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Cell Bio & Developmental Genetics > Lecture 13 (8a) - Teratogenesis > Flashcards

Lecture 13 (8a) - Teratogenesis Flashcards

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1
Q

Embryonic cells communicate

A

with their environment during normal development
eg environmental sex determination - in most turtles and in all crocodilians, they sex is determined after fertilization by the incubation temperature of the eggs

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2
Q

Temperature dependent sex determination

A
  • alligator - females at low temperature
  • red turtle - females at hot and cold temperatures
  • green turtle - females at hot temperature
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3
Q

Environmental signals can

A

disrupt normal development
• 2-5% of human infants are born w/ anatomical abnormalities
(eg missing limbs and digits, extra digits, lack of heart valves)
• defects can be caused by mutations but also by environment

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4
Q

The medical term for birth defects is

A

congenital anomalies

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5
Q

There are 2 main classes of congenital anomalies

A
  • malformations

* disruptions

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6
Q

Malformations

A

caused by genetic defects
• mutations
• abnormal number of chromosomes
• translocation

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7
Q

Disruptions

A 
caused by exogenous agents
• chemicals
• viruses
• radiation
• excessive heat
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8
Q

Some congenital anomalies can be the result of either

A

malformation or disruption

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9
Q

Chondrodysplasia punctata

A
  • abnormal bone mineralization
  • underdevelopment of nasal cartilage
  • short fingers
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10
Q

Malformation example

A

mutation in CPDX2

• gene product is an enzyme necessary for cartilage growth

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11
Q

Disruption example

A

Warfarin (anticoagulant)

• inhibits the function of the enzyme

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12
Q

Some agents in the environment can cause

A

genetic damage

• mutagens - eg X-rays, UV radiations, free radicals, viruses

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13
Q

This lecture is about teratogens

A

from Greek “monster-formers”

• exogenous agents responsible for disruptions

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14
Q

The fetus is not completely protected from

A

the environment

• 1941 Gregg (Australian opthalmologist) was first to connect birth defect with environmental agent

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15
Q

Normal Gregg

1941, Australian opthalmologist

A

If German measles (rubella) during first trimester of pregnancy, 1:6 chance of birth defects
• eye cataracts
• heart malformations
• deafness

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16
Q

In 1956, James Wilson

A

established 6 principles of teratology

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17
Q

Wilson’s Principles of Teratology

1. Susceptibility to the teratogenic effect of an agent depends on

A
  • the genotype of the embryo

* the genotype of the mother

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18
Q

Wilson’s Principles of Teratology

2. There are critical periods of development when

A

embryos are susceptible to being disrupted by teratogenic agents (organogenesis)

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19
Q

Wilson’s Principles of Teratology

3. Teratogenic agents act in specific ways on

A

• genes
• cells
• tissues
to disrupt normal sequences of development

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20
Q

Wilson’s Principles of Teratology

4. Several conditions affect the ability of a teratogen to

A

disrupt normal development

eg. route and degree of maternal exposure, rate of transfer through placenta

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21
Q

Wilson’s Principles of Teratology

5. There are 4 manifestations of disrupted development

A
  • death
  • malformation
  • growth retardation
  • functional defects
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22
Q

Wilson’s Principle of Teratology

6. Manifestations of abnormal development increase in frequency and degree as

A

the dosage of the teratogen increases
• dosage-dependent
(more = more harm to embryo)
• exceptions eg endocrine disruptors

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23
Q

Wilson also noted in 1961

A

“An agent which is very damaging to the embryo may be relatively harmless to the mother”

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24
Q

Thalidomide and the window of susceptibility

Study These Flashcards
A
  • Phocomelia = absence or deficiency of long bones of limbs
  • 7,000 affected
  • 1 tablet enough
  • withdrawn in November 1961
  • susceptibility only 20-36 days after conception
25
Thalidomide upregulates... and downregulates ...
* upregulates BMP signalling * downregulates WNT signalling • in areas of specific combination of Hox proteins RA is expressed hox proteins - retinoic acid - Tbx transcription factors - Fgf10 (mesoderm) - Fgf8 (ectoderm) ``` Tbx --> Fgf10 --> WNT (thalidomide) --> Fgf8 (limb bud growth) --> Fgf10 ```
26
WNT signalling causes the expression of
FGFs in surface ectoderm • formation of apical ectodermal ridge • somites have different hox genes (concentrations)
27
The period of maximal susceptibility to teratogens is between
weeks 3 and week 8 | • embryo may die - or recover - if eg 1 type of cell affected
28
The first disaster to raise public awareness of the danger from industrial compounds
1951 Minimata Bay, Japan (layering affected)
29
The Minimata Plant of Japan's Chisso Corporation produced more than
6,000 tons of acetaldehyde per year and dumped the by-product (mercury) into Minimata Bay • microbes int he water converted the mercury into methylmercury • fish and shell fish consumed and concentrated methylmercury • the villagers who ate the fish began having neurological problems and eventually died of convulsions
30
Mercury is selectively absorbed by regions of the
developing cerebral cortex
31
More and more untested chemical compounds enter the environment
* over 50,000 chemicals are currently used int he USA * 200-500 new compounds are manufactured each year * most industrial chemicals have not been screened for teratogenic effects * reasons - too expensive, different metabolism between humans and test animals
32
Most devastating human teratogens in terms of frequency and costs
ALCOHOL
33
Fetal alcohol syndrome (FAS)
* first described in 1968 by Lemoine * FAS babies have small heads and brains, and are developmentally and mentally retarded * mean IQ of 68
34
A single drink during susceptible time in pregnancy can lead to
fetal alcohol effect | • in contrast to FAS, no distinct facial appearance but lower functional and intellectual abilities
35
The effect of alcohol on a fetus varies due to
difference in alcohol dehydrogenase (enzyme that detoxifies) • some alleles of the alcohol-metabolizing enzymes appear to be better than others at detoxifying ethanol • 30-40% of the children born to alcoholic mothers will be affected by FAS
36
A mouse model system has been used to explain the effects of alcohol on
face and nervous system • mice show same developmental defects as humans after ethanol exposure • abnormal craniofacial structures and brain reduced
37
Which developmental pathway/mechanism is affected
1. neural crest cell migration and differentiation is affected in FAS 2. Ethanol-induced apoptosis can delete millions of neurons 3. Ethanol blocks the function of cell adhesion molecule L1
38
1. Neural crest cell migration and differentiation is affected by FAS
• neural crest cells are formed dorsally to the neural tube - neural crest cells dorsal to neural tube --> migrate • neural crest cells prematurely differentiate into facial bones • apoptosis in pharyngeal arches correlates with loss of Sonic hedgehog expression • the facial skeleton is affected in FAS
39
Neural crest cells from various cell types
* cartilage/bone * Schwann cells and other glia * neurons * melanocytes * paracrine factors (cells signal to each other) regulate formation of various cell types
40
Apoptosis in pharyngeal arches correlates w/ loss of Sonic hedgehog expression
* cranial neural crest cells migrate to pharyngeal arches * in mice, ethanol downregulates shh * Shh is required for formation of facial skeleton
41
The facial skeleton is affected in FAS
• crest cells form dorsal to the neural tube • depend on level of ant/post --> different types of bones • cranial neural crest cells = face (eg bones) affects nasal process, maxillo-mandibular process
42
2. Ethanol-induced apoptosis
• can delete millions of neurons • alcohol generates superoxide radicals that can oxidize membranes and lead to cytolysis • black = apoptotic cells esp. in brain • another ethanol-induced defect is failure of neural tube closure brain outside --> apoptosis --> no brain
43
3. Ethanol blocks the function of cell adhesion molecule L1
* could be 1 of the reasons for mental retardation * mutations in human L1 cause syndrome similar to FAS * no cell adhesion
44
Retinoic acid
* involved in normal development but ca disrupt development if present in the wrong amounts or at wrong times * 13-cis retinoic acid (Accutane) is used for treating severe cystic acne * if used during pregnancy, can result in syndrome in infant (absent ears, small jaws, abnormal CNS)
45
Developmental disruption is due to
RA changing Hox gene expression • cranial neural crest cells are transformed in more posterior neural crest cells • no formation of facial cartilage
46
Fusion of first and second
``` pharyngeal arch in RA exposed mice • retinoic acid = limb development • wrong concentration (morphogen) --> birth defects • anterior structures replaced by posterior = transformation ```
47
In RA mice, partial failure of
ossification and limb abnormalities
48
Valproic acid
• used for treatment of epilepsy, bipolar disorder, and migraines, etc.
49
Valproic acid blocks the absorption of
folate (vitamin B9) bu the embryo | • folate is critical for neural tube closure
50
Valproic acid decreases the level of
Pax1 transcription in chick somites • malformation of vertebrae and ribs • transcription factor
51
Valproic acid might also cause
autism | • similar neurological alterations in exposed rates as in humans with autism
52
In VA exposed mice, there's a misregulation of
Hox1a | • in area where brain forms
53
Pathogens can act as
teratogens • the rubella virus (German measles) produces a protein that stops mitosis by blocking kinases for cell cycle progression • many organs affected • first 5 weeks of pregnancy most critical (formation of heart, eyes, ears)
54
Protists and bacteria are rarely teratogenic, but some can
damage the fetus • Toxoplasma gondii (cats, rabbits) causes fetal brain and eye defects in human embryos • Treponema pallidum (Syphilis bacterium) can either kill embryos or produce deafness and facial damage
55
Heat can act as a
teratogen • hypothermia can be dangerous to the fetus • maternal temperature higher than 38.9C during the first 6 weeks of pregnancy can affect neural tube closure
56
Veratum californicum
* corn lily | * produces alkaloids that block the function of Hedgehog functioning
57
Hedgehog signalling is required for
cell proliferation in the midline of the face
58
Blocking Shh leads to
failure of the optic field to separate
59
If a pregnant sheep eats corn lillies
her lamb will be born with a single eye

Cell Bio & Developmental Genetics (27 decks)

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