Module 2: Epigenetics & Gestational Diabetes Flashcards
Birth weights of offspring from mothers affected by the hunger winter
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!
The barker hypothesis
“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)
Nutritional perturbations during pregnancy- trimester 1
EMBRYONIC GROWTH slowed by undernutrition, over-nutrition cause hyperglycemia (gestational diabetes)
Nutritional perturbations during pregnancy-trimester 2
Undernutrition affects PLACENTAL FUNCTION - alters relationship between fetus, placenta, and mother
Nutritional perturbations during pregnancy - trimester 3
Undernutrition slows FETAL GROWTH to maintain PLACENTAL FUNCTION
-effects on fetus depends on deficiency duration
Undernutrition on fetal and placental hormones
Lowers hormones (insulin, IGF), affects pancreatic development
Relationship between placental weight and birth weight
small placentas (in relation to birthweight) associated with babies who develop diabetes
Hypothesized mechanisms for health of fetus (4 answers)
- Quality and quantity of maternal nutrition
2.Exposure to stress/high levels of glucocorticoids
- Thrifty phenotype hypothesis
4.Genetic/epigenetic influence
1.Quality and quantity of maternal nutrition(under/overnutrition, junk food diet)
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
2.Exposure to stress/high levels of glucocorticoids (cortisol)
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)
- The thrifty phenotype hypothesis
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)
Epigenetics
Changes in cell function, do not involve DNA sequence
-ex. DNA methylation impacts how genes are expressed, does not alter sequence
4.Genetic/epigenetic influence
-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)
Best studied examples of epigenetic changes in genome
-DNA methylation (CH3 groups added to specific bases)
-Histone modification (acetylation,methylation,etc)
“Histone code”
Collection of all modifications to histones - acetylation, methylation, phosphorylation, ubiquitination
Adding and removing acetyl groups - enzymes
HAT- histone acetylase (adds)
HDAC-histone deacetylase (removes acetyl groups)
Methylation and de-methylation - gene expression
Methylation - turns OFF gene expression –> promotes binding of proteins that silence transcription
De-methylation - turns ON gene expression –> favours transcription
Diet and epigenome
food contains inhibitors and activators of chromatin remodelling enzymes (DNA methyltransferases, histone acetylases, hisone deacetylases)
-can “program” epigenome
Is epigenetic changes inherited through mitosis or meiosis?
Both
Epigenetic “sensitive regions”
-Promotor region
-Metastable epialleles
–>regions of genome that can be epigenetically modified in a variable and reversible manner
Gene promotor example
-Genomic regions at which epigenetic status varies amongst individuals in a population
-DNA methyl & acetyl. of histone tails most studied
3 Types of epialleles
1.Obligatory
-determined by genetic variation, DNA mutation
2.Facilitated
- determined by genetic and environmental factors
3.Pure
- determined by environmental factors
Cis and Trans Obligatory
Cis: epigenetic change occurs at site of mutation
Trans: mutation in one gene causes epigenetic changes elsewhere in genome
Pure epiallele is DNA already capable of being methylated?
Yes, the amount its methylated depends on amount of environmental factor present
Facilitated epiallele-Axin fused mouse pathway
-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)
Axin fused mouse result
Hyper-methylated:
-silence IAP –> normal promotor function –> straight tail
Methylation decrease –> kinked tail
Agouti mouse
-Mouse agouti region - only 1 allele is functional
-IAP retrotransposon (upstream of agouti gene)
-IAP methylation status range from hypo-methylated to hyper-methylated
Agouti mouse result
IAP-silenced when hypermethylated = normal weight, brown fur mouse
Hypomethylated = yellow mouse, obsese????
How does mothers (mouse) diet affect offspring phenotype via epigenetics?
-altering methylation status at IAP retrotransposon
Sibling born after mother had bariatric surgery vs before
After: offspring less obese, improved cardiometabolic parameters (fasting insulin and BP)
Normal hormone production during pregnancy (insulin)
-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
How does GDM occur
Mother is unable to produce insulin necessary to maintain normal bl glucose levels
Risk factors of GDM
-Age>25
-Genetics
-History of diabetes in first-degree relatives
-Previous hitory of GDM, still births or large babies
-eating habits
-overweight or obese
Consequences of GDM on offspring
-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)
Risks on offspring of GDM mothers
-macrosomia (increased birth weight and size)
-respiratory distress syndrome -requires oxygen
-increased blood pressure
-lower HDL-cholesterol (“good cholesterol”)
-increase risk of metabolic diseases
Affect on blood pressure in offspring of mom with GDM
-increase SBP, no affect on DBP
-SBP higher in offspring males
Children born to mothers with diabetes have what times chance of having diabetes?
-children born to mothers w diabetes have 3x the risk as they age
-fathers status has little influence
Mesoderm-specific transcript (MEST) in non-GDM, D-GDM and I-DGM mothers
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
When does GDM develop?
3rd trimester
Prevalence for T2D in GDM women
7x higher risk in GDM women
1 in 5 will develop diabetes within 9 years
How to treat at risk women to reduce GDM risk
- Reduce caloric intake, increase physical activity
- Insulin and metformin therapy if (1) is unsuccessful within 2 weeks
Vitamin D and GDM relationship
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
