-Genomic regions at which epigenetic status varies amongst individuals in a population
-DNA methyl & acetyl. of histone tails most studied

Question 23

3 Types of epialleles

Answer 23

1.Obligatory
-determined by genetic variation, DNA mutation
2.Facilitated
- determined by genetic and environmental factors
3.Pure
- determined by environmental factors

Question 24

Cis and Trans Obligatory

Answer 24

Cis: epigenetic change occurs at site of mutation
Trans: mutation in one gene causes epigenetic changes elsewhere in genome

Question 25

Pure epiallele is DNA already capable of being methylated?

Answer 25

Yes, the amount its methylated depends on amount of environmental factor present

Question 26

Facilitated epiallele-Axin fused mouse pathway

Answer 26

-Axin expressed in embryo and adult gene product regulates signalling path
-Transposable element inserted into intron 6 of axin gene
-activates promotor: IAP retrotransposon - can range from low (hypo-methylated) to high (hyper-methylated)

Question 27

Axin fused mouse result

Answer 27

Hyper-methylated:
-silence IAP –> normal promotor function –> straight tail
Methylation decrease –> kinked tail

Question 28

Agouti mouse

Answer 28

-Mouse agouti region - only 1 allele is functional
-IAP retrotransposon (upstream of agouti gene)
-IAP methylation status range from hypo-methylated to hyper-methylated

Question 29

Agouti mouse result

Answer 29

IAP-silenced when hypermethylated = normal weight, brown fur mouse
Hypomethylated = yellow mouse, obsese????

Question 30

How does mothers (mouse) diet affect offspring phenotype via epigenetics?

Answer 30

-altering methylation status at IAP retrotransposon

Question 31

Sibling born after mother had bariatric surgery vs before

Answer 31

After: offspring less obese, improved cardiometabolic parameters (fasting insulin and BP)

Question 32

Normal hormone production during pregnancy (insulin)

Answer 32

-develop temporary insulin resistance to reduce glucose uptake in sk muscle and tissues
-send more to fetus,
-pancreas responds by producing 2x more insulin to clear bl.guose

Question 33

How does GDM occur

Answer 33

Mother is unable to produce insulin necessary to maintain normal bl glucose levels

Question 34

Risk factors of GDM

Answer 34

-Age>25
-Genetics
-History of diabetes in first-degree relatives
-Previous hitory of GDM, still births or large babies
-eating habits
-overweight or obese

Question 35

Consequences of GDM on offspring

Answer 35

-higher blood sugar levels for the fetus = higher fetal insulin production
-insulin is an anabolic hormone: high levels promote growth in fetus (high birth weight)

Question 36

Risks on offspring of GDM mothers

Answer 36

-macrosomia (increased birth weight and size)
-respiratory distress syndrome -requires oxygen
-increased blood pressure
-lower HDL-cholesterol (“good cholesterol”)
-increase risk of metabolic diseases

Question 37

Affect on blood pressure in offspring of mom with GDM

Answer 37

-increase SBP, no affect on DBP
-SBP higher in offspring males

Question 38

Children born to mothers with diabetes have what times chance of having diabetes?

Answer 38

-children born to mothers w diabetes have 3x the risk as they age
-fathers status has little influence

Question 39

Mesoderm-specific transcript (MEST) in non-GDM, D-GDM and I-DGM mothers

Answer 39

MEST gene methylation status lower in GDM mothers = higher MEST gene expression higher
-hypometh may foreshadow obesity
-over-express = enlarged adipocytes and fat mass expansion

Question 40

When does GDM develop?

Answer 40

3rd trimester

Question 41

Prevalence for T2D in GDM women

Answer 41

7x higher risk in GDM women
1 in 5 will develop diabetes within 9 years

Question 42

How to treat at risk women to reduce GDM risk

Answer 42

1. Reduce caloric intake, increase physical activity
2. Insulin and metformin therapy if (1) is unsuccessful within 2 weeks

Question 43

Vitamin D and GDM relationship

Answer 43

Not well known
-vitamin D MAY act on pancreatic beta cells to regulate intracellular calcium
-intracell calc. regulates insulin release from beta cells
LOW VIT D W GDM