Teratogen Flashcards
What percentage of live births have major birth defects?
3 - 4%
When do chromosomal abnormalities take place?
Chromosomal abnormalities preclude conception.
When does microcephaly develop?
Can develop relatively late in pregnancy
When does cleft palate typically occur?
Occurs towards the end of the first trimester
When do neural tube defects typically occur?
Occur in earliest weeks of gestation
What does Sonic hedgehog do?
Mammalian morphogen, regulating organogenesis, including growth of digits, brain organisation, sex organ differentiation, and lots more.
Where is sonic hedgehog produced?
In the notocord by node cells.
What type of protein is Sonic hedgehog?
It is a signalling morphogen. Determines cell responses in development: Key role in regulating vertebral organogenesis, growth of digits on limbs and brain organisation.
What is the job of Shh?
Important in the adult
Controls division of adult stem cells
Implicated in cancer development
Role in energy metabolism
What happens when Shh is mutated?
Mutations in SHH gene cause holoprosencephaly due to loss of ventral midline (it is a lethal mutation)
No Shh = no transcription of hedgehog-responsive genes.
What is the role of BMP4?
Involved in limb development
Knock outs are embryonic lethal
Mutants fail to properly form the mesoderm
Which fingers are SHH dependent?
The thumb is not SHH dependent.
The 3 most medial fingers are SHH dependent.
What happened to rhesus monkeys given thalidomide on the 26th day of pregnancy?
Abnormalities in forelimb, lower jaw, ear, and tail in 100 day rhesus monkey foetus.
How do teratogens affect birth defects?
Teratogens do not uniformly increase rates of all birth defects. They instead increase rates of specific defects:
Thalidomide affects limbs
Isotretinoin affects ear, CNS, and heart
Valproic acid affects neural tube etc
How does timing of teratogen affect what body system is hurt?
Each stage affects a specific system. Early stage affects CNS, Heart, and upper limbs.
How was thalidomide sold?
As a racemic mixture of glutamic acid derivative 1:1 mix of enantiomers (R, S) R(+) acts as a sedative mediated by sleep receptors in the forebrain. S(-) potentially inhibits the release of tumour necrosis factor alpha (TNFalpha) this is why thalidomide caused teratogenic effects.
What is the role of TNF-alpha?
induces NF-kappaB and activates gene expression for:
Cell growth
Suppression of apoptosis
Metastasis
Immune and inflammatory response.
Thalidomide decreases TNFalpha production by accelerating mRNA degradation.
What does BMP do to limb development?
BMP regulates level of apoptosis & have balance to give proper limb bud formation from AER.
BMP upregulates Smad which upregulates Msx-2.
BMP is inhibited by NFkappaB
What does NFkappaB do to BMP?
It decreases levels of BMP which makes it turn off apoptosis.
What does thalidomide do?
Increases ROS which leads to less active NF-kappaB which results in de-repression of BMP which results in apoptosis and limb truncations.
What are other uses of thalidomide?
Inhibits angiogenesis making it useful in cancer.
It is anti-inflammatory
Stimulates the immune system - against tuberculosis in AIDS patients.
Can be used to treat 1 form of leprosy called Erythema Nodosum Leprosum (ENL) which is very effective
What are the factors that influence the extent of foetal damage?
Time and duration of exposure: Exposure during organogenesis will result in major impairments and malformations.
Genetic susceptibility: Genotype of mother and foetus play an important role. Way mother metabolises a certain drug will determine what and how much the foetus is exposed to
What kinds of diseases in the mother can result in malformations?
Rubella
Herpes simplex
AIDS
Chickenpox
Zika
