2) Embryology and Teratology (Part II) Flashcards

1
Q

Methotrexate is a _______ antagonist.

A

folate

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What is methotrexate associated with?

A

30% risk of NTD

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Coumadin is a _________ antagonist.

A

vitamin K

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Which nutrient deficiencies are anti-convulsants associated with?

A

Folate and zinc deficiencies

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What is fetal alcohol syndrome?

A

Collective term to describe a set of features associated with infants exposed to alcohol during pregnancy

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What is fetal alcohol syndrome characterized by?

A
  • Craniofacial dimorphism (palpebral eyelid fissures, elongated mid-face, thin upper lip)
  • Growth retardation
  • Retarded psychomotor and intellectual development
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What is the leading cause of birth defects and intellectual handicap in North America?

A

Fetal alcohol syndrome

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Which trimester of pregnancy confers the greatest sensitivity of the fetal brain to FAS?

A

The third trimester

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What characterizes a high risk for FAS?

A
  • 3 ounces of alcohol per day

- Or, 4 drinks per day

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What characteristics determine the risk of FAS?

A
  • Quantity of alcohol
  • Frequency of drinking
  • Timing of the consumption of alcohol during pregnancy
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

How is FAS diagnosed?

A

2 of the 3 diagnostic criteria must be present

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What are characteristics of alcohol-related birth defects (ARBD)?

A
  • Microcephaly
  • Heart and lung malformations
  • Minor physical abnormalities
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

ARBD occurs in the absence of what?

A

Apparent neurobehavioral or brain disorders

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What are characteristics of CNS disturbances due to alcohol?

A
  • Decreased attention span
  • Decreased IQ
  • Hyperactivity
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

95% of alcohol is metabolized by ____________.

A

alcohol dehydrogenase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What is the primary region where alcohol is metabolized? Where is it also metabolized?

A
  • Primarily metabolized in the liver

- Also, metabolized in the stomach, which reduces the quantity of active alcohol within the blood

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Why may men consume twice the amount of alcohol as women?

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

What occurs to alcohol after absorption? How does that affect pregnant women?

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Why is the half-life of alcohol increased in the embryo/fetus?

A
  • The embryo/fetus has decreased blood detoxification abilities due to their limited organ development
  • There is very little alcohol dehydrogenase within the placenta
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

Why is the fetus more susceptible to alcohol-related effects?

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

Which nutrient deficiencies is alcohol associated with? How does that affect pregnancy?

A
  • Folate and zinc deficiencies

- In pregnancy, the ingestion of alcohol decreases folate available for the fetus

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

Which nutrient deficiencies enhance the deleterious effect of alcohol?

A

Protein and zinc deficiencies

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

How is alcohol association with potassium?

A

A heavy consumption of alcohol may deplete potassium stores, which results in hypokalemia

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

Describe alcohol metabolism.

A

1) Alcohol is metabolized into acetaldehyde by alcohol dehydrogenase
2) Acetaldehyde is metabolized into acetic acid by acetaldehyde dehydrogenase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

What is produced alongside acetic acid during alcohol metabolism?

A

Free radicals (inflammatory process)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

How does the toxicity of alcohol compare to acetaldehyde?

A
  • Alcohol is toxic at mM concentrations

- Acetaldehyde is toxic at uM concentrations

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

What are the molecular effects of alcohol toxicity on the developing fetus?

A
  • Excessive cell death (apoptosis) in sensitive cell populations
  • Placental toxicity
  • Fetal hypoxia
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

What are NTDs?

A

General term for congenital abnormalities of the fetal spine and CNS, including defects of the neural tube

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

What are NTDs due to? What determines the type of NTD?

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

What is the most common type of birth defect?

A

NTDs

31
Q

What are the most severe forms of NTDs?

A

Anencephaly and exencephaly

32
Q

Differentiate anencephaly and exencephaly.

A
  • Anencephaly implies that the brain is exposed, due to the lack of skull
  • Exencephaly implies that the brain protrudes out of the skull
33
Q

What is the most common type of NTD? What is it?

A
  • Spina bifida

- A lack of bone encases the spine, causing permanent spinal cord and spinal nerve damage

34
Q

When does spina bifida normally occur?

A

During the first month of gestation

35
Q

What are the consequences of spina bifida?

A
  • Inability to walk
  • Abnormal bladder and bowel function
  • Fatality
36
Q

What factors contribute to the etiology of NTDs?

A
  • 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
37
Q

Which population group has a much higher risk of conceiving a child with an NTD?

A

Mothers who have previously had an offspring with an NTD

38
Q

50 to 75% of NTDs are related to what?

A

Folate deficiency or abnormal folate metabolism

39
Q

Which study analyzed the effects of folate deficiency on NTDs?

A

The MRC Environment Study

40
Q

What was the MRC Environment Study?

A
  • 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
41
Q

What did the MRC Environment Study uncover?

A
  • Multivitamins did NOT affect the incidence of NTDs

- Solely the presence or lack of adequate folic acid affected the incidence of NTDs

42
Q

What quantity of folate is recommended for women with previous NTDs? When should they begin taking the folate supplement?

A
  • 4 mg

- The folate should be provided at least 4 weeks prior to conception

43
Q

How long was the MRC Environment Study?

A

The trial was stopped early due to the success of folate supplementation, for ethical reasons

44
Q

What is homocysteine?

A
  • Homocysteine is an amino acid (not used in protein synthesis)
  • Serves as an intermediate in the synthesis of methionine (used for protein synthesis)
45
Q

What is methionine converted to? Which enzyme catalyzes the conversion?

A

Methionine is converted to SAM by methionine adenosyl transferase

46
Q

What is the function of the additional methyl group of SAM?

A

The methyl group may be transferred to a substrate (gene or protein) by a methyltransferase, altering cellular function

47
Q

What are the results of methylation of a gene?

A

Increase or decrease gene expression (epigenetic modifications)

48
Q

What are the results of methylation of a protein?

A

Variation in the interactions of the protein (protein-protein, or protein-DNA)

49
Q

What is SAM converted to after transferring its methyl group? What occurs to the substrate afterwards?

A

SAM is converted to SAH, which is hydrolyzed to homocysteine

50
Q

What are circulating homocysteine levels normally? What do abnormal levels of homocysteine indicate?

A
  • Normally, homocysteine is rapidly metabolized, keeping its circulating concentration low
  • High levels of circulating homocysteine indicate an impairment in the metabolism of homocysteine
51
Q

Homocysteine is metabolized via two pathways. What are they?

A
  • Vitamin B12 and folate-dependent pathway

- Vitamin B6-dependent pathway

52
Q

What occurs in the vitamin B12 and folate-dependent pathway? What does it require?

A

Homocysteine is metabolized to regenerate methionine, which requires folate

53
Q

What occurs in the vitamin B6-dependent pathway? What enzyme does it utilize?

A
  • 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
54
Q

A _____________ deficiency results in the inability of methionine synthase to convert homocysteine to methionine.

A

5-Me-TH4-Folate

55
Q

What enzyme is required for the regeneration of 5-Me-TH4-Folate?

A

5-methylene tetrahydrofolate reductase

56
Q

How is a high intake of vitamin A linked to the development of NTDs?

A
  • 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
57
Q

What product accumulates as a result of homocysteine accumulation?

A

SAH

58
Q

What are the effects of SAH accumulation?

A
  • Inhibition of DNA methyltransferase reactions
  • DNA hypo-methylation (issues with cellular differentiation and apoptosis)
  • Altered gene expression
59
Q

What are the effects of oxidative stress?

A
  • Damages mitochondria and nuclear DNA

- Damages protein structure and function, lipid membranes, and signal transduction pathways

60
Q

What occurs by limiting the availability of vitamin B12 by decreasing folate stores?

A

Decrease in the functional activity of methionine synthase

61
Q

Which lifestyle factors are associated with methionine synthase? How?

A
  • Alcohol and cigarette smoking are associated with increased oxidative stress
  • Increased oxidative stress decreases the functional activity of methionine synthase
62
Q

What is evidence for the causal role of hyperhomocysteinemia in NTDs?

A
  • Mothers with NTD infants have lower plasma folate and elevated homocysteine levels
  • Largely due to a genetic defect
63
Q

Families with NTDs tend to have in-born errors of metabolism, such as what?

A

Shortage of methyl tetrahydrofolate reductase

64
Q

How does folic acid supplementation prevent the onset of NTDs in genetically susceptible mothers?

A

Supplementation normalizes RBC folate, decreasing blood homocysteine to normalize these metabolic defects

65
Q

How do plasma homocysteine levels vary during pregnancy? Why?

A
  • Levels are 30 to 60% lower

- Partially due to hemodilution

66
Q

What is high homocysteine a risk factor for in pregnant women?

A
  • Pre-eclampsia
  • Spontaneous abortion
  • Placental abruption
  • Recurrent early miscarriages
67
Q

What is pre-eclampsia?

A

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

68
Q

Maternal homocysteine at pre-conception, 8 weeks, and birth are inversely related to what?

A

The baby’s birth weight

69
Q

How does an increased intake of folate-rich foods affect RBC folate? Why?

A
  • Does not substantially affect RBC folate

- As the folate absorption from dietary intake is highly variable

70
Q

Which type of folic acid supplementation increases RBC folate substantially?

A
  • Folic acid supplementation

- Fortified foods

71
Q

Why do folic acid supplementation and fortified foods substantially increase RBC folate, while folate-rich foods do not?

A
  • 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
72
Q

What occurs to folate-rich foods in the GI tract?

A

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

73
Q

When should women consume folic acid supplements?

A
  • Women of child-bearing age should consume folic acid supplements PRIOR to pregnancy
  • 71% of women do not
74
Q

What does the CDC and Health Canada recommend for folate intake to reduce the risk of having an infant with an NTD?

A

400 ug of folate per day