2) Embryology and Teratology (Part II) Flashcards
Methotrexate is a _______ antagonist.
folate
What is methotrexate associated with?
30% risk of NTD
Coumadin is a _________ antagonist.
vitamin K
Which nutrient deficiencies are anti-convulsants associated with?
Folate and zinc deficiencies
What is fetal alcohol syndrome?
Collective term to describe a set of features associated with infants exposed to alcohol during pregnancy
What is fetal alcohol syndrome characterized by?
- Craniofacial dimorphism (palpebral eyelid fissures, elongated mid-face, thin upper lip)
- Growth retardation
- Retarded psychomotor and intellectual development
What is the leading cause of birth defects and intellectual handicap in North America?
Fetal alcohol syndrome
Which trimester of pregnancy confers the greatest sensitivity of the fetal brain to FAS?
The third trimester
What characterizes a high risk for FAS?
- 3 ounces of alcohol per day
- Or, 4 drinks per day
What characteristics determine the risk of FAS?
- Quantity of alcohol
- Frequency of drinking
- Timing of the consumption of alcohol during pregnancy
How is FAS diagnosed?
2 of the 3 diagnostic criteria must be present
What are characteristics of alcohol-related birth defects (ARBD)?
- Microcephaly
- Heart and lung malformations
- Minor physical abnormalities
ARBD occurs in the absence of what?
Apparent neurobehavioral or brain disorders
What are characteristics of CNS disturbances due to alcohol?
- Decreased attention span
- Decreased IQ
- Hyperactivity
95% of alcohol is metabolized by ____________.
alcohol dehydrogenase
What is the primary region where alcohol is metabolized? Where is it also metabolized?
- Primarily metabolized in the liver
- Also, metabolized in the stomach, which reduces the quantity of active alcohol within the blood
Why may men consume twice the amount of alcohol as women?
- Because they possess twice the amount of alcohol dehydrogenase
- Also, women have a lower body weight than men, so the alcohol consumed is distributed at a higher concentration in the blood
What occurs to alcohol after absorption? How does that affect pregnant women?
- Alcohol is evenly distributed to all bodily fluids, crossing the blood-brain and placental barriers until reaching equilibrium with the mother’s blood
- The equilibrium with the placenta occurs almost immediately
Why is the half-life of alcohol increased in the embryo/fetus?
- The embryo/fetus has decreased blood detoxification abilities due to their limited organ development
- There is very little alcohol dehydrogenase within the placenta
Why is the fetus more susceptible to alcohol-related effects?
- Their developing CNS is more susceptible to alcohol-related effects than the adult brain
- On a body-weight basis, the fetus is also more susceptible than the mother to alcohol
Which nutrient deficiencies is alcohol associated with? How does that affect pregnancy?
- Folate and zinc deficiencies
- In pregnancy, the ingestion of alcohol decreases folate available for the fetus
Which nutrient deficiencies enhance the deleterious effect of alcohol?
Protein and zinc deficiencies
How is alcohol association with potassium?
A heavy consumption of alcohol may deplete potassium stores, which results in hypokalemia
Describe alcohol metabolism.
1) Alcohol is metabolized into acetaldehyde by alcohol dehydrogenase
2) Acetaldehyde is metabolized into acetic acid by acetaldehyde dehydrogenase
What is produced alongside acetic acid during alcohol metabolism?
Free radicals (inflammatory process)
How does the toxicity of alcohol compare to acetaldehyde?
- Alcohol is toxic at mM concentrations
- Acetaldehyde is toxic at uM concentrations
What are the molecular effects of alcohol toxicity on the developing fetus?
- Excessive cell death (apoptosis) in sensitive cell populations
- Placental toxicity
- Fetal hypoxia
What are NTDs?
General term for congenital abnormalities of the fetal spine and CNS, including defects of the neural tube
What are NTDs due to? What determines the type of NTD?
- NTDs are due to disruptions in the orderly formation of the neural tube during gestation
- The type of NTD depends on the region where the NTD occurs
What is the most common type of birth defect?
NTDs
What are the most severe forms of NTDs?
Anencephaly and exencephaly
Differentiate anencephaly and exencephaly.
- Anencephaly implies that the brain is exposed, due to the lack of skull
- Exencephaly implies that the brain protrudes out of the skull
What is the most common type of NTD? What is it?
- Spina bifida
- A lack of bone encases the spine, causing permanent spinal cord and spinal nerve damage
When does spina bifida normally occur?
During the first month of gestation
What are the consequences of spina bifida?
- Inability to walk
- Abnormal bladder and bowel function
- Fatality
What factors contribute to the etiology of NTDs?
- Multifactorial inheritance
- Single gene (autosomal recessive) disorders
- Chromosomal aneuploidy
- Teratogens
- Maternal IDDM
- Severe overweight
- Environmental factors
- Family history or prior NTD-affected pregnancy
- Hot tub use or fever in early pregnancy
- Folate deficiency or inborn error of folate metabolism
Which population group has a much higher risk of conceiving a child with an NTD?
Mothers who have previously had an offspring with an NTD
50 to 75% of NTDs are related to what?
Folate deficiency or abnormal folate metabolism
Which study analyzed the effects of folate deficiency on NTDs?
The MRC Environment Study
What was the MRC Environment Study?
- Pregnancy women (who had previous pregnancies resulting in an NTD) were given capsules for 12 weeks
- Utilized a large sample size in a double-blind randomized controlled prospective trial
- These women were distributed in four groups
What did the MRC Environment Study uncover?
- Multivitamins did NOT affect the incidence of NTDs
- Solely the presence or lack of adequate folic acid affected the incidence of NTDs
What quantity of folate is recommended for women with previous NTDs? When should they begin taking the folate supplement?
- 4 mg
- The folate should be provided at least 4 weeks prior to conception
How long was the MRC Environment Study?
The trial was stopped early due to the success of folate supplementation, for ethical reasons
What is homocysteine?
- Homocysteine is an amino acid (not used in protein synthesis)
- Serves as an intermediate in the synthesis of methionine (used for protein synthesis)
What is methionine converted to? Which enzyme catalyzes the conversion?
Methionine is converted to SAM by methionine adenosyl transferase
What is the function of the additional methyl group of SAM?
The methyl group may be transferred to a substrate (gene or protein) by a methyltransferase, altering cellular function
What are the results of methylation of a gene?
Increase or decrease gene expression (epigenetic modifications)
What are the results of methylation of a protein?
Variation in the interactions of the protein (protein-protein, or protein-DNA)
What is SAM converted to after transferring its methyl group? What occurs to the substrate afterwards?
SAM is converted to SAH, which is hydrolyzed to homocysteine
What are circulating homocysteine levels normally? What do abnormal levels of homocysteine indicate?
- Normally, homocysteine is rapidly metabolized, keeping its circulating concentration low
- High levels of circulating homocysteine indicate an impairment in the metabolism of homocysteine
Homocysteine is metabolized via two pathways. What are they?
- Vitamin B12 and folate-dependent pathway
- Vitamin B6-dependent pathway
What occurs in the vitamin B12 and folate-dependent pathway? What does it require?
Homocysteine is metabolized to regenerate methionine, which requires folate
What occurs in the vitamin B6-dependent pathway? What enzyme does it utilize?
- Homocysteine is converted to cysteine via a transsulfuration pathway
- Utilizes cystationase
- The extraction of a methylene group from homocysteine results in the conversion to cysteine
A _____________ deficiency results in the inability of methionine synthase to convert homocysteine to methionine.
5-Me-TH4-Folate
What enzyme is required for the regeneration of 5-Me-TH4-Folate?
5-methylene tetrahydrofolate reductase
How is a high intake of vitamin A linked to the development of NTDs?
- A high intake of vitamin A suppresses 5-methylene tetrahydrofolate reductase
- Decreased capacity of re-generating methionine from homocysteine, resulting in an accumulation of homocysteine
What product accumulates as a result of homocysteine accumulation?
SAH
What are the effects of SAH accumulation?
- Inhibition of DNA methyltransferase reactions
- DNA hypo-methylation (issues with cellular differentiation and apoptosis)
- Altered gene expression
What are the effects of oxidative stress?
- Damages mitochondria and nuclear DNA
- Damages protein structure and function, lipid membranes, and signal transduction pathways
What occurs by limiting the availability of vitamin B12 by decreasing folate stores?
Decrease in the functional activity of methionine synthase
Which lifestyle factors are associated with methionine synthase? How?
- Alcohol and cigarette smoking are associated with increased oxidative stress
- Increased oxidative stress decreases the functional activity of methionine synthase
What is evidence for the causal role of hyperhomocysteinemia in NTDs?
- Mothers with NTD infants have lower plasma folate and elevated homocysteine levels
- Largely due to a genetic defect
Families with NTDs tend to have in-born errors of metabolism, such as what?
Shortage of methyl tetrahydrofolate reductase
How does folic acid supplementation prevent the onset of NTDs in genetically susceptible mothers?
Supplementation normalizes RBC folate, decreasing blood homocysteine to normalize these metabolic defects
How do plasma homocysteine levels vary during pregnancy? Why?
- Levels are 30 to 60% lower
- Partially due to hemodilution
What is high homocysteine a risk factor for in pregnant women?
- Pre-eclampsia
- Spontaneous abortion
- Placental abruption
- Recurrent early miscarriages
What is pre-eclampsia?
Pregnancy complication, characterized by high blood pressure, which may lead to organ system damage in the mother (liver, kidney) and is a risk factor for eclampsia
Maternal homocysteine at pre-conception, 8 weeks, and birth are inversely related to what?
The baby’s birth weight
How does an increased intake of folate-rich foods affect RBC folate? Why?
- Does not substantially affect RBC folate
- As the folate absorption from dietary intake is highly variable
Which type of folic acid supplementation increases RBC folate substantially?
- Folic acid supplementation
- Fortified foods
Why do folic acid supplementation and fortified foods substantially increase RBC folate, while folate-rich foods do not?
- The synthetic form of folate (monoglutamate) is more stable and bioavailable than the polyglutamate form, normally found in food
- Conjugase enzymes are bypassed when ingesting the monoglutamate form
- Also, cooking decreases folate bioavailability
What occurs to folate-rich foods in the GI tract?
Conjugase enzymes within the GI tract convert the polyglutamate form of folate to the monoglutamate form, as well as attach a methyl group to allow for their absorption
When should women consume folic acid supplements?
- Women of child-bearing age should consume folic acid supplements PRIOR to pregnancy
- 71% of women do not
What does the CDC and Health Canada recommend for folate intake to reduce the risk of having an infant with an NTD?
400 ug of folate per day
