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

Lecture 13 (8a) - Teratogenesis Flashcards

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

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
Q

Thalidomide upregulates… and downregulates …

A
  • 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
Q

WNT signalling causes the expression of

A

FGFs in surface ectoderm
• formation of apical ectodermal ridge
• somites have different hox genes (concentrations)

27
Q

The period of maximal susceptibility to teratogens is between

A

weeks 3 and week 8

• embryo may die - or recover - if eg 1 type of cell affected

28
Q

The first disaster to raise public awareness of the danger from industrial compounds

A

1951
Minimata Bay, Japan
(layering affected)

29
Q

The Minimata Plant of Japan’s Chisso Corporation produced more than

A

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
Q

Mercury is selectively absorbed by regions of the

A

developing cerebral cortex

31
Q

More and more untested chemical compounds enter the environment

A
  • 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
Q

Most devastating human teratogens in terms of frequency and costs

A

ALCOHOL

33
Q

Fetal alcohol syndrome (FAS)

A
  • first described in 1968 by Lemoine
  • FAS babies have small heads and brains, and are developmentally and mentally retarded
  • mean IQ of 68
34
Q

A single drink during susceptible time in pregnancy can lead to

A

fetal alcohol effect

• in contrast to FAS, no distinct facial appearance but lower functional and intellectual abilities

35
Q

The effect of alcohol on a fetus varies due to

A

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
Q

A mouse model system has been used to explain the effects of alcohol on

A

face and nervous system
• mice show same developmental defects as humans after ethanol exposure
• abnormal craniofacial structures and brain reduced

37
Q

Which developmental pathway/mechanism is affected

A
  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
Q
  1. Neural crest cell migration and differentiation is affected by FAS
A

• 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
Q

Neural crest cells from various cell types

A
  • cartilage/bone
  • Schwann cells and other glia
  • neurons
  • melanocytes
  • paracrine factors (cells signal to each other) regulate formation of various cell types
40
Q

Apoptosis in pharyngeal arches correlates w/ loss of Sonic hedgehog expression

A
  • cranial neural crest cells migrate to pharyngeal arches
  • in mice, ethanol downregulates shh
  • Shh is required for formation of facial skeleton
41
Q

The facial skeleton is affected in FAS

A

• 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
Q
  1. Ethanol-induced apoptosis
A

• 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
Q
  1. Ethanol blocks the function of cell adhesion molecule L1
A
  • could be 1 of the reasons for mental retardation
  • mutations in human L1 cause syndrome similar to FAS
  • no cell adhesion
44
Q

Retinoic acid

A
  • 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
Q

Developmental disruption is due to

A

RA changing Hox gene expression
• cranial neural crest cells are transformed in more posterior neural crest cells
• no formation of facial cartilage

46
Q

Fusion of first and second

A 
pharyngeal arch in RA exposed mice
• retinoic acid = limb development
• wrong concentration (morphogen)
--> birth defects
• anterior structures replaced by posterior = transformation
47
Q

In RA mice, partial failure of

A

ossification and limb abnormalities

48
Q

Valproic acid

A

• used for treatment of epilepsy, bipolar disorder, and migraines, etc.

49
Q

Valproic acid blocks the absorption of

A

folate (vitamin B9) bu the embryo

• folate is critical for neural tube closure

50
Q

Valproic acid decreases the level of

A

Pax1 transcription in chick somites
• malformation of vertebrae and ribs
• transcription factor

51
Q

Valproic acid might also cause

A

autism

• similar neurological alterations in exposed rates as in humans with autism

52
Q

In VA exposed mice, there’s a misregulation of

A

Hox1a

• in area where brain forms

53
Q

Pathogens can act as

A

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
Q

Protists and bacteria are rarely teratogenic, but some can

A

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
Q

Heat can act as a

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
Q

Veratum californicum

A
  • corn lily

* produces alkaloids that block the function of Hedgehog functioning

57
Q

Hedgehog signalling is required for

A

cell proliferation in the midline of the face

58
Q

Blocking Shh leads to

A

failure of the optic field to separate

59
Q

If a pregnant sheep eats corn lillies

A

her lamb will be born with a single eye

Cell Bio & Developmental Genetics (27 decks)

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