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SMP - SDR > Lectures 9 & 10 - Teratology I & II > Flashcards

Lectures 9 & 10 - Teratology I & II Flashcards

1
Q

Endpoints of concern of developmental toxicity studies?

A
  1. Embryo/fetal death
  2. Structural malformations
  3. Growth alteration
  4. Functional deficits
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2
Q

What % of human zygotes implant?

A

< 20-30%

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3
Q

What % of pregnancies result in a healthy infant?

A

< 50%

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4
Q

Out of the 10 leading causes of infant mortality, what 5 would be classified within teratology?

A
  1. Birth defect
  2. Pre-term/low birth weight
  3. Pregnancy complication
  4. Birth complication
  5. Hypoxia
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5
Q

Speed of human development compared to other mammals?

A

Actually pretty slow

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6
Q

Duration of human pregnancy?

A

266 days

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7
Q

What are the 5 gestational milestones? What are these associated with? What happens in between?

A 
1. Fertilization
PRE-IMPLANTATION
2. Implantation
GASTRULATION
3. Primitive streak formation
GERM LAYERS
4. Differentiation
MAJOR ORGANOGENESIS
5. Palate closure
FETAL PERIOD

All are associated with varying degrees of susceptibility to developmental issues

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8
Q

What does an issue arising during the pre-implantation stage usually lead to?

A

Either fatal or minor enough to not impact development (because cells are totipotent and can recover)

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9
Q

During what 2 gestational milestones is the embryo most susceptible to malformations?

A

Between primitive streak formation and differentiation

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10
Q

Describe the fetus’ susceptibility to malformations following the initiation of differentiation.

A

Less susceptible because more resistant to teratogens, BUT functional limitation risks remain

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11
Q

What is teratology?

A

That branch of science that studies the causes, mechanisms, and manifestations of abnormal development

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12
Q

What is a teratogen?

A

Any agent or factor, the exposure to which during embryonic or fetal life produces a permanent adverse alteration in form or function of the offspring

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13
Q

Risk of child with birth defect if you already have one?

A

Risk is multiplied by 7.6

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14
Q

5 causes of birth defects? Include %

A 
♦ Chromosomal aberrations (6-7%)
♦ Mutant genes (7-8%)
♦ Environmental agents (7-10%) 
♦ Multifactorial: genetic + environmental (20-25%)
♦ Unknown etiology (50-60%)
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15
Q

What does susceptibility to teratogenesis of an embryo depend on?

A

Depends on the genetic background of the conceptus, which helps determine the manner in which it interacts with adverse environmental factors, often due to polymorphisms in drug metabolizing enzymes (e.g. phenytoin/dilantin)

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16
Q

How do tissue interactions in the embryo occur?

A

By way of intercellular signal molecules between a competent cell and an inducing cell that are in spatial proximity leading to a signal transduction pathway => developmental state to maturational and stable one

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17
Q

What restricts the competent cell from responding to signals from inducing cells?

A

Presence of receptors to those signals in the time frame during which the signals are sent

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18
Q

What is embryonic regulation?

A

Possibility for some limited internal rearrangements in development schedules and/or cell populations to ensure that tissue inductions still occur even in the face of challenges

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19
Q

What % of birth defects due to genetic abnormalities?

A

~15% of all birth defects

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20
Q

The disruption of what 3 processes can lead to abnormal gene-environment interactions during development?

A
  1. Embryonic induction
  2. Maintenance of developmental schedules
  3. Control of migration and size of blastemata
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21
Q

What is the concept of developmental plasticity? What is it postulated to explain?

A

Ability of a single gene to express more than one phenotype based on environmental conditions

Could explain metabolic syndrome

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22
Q

What are the 3 types of genetic birth defects?

A
  1. Chromosomal abnormalities
  2. Mutant genes
  3. Genotype of embryo
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23
Q

What are the 7 types of chromosomal abnormalities?

A
  1. Aneuploidy
  2. Polyploidy
  3. Translocation
  4. Terminal deletion
  5. Duplication
  6. Inversion
  7. Isochromosomes
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24
Q

What is aneuploidy? Typical cause?

A

Condition in which an individual has chromosome number that is not a multiple of 23 (for example, has one extra chromosome, or is missing one chromosome)

Typically caused by nondisjunction during gametogenesis (usually first meiotic division) or during zygotic cleavage, resulting in mosaicism (some cells are aneuploid, some are not)

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25
Q

Effect of mosaicism on patients with aneuploidy?

A

Clinical outcomes are typically less serious in mosaic individuals than in those with aneuploidy in all cells

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26
Q

What % of ova are aneuploid in humans? Does this number vary?

A

15%

increases with age

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27
Q

What are 5 examples of aneuploidies? Symptoms?

A
  1. Down syndrome aka trisomy 21: mental deficiency, brachycephaly, flat nasal bridge, upward slanting palpebral fissures; protruding tongue; simian crease; clinodactyly of fifth digit; heart defects
  2. Edward syndrome aka trisomy 18: mental deficiency; growth retardation; prominent occiput; short sternum; ventricular septal defect; micrognathia (small jaw); low-set malformed ears; flexed digits; hypoplastic nails; rocker-bottom feet
  3. Patau syndrome aka trisomy 13: mental deficiency; severe CNS malformations; sloping forehead; malformed ears; scalp defects; microphthalmia; cleft lip/palate; polydactyly
  4. Turner syndrome, 45X (paternal X usually missing): lack of secondary sex characteristics, webbed neck, broad chest, lymphedema, infertility
  5. Extra sex chromosomes
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28
Q

What % of Down syndrome babies spontaneously abort? What % are stillborn?

A

75% spontaneously abort

20% are stillborn

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29
Q

Life expectancy of down syndrome patients?

A

50s

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30
Q

What % of Edward/Patau syndrome babies spontaneously abort? Life expectancy?

A

50%

Rarely past 6 mos

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31
Q

What % of Turner syndrome babies survive to term?

A

1%

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32
Q

What are 3 examples of aneuploidies with extra sex chromosomes? Describe each.

A
  1. 47, XXX: normal female appearance, fertile, 20% mentally retarded
  2. 47, XXY/Klinefelter Syndrome: male, small testes, aspermatogenesis, long legs, intelligence deficit, gynecomastia
  3. 47, XYY: normal male appearance, tall, aggressive?
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33
Q

What is polyploidy?

A

Condition in which an individual has an entire extra set (or sets) or chromosomes

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34
Q

2 types of polyploidy? Describe each.

A
  1. Triploidy (69 chromosomes): intrauterine growth retardation; small trunk, large head
  2. Tetraploidy
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35
Q

Incidence of triploidy? Cause? What % of embryos?

A

Occurs in 2% of embryos, but live births extremely rare

Usually caused by dispermy

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36
Q

Do tetraploid embryos usually spontaneously abort?

A

Rarely

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37
Q

What is tetraploidy due to?

A

Failure of cytoplasmic cleavage or chromosomal segregation at first mitotic cleavage division

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38
Q

What is chromosomal translocation? Effect?

A

Swapping of DNA from one chromosome to another nonhomologous chromosome due to breakage induced by radiation, drugs, chemicals, viruses

Severity of resulting phenotypic defect depends on the nature of the translocation

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39
Q

2 types of chromosomal translocations? What does each lead to?

A
  1. Balanced translocation: the DNA is equally exchanged between chromosomes and none is lost or added => may have no phenotypic effect (if no exons were disrupted), but chromosome may be unstable during gametogenesis so there is a risk of passing an unbalanced chromosome to a conceptus
  2. Unbalanced translocation: DNA is added or lost => more severe phenotypic effects
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40
Q

Example of unbalanced chromosomal translocation?

A

3-4% of people with Down syndrome have the extra chromosome 21 attached to another chromosome

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41
Q

Example of terminal deletion?

A

Cri du chat syndrome: deletion of short arm of chromosome 5: microcephaly, severe mental retardation, heart anomalies, weak cat-like cry

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42
Q

What are chromosomal duplications?

A

Part of a chromosome is duplicated (same direction or reversed) and exists as a tandem repeat within a chromosome, attached to a chromosome, or as a separate fragment

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43
Q

Which is more common: deletions or duplications? Which is more harmful?

A

Duplications more common

Deletions more harmful

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44
Q

What are chromosomal inversions? 2 types?

A

Segment of chromosome reversed

  1. Paracentric = confined to single arm of chromosome
  2. Pericentric = both arms, including centromere so can cause aberrant crossing over and segregation during meiosis
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45
Q

What are isochromosomes? What to note?

A

Centromere divides transversely instead of longitudinally, so short and long arms separate and effectively duplicate

Note: most common structural defect of X chromosome and babies tend to not survive

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46
Q

What is a mutant gene?

A

Heritable change in gene sequence resulting in loss or change of function of encoded protein

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47
Q

In what 3 cases are mutations not deleterious?

A
  1. Base changes that do not change the encoded amino acid (degenerate code):
    ⇒ e.g. UCU (Ser) to UCC (Ser)
  2. Base changes that change amino acid to a similar amino acid
    ⇒ e.g. GCU (Ala) to GUU (Val)
  3. Gene is redundant, that is, there is another gene(s) that performs a similar function
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48
Q

How are mutant genes causing human diseases identified?

A

By positional cloning

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49
Q

2 types of mutations? Describe each.

A
  1. Dominant mutations cause phenotype in heterozygous individuals
  2. Recessive mutations cause phenotype in homozygous individuals
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50
Q

Where do genetic mutations come from?

A 
Inherited from parents, or arise de novo due to:
•	Radiation
•	Alkylating agents
•	Metals (interfere with DNA synthesis)
•	Other factors
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51
Q

3 mutations possible?

A
  1. Deletion
  2. Point mutation
  3. Duplication
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52
Q

6 single gene mutation diseases?

A
  1. Cystic fibrosis
  2. Adrenal hyperplasia
  3. Achondroplasia
  4. Synpolydactyly
  5. Holoprosencephaly
  6. Alagille syndrome
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53
Q

Achondroplasia

  1. Gene?
  2. Function?
  3. Mutation?
  4. Type?
A
  1. Fibroblast growth factor 3
  2. Tyrosine kinase receptor
  3. Point mutation
  4. Dominant
54
Q

Holoprosencephaly

  1. Gene?
  2. Function?
  3. Mutation?
  4. Type?
  5. Consequence?
A
  1. Shh
  2. Ligand for transmembrane receptor
  3. Various point mutations
  4. Dominant
  5. Failure of forebrain to completely separate into 2 lobes causing a wide range of brain, skull, and facial defects (cleft lip to cyclopia/hypotelorism with proboscis)
55
Q

What is fetal hydantoin (dilantin) syndrome? Symptoms?

A

Pregnant women with seizures may take phenytoin/dilantin and 5-10% of exposed fetuses will be affected by this because they do not have the enzyme epoxide hydrolase (metabolizes toxic intermediate)

Symptoms: IUGR, microcephaly, mental retardation, altered facies, underdeveloped nails

56
Q

What 8 maternal factors can affect the developing embryo?

A
  1. Genetics
  2. Age
  3. Metabolism (pharmacokinetics)
  4. Nutrition
  5. Stress
  6. Disease
  7. Uterine conditions
  8. Fetal membranes
57
Q

What are the progressive maternal physiological changes during normal gestation?

A
  1. 50% plasma volume increase
  2. 30-50% CO increase
  3. 50% increase GFR
  4. Decreased systemic vascular resistance
  5. Decreased plasma protein binding
  6. Altered electrolyte and mineral metabolism
  7. Enhanced pulmonary ventilation
58
Q

What 3 chemicals cause both maternal and fetal toxicity?

A
  1. Aminopterin: chemotherapeutic agent
  2. Methylmercury
  3. Polychlorinated biphenyls
59
Q

What 3 maternal stresses can cause embryo/fetal toxicity?

A
  1. Steroidal hormones
  2. Ethanol
  3. Cigarette smoking
60
Q

What 4 chemicals cause only fetal/embryo toxicity but not maternal?

A
  1. Thalidomide: for morning sickness
  2. Accutane
  3. Diethylstilbestrol
  4. Ionizing radiation
61
Q

What is IUGR?

A

Intrauterine growth retardation

62
Q

How does maternal diabetes affect the fetus/embryo?

A

The incidence of congenital anomalies is 2X-3X greater in offspring from diabetic mothers (especially if glucose levels are poorly controlled and risk increases with hyperglycemia); this includes Type 1 & 2 plus gestational diabetes

Leads to:

  1. Macrosomia = excessive fetal size =increased risk of difficult labor
  2. Holoprosencephaly = failure of forebrain to divide into hemispheres
  3. Sacral agenesis
  4. Skeletal defects
  5. Heart defects
  6. Spina bifida
  7. Urinary, reproductive, and GIT defects
63
Q

How can maternal hyperthermia affect the embryo/fetus?

A

Body temp >101 F (39.5 C) due to fever, extremely vigorous exercise or hot tubs can lead to neural tube defects from spina bifida to anencephaly

64
Q

What is anencephaly?

A

Failure of the anterior neuropore to close

65
Q

What is phenylketonuria (PKU)? How can maternal PKU affect the fetus/embryo?

A

Defect in phenylalanine metabolism (lack of Phe hydroxylase) which is easily controlled by diet restrictions

Excess maternal Phe can lead to abnormal brain development, mental retardation, heart defects, and behavior problems

66
Q

What are 2 mechanical factors that can be teratogens?

A
  1. Uterine conditions

2. Fetal membranes

67
Q

What is the difference between malformations and deformations?

A
  1. Deformation = alteration in shape and/or position of a previously normal structure and is more likely to occur during the fetal period
  2. Malformation = of a given structure usually can be caused only when that structure is undergoing early morphogenesis and differentiation (i.e. the sensitive period)
68
Q

What is the most common cause of deformations?

A

Uterine constraint

69
Q

Why do deformations typically occur in the late fetal period?

A

Because between the 35th and 38th weeks of gestation, the rapidly increasing growth of the fetus outpaces the growth of the uterus while at the same time there is a relative decrease in amniotic fluid which acts as a cushion

70
Q

Provide examples of uterine constraints and their effects.

A
  1. Maternal: first pregnancy, small uterus, myometrial tumors
  2. Fetal membranes: oligohydramnios or amniotic bands
  3. Twins/Multiple fetuses: may cause extrinsic impingements
  4. Septate uterus: septum in uterus compresses fetus leading to club foot, hip dislocation, skull deformation, reduction defects of limbs, face
71
Q

Are the teratogenic mechanisms of diabetic embryopathy known?

A

NOPE

72
Q

What are the 3 major embryonic factors influencing agent-induced teratogenesis?

A
  1. Genotype of embryo
  2. Time of exposure: critical (sensitive) developmental periods
  3. Dosage
73
Q

How is the effects of toxicants in adults different than in embryos?

A

In embryos gestational age is very important and toxicants will have multiple sites of action

74
Q

What factors affect the dosage/exposure of toxicants of the embryo/fetus?

A
  1. Maternal influences
  2. Embryonic influences
  3. Teratogens
75
Q

What are 4 types of teratogens that are developmental toxicans?

A
  1. Infectious agents
  2. Environmental contaminants
  3. Recreational drugs
  4. Medicines
76
Q

What is the critical period of development during which teratogens are most dangerous?

A

Week 3 to 8 during the embryonic period

77
Q

What are the routes of exposure for teratogens to reach the embryo/fetus? Which is the most common?

A
  1. *Maternal route: intravenous to fetus, or via placental toxicity, or via maternal effects
  2. Paternal route: germ cell mutagenesis, toxicant in semen (unlikely to cause defects though), and workplace chemical exposure causing maternal exposure
78
Q

What is an example of paternal exposure-associated anomaly? Explain.

A

Prader-Willi syndrome: associated with 15q deletion in paternally-derived chromosome (or maternal uniparental disomy - genetic imprinting), which is associated with paternal hydrocarbon exposure (with or without 15q deletion)

Results in:

  1. Hypothalamic dysfunction
  2. Hyperphagia
  3. Obesity
79
Q

3 types of infectious agents teratogens?

A
  1. Viruses
  2. Bacteria
  3. Protozoa
80
Q

Can the maternal immune system combat infectious agents teratogens?

A

Maternal IgG can cross the placenta but protection provided may not be enough to combat the infection

81
Q

Do in utero infections affect the mother?

A

Yeah but since her immune system is much stronger is is barely noticeable

82
Q

What was the first infectious agent to be associated with congenital abnormalities?

A

Rubella virus (German measles)

83
Q

What are 3 classical signs of the rubella virus in embryo/fetus?

A
  1. Cataract
  2. Hearing defect
  3. Patent ductus arteriosus
84
Q

Sensitive period of birth defects caused by rubella virus?

A

Up to 5 weeks gestation (the earlier, the greater the risk), and can also have an effect later in 1st trimester

85
Q

By what 2 mechanisms does the rubella virus cause birth defects?

A
  1. Rubella virus has a primary effect on blood vessels in developing organs
  2. Rubella virus also can inhibit cell mitosis
86
Q

What is the most common viral infection at birth in the US?

A

Cytomegalovirus

87
Q

5 health issues developed by embryos due to cytomegalovirus? What to note?

A
  1. Hearing loss
  2. Vision impairment
  3. Mental disability
  4. Impaired liver function
  5. Poor growth

Note: many infants (10-15%) that are asymptomatic at birth manifest problems within first few years of life

88
Q

What is the cytomegalovirus sometimes called? Why?

A

Silent teratogen

It is rampant in young children so pregnant moms should avoid contact with saliva of young children

89
Q

What are 4 examples of infectious agents that are teratogens?

A
  1. Rubella virus
  2. Cytomegalovirus
  3. Toxoplasma gondii
  4. Treponema pallidum
90
Q

Effect of toxoplasma gondii on embryological development?

A

Congenital toxoplasmosis:

SYMPTOMS AT BIRTH (10% of babies)

  1. Eyes infections
  2. Enlarged liver and spleen
  3. Jaundice

SYMPTOMS LATER IN LIFE (55-85%)

  1. Eye infections
  2. Vision impairment
  3. Hearing loss
  4. Learning disabilities
91
Q

How can exposure to toxoplasma gondii occur?

A

Raw meat or cat feces

92
Q

What kind of infectious agent is toxoplasma gondii?

A

Protozoan

93
Q

What causes vision issues in babies exposed to toxoplasma gondii?

A

Retinochoroiditis

94
Q

What is treponema pallidum? What does it cause?

A

Spirochete bacterium that causes syphilis

Causes:

  1. Stillbirth/neonatal death
  2. Dental anomalies
  3. Deafness
  4. Mental retardation
  5. Skin, bone lesions
  6. Meningitis
95
Q

How can developmental toxicity of pregnant women with syphilis be prevented?

A

Antibiotics before 16 weeks gestation

96
Q

Are most developmental anomalies unique to a single cause/etiology?

A

NOPE

97
Q

Is spina bifida a pathognomic sign of exposure to a particular teratogen?

A

No, it’s a characteristic lesion of many teratogens:

  1. Genetic mutation
  2. Methotrexate: chemotherapeutic treatment
  3. Valproic acid to treat psoriasis and epilepsy
  4. Maternal diabetes
  5. Hyperthermia
  6. Folate deficiency
98
Q

What is Minamata Bay disease? Explain.

A

During 1956, in a small fishing village of Minamata Bay, Japan, many babies were born with severe CNS disorders in numbers too great to be coincidental and adults also became ill with stomach aches, convulsions, psychosis, coma, death so severe the condition was called itai-itai (“ouch-ouch disease”) BUT pregnant women had no symptoms

Reason: they were eating shellfish from the bay which was contaminated with methylmercury, formed by plankton exposed to mercury-containing waste water dumped from nearby chemical plants

99
Q

Effect of methylmercury (organic mercury) on development? When do symptoms appear?

A

Causes neurological and behavioral disturbances resembling cerebral palsy (brain damage, mental retardation, blindness), plus instable neck, convulsions, microcephaly due to a derangement of neuronal migration and proliferation during fetal development that is likely caused by stabilization of the microtubular system

Symptoms appear at 6 mos

100
Q

What are examples of environmental contaminants that are teratogens?

A
  1. Methylmercury

2. Halogenated aromatic hydrocarbons

101
Q

What are 3 examples of halogenated aromatic hydrocarbons? Where does each come from? What to note?

A
  1. PCBs = polychlorinated biphenyls: used in insulators, hydraulic fluids, plastic paints until 1977 + continued input due to disposal
  2. PCDFs = polychlorinated dibenzofurans: by-product of inceneration, smelting, steel prod, burning of fossil fuels, manufacturing of chlorinated compounds, bleaching of pulp and paper
  3. PCDDs = polychlorinated dibenzo-p-dioxins: same sources as PCDFs

Note: most infamous HAH was used in Agent Orange

102
Q

What do halogenated aromatic hydrocarbons cause?

A
  1. Prematurity, low birth weight, neonatal death
  2. Growth abnormalities
  3. Neurological damage
  4. Hyperpigmentation
  5. Chloracne in adults
  6. Gum and dental disorders
  7. Rocker bottom heel
  8. Sperm defects
103
Q

What is fetal alcohol syndrome (FAS)?

A

A set of physical and mental birth defects stemming from in utero alcohol exposure

104
Q

What are fetal alcohol spectrum disorders (FASD)? What to note?

A

An umbrella term describing range of fetal alcohol effects - not a clinical diagnosis

105
Q

What is the leading known preventable cause of mental retardation and birth defects?

A

FASD

106
Q

FAS incidence in US?

A

1-2 out of 1000 live births

107
Q

FASD incidence in US?

A

1 in 100 live births

108
Q

8 characteristics of FAS children?

A
  1. Mental retardation: mean IQ of FAS child: 68
  2. Small head circumference
  3. Facial abnormalities: poor frontonasal process development:
    - Reduced/indistinct philtrum
    - Thin upper lip
    - Epicanthal folds
    - Short palpebral fissures
    - Maxillary hypoplasia
  4. Growth deficits
  5. Microcephaly and holoprosencephaly
  6. Heart, liver, kidney defects
  7. Vision and hearing problems
  8. Functional deficits arising from later exposure:
    - Motor skill deficits
    - Hyperactivity
    - Memory, attention, and judgment problems
    - Language problems
    - Difficulties in school
109
Q

What is the mechanism of action of alcohol on a developing embryo?

A
  1. Excessive cell death (esp. neurons during synaptogenesis)
  2. Decreased cell proliferation
  3. Altered cell migration (esp. neural crest)
  4. Loss of cell adhesion
  5. Altered neuronal/glial interactions
  6. Altered differentiation (e.g. premature differentiation of prechondrogenic mesenchyme)
  7. Holoprosencephaly may result from disturbance of cholesterol metabolism which disrupts the Sonic hedgehog (Shh) signaling process
110
Q

What can the combined effects of alcohol and nicotine cause?

A

Greatly increase the risk of heart defects and cleft lip/palate

111
Q

What is the sensitive period for alcohol as a teratogen? What to note?

A

1st month but functional deficits can result from excessive alcohol exposure throughout gestation

112
Q

So what is the story with thalidomide?

A

For decades it was believed that the placenta served as a barrier that protected the fetus from the adverse effects of drugs but the thalidomide disaster drastically changed this perspective as it was prescribed for morning sickness but cause birth defects:

  1. Limb malformations: phocomelia (“seal” limbs), amelia (absence of limbs)
  2. Internal organ malformations: heart defects, duodenal stenosis
  3. Eye and ear defects
113
Q

Should pregnant women take medications while pregnant?

A

Best for women to avoid using medications during the first trimester unless there is a strong medical reason for its use, and then only if it is recognized as reasonably safe for the human embryo

114
Q

What is the sensitive period for thalidomide as a teratogen? What to note?

A

Limb morphogenesis (4-5 weeks), so 24-36 days of gestation

Note: there is a high rate of malformation in exposed embryos = 50-80%! Only one dose can cause birth defects in the fetus

115
Q

What is the mechanism of action of thalidomide on a developing embryo?

A
  1. Inhibition of angiogenesis by inhibiting basic fibroblast growth factor (bFGF), which is an endothelial cell mitogen that stimulates limb growth
  2. Inhibition of tumor necrosis factor (TNF) production by monocytes/macrophages which can have both anti-inflammatory and immunomodulating effects
116
Q

What is thalidomide used for now?

A

Cancer, leprosy, and certain types of blindness

117
Q

What are retinoids? How do they affect the developing embryo? Example?

A

Natural and synthetic compounds with a chemical structure and functional properties similar to vitamin A

Maternal hypervitaminosis A during pregnancy is teratogenic in several animal species:

  1. Craniofacial malformations (e.g. microtia/anotia)
  2. Congenital heart disease
  3. Thymic problems
  4. CNS malformations (e.g. hydrocephalus)
  5. Limb abnormalities
  6. Postnatal neuropsychological problems
  7. Eye and ear deformities
  8. Cleft palate

Example: isotretinoin (Accutane) is a retinoid indicated for the treatment of severe, cystic acne

118
Q

What is the sensitive period for retinoids as teratogens?

A

Weeks 3-5 (cranial neural crest cell specification)

119
Q

What is the mechanism of action of retinoids on a developing embryo?

A

Retinoic acid normally binds to nuclear receptors and serves as an upstream regulator of certain HOX genes in normal morphogenesis

Teratogenic effects may be mediated in part by disruptions of the retinoic acid-sensitive HOX genes causing disruption of cranial and cardiac neural crest cells and somite-derived structures

120
Q

What % of pregnancies are unplanned?

A

50%

121
Q

What are the 2 major tenets of animal testing?

A
  1. Corollary 1. It is important to recognize and understand similarities and differences between animal models and humans
  2. Corollary 2. It is even more important to know how these similarities and differences influence the results of experiments so that the data can be interpreted correctly and the appropriate extrapolations are made
122
Q

What are the 3 different type of animal studies to test the effect of a compound on embryological development?

A
  1. Fertility and early embryonic development study: dosing period from pre-fertilization to implantation to test ability to fertilize and implant
  2. Embryo-fetal development study: dosing period from implantation to palate closure to test potential birth defects
  3. Pre- and post-natal study: dosage period from implantation to past birth (weaning) to test functional deficits
123
Q

What is chorionic villus sampling?

A

Procedure performed at 8-10 weeks gestation during which chorionic villus cells are collected and a genetic/karyotypic analysis is performed

124
Q

Risk of miscarriage due to chorionic villus sampling?

A

1:100

125
Q

Which is more risky: amniocentesis or chorionic villus sampling?

A

Chorionic villus sampling

126
Q

When is the a nuchal translucency ultrasound?

A

Procedure performed at 9-13 weeks gestation to check for potential increased thickness of the nuchal fold (>3 mm), which would indicate lymphedema and correlates with trisomies 13, 18, and 21

127
Q

Risks of nuchal translucency ultrasound?

A

Possible disturbance of developing neural architecture

128
Q

What maternal serum values can help making birth defect diagnoses? When is this done?

A

Maternal serum analyzed at 13-16 weeks:

  1. α-fetoprotein (AFP) => neural tube defects if high
  2. Estriol (E3; placental estrogen only during gestation)
  3. β-hCG (human chorionic gonadotropin)

=> Low AFP & E3 + high hCG: Down Syndrome (trisomy 21)

=> Low AFP, E3, hCG: Edward syndrome (trisomy 18)

129
Q

What is an emerging technology to perform embryological genetic/karyotypic analyses?

A

Analysis of fetal cells in maternal blood (likely trophoblast cells), which have different surface receptors and methylation patterns and can be separated, cloned, and then analyzed

130
Q

Describe the 5 previously used labeling categories for drugs and their potential teratogenic effects.

A

A = no fetal risks based on controlled human studies

B = no fetal risks based on animal studies

C = fetal risks based on animal studies OR no adequate animal/human studies

D = evidence of human fetal risk but risk may outweigh benefits

X = proven human fetal risk that outweighs benefit

131
Q

7 effect of smoking mother on baby?

A
  1. Spontaneous abortion
  2. Preterm delivery
  3. Birth and delivery problems
  4. Intrauterine Growth Retardation (IUGR)/Low Birth Weight
  5. Altered infant blood pressure
  6. Respiratory disorders during childhood
  7. Ectopic pregnancy
132
Q

Do most women know they are pregnant during the most susceptible period to teratogens?

A

NOPE

SMP - SDR (23 decks)

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