Lecture 13 (8a) - Teratogenesis Flashcards
Embryonic cells communicate
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
Temperature dependent sex determination
- alligator - females at low temperature
- red turtle - females at hot and cold temperatures
- green turtle - females at hot temperature
Environmental signals can
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
The medical term for birth defects is
congenital anomalies
There are 2 main classes of congenital anomalies
- malformations
* disruptions
Malformations
caused by genetic defects
• mutations
• abnormal number of chromosomes
• translocation
Disruptions
caused by exogenous agents • chemicals • viruses • radiation • excessive heat
Some congenital anomalies can be the result of either
malformation or disruption
Chondrodysplasia punctata
- abnormal bone mineralization
- underdevelopment of nasal cartilage
- short fingers
Malformation example
mutation in CPDX2
• gene product is an enzyme necessary for cartilage growth
Disruption example
Warfarin (anticoagulant)
• inhibits the function of the enzyme
Some agents in the environment can cause
genetic damage
• mutagens - eg X-rays, UV radiations, free radicals, viruses
This lecture is about teratogens
from Greek “monster-formers”
• exogenous agents responsible for disruptions
The fetus is not completely protected from
the environment
• 1941 Gregg (Australian opthalmologist) was first to connect birth defect with environmental agent
Normal Gregg
1941, Australian opthalmologist
If German measles (rubella) during first trimester of pregnancy, 1:6 chance of birth defects
• eye cataracts
• heart malformations
• deafness
In 1956, James Wilson
established 6 principles of teratology
Wilson’s Principles of Teratology
1. Susceptibility to the teratogenic effect of an agent depends on
- the genotype of the embryo
* the genotype of the mother
Wilson’s Principles of Teratology
2. There are critical periods of development when
embryos are susceptible to being disrupted by teratogenic agents (organogenesis)
Wilson’s Principles of Teratology
3. Teratogenic agents act in specific ways on
• genes
• cells
• tissues
to disrupt normal sequences of development
Wilson’s Principles of Teratology
4. Several conditions affect the ability of a teratogen to
disrupt normal development
eg. route and degree of maternal exposure, rate of transfer through placenta
Wilson’s Principles of Teratology
5. There are 4 manifestations of disrupted development
- death
- malformation
- growth retardation
- functional defects
Wilson’s Principle of Teratology
6. Manifestations of abnormal development increase in frequency and degree as
the dosage of the teratogen increases
• dosage-dependent
(more = more harm to embryo)
• exceptions eg endocrine disruptors
Wilson also noted in 1961
“An agent which is very damaging to the embryo may be relatively harmless to the mother”
Thalidomide and the window of susceptibility
- 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
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
WNT signalling causes the expression of
FGFs in surface ectoderm
• formation of apical ectodermal ridge
• somites have different hox genes (concentrations)
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
The first disaster to raise public awareness of the danger from industrial compounds
1951
Minimata Bay, Japan
(layering affected)
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
Mercury is selectively absorbed by regions of the
developing cerebral cortex
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
Most devastating human teratogens in terms of frequency and costs
ALCOHOL
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
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
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
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
Which developmental pathway/mechanism is affected
- neural crest cell migration and differentiation is affected in FAS
- Ethanol-induced apoptosis can delete millions of neurons
- Ethanol blocks the function of cell adhesion molecule L1
- 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
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
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
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
- 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
- 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
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)
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
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
In RA mice, partial failure of
ossification and limb abnormalities
Valproic acid
• used for treatment of epilepsy, bipolar disorder, and migraines, etc.
Valproic acid blocks the absorption of
folate (vitamin B9) bu the embryo
• folate is critical for neural tube closure
Valproic acid decreases the level of
Pax1 transcription in chick somites
• malformation of vertebrae and ribs
• transcription factor
Valproic acid might also cause
autism
• similar neurological alterations in exposed rates as in humans with autism
In VA exposed mice, there’s a misregulation of
Hox1a
• in area where brain forms
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)
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
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
Veratum californicum
- corn lily
* produces alkaloids that block the function of Hedgehog functioning
Hedgehog signalling is required for
cell proliferation in the midline of the face
Blocking Shh leads to
failure of the optic field to separate
If a pregnant sheep eats corn lillies
her lamb will be born with a single eye
