Prenatal toxicity Flashcards
Embryotoxicity
Is toxicity which can cause growth retardation or delayed growth
Embryolethality
Is lethal embryotoxicity which can lead to the embryo’s death
Teratogenicity
Is the ability to induce irreversible structural alteration in the embryo
What is human teratogen?
is an agent which can alter the structure or growth of the developing embryo or foetus, leading to birth defects
like thalidomide, alcohol, tetracyclines, viruses
why is the timing of exposure important in drug-induced teratogenicity?
it can determine the outcome
what happens in the first 2 weeks of exposure to teratogen?
death of the embryo or embryo survives without defects
this is the period of cell division in the embryo
what happens during weeks 3-8 if exposed to a teratogen?
this is the period of organogenesis hence exposure here is very sensitive & can cause structural malformation
Maximal sensitivity to abnormal development period
from week 3 to birth there are specific time windows where if there is an exposure to human teratogen (thalidomide), then it will result in different effects
however, the embryo is sensitive to alcohol throughout development
what happens in week 9 to birth if exposed to a teratogen?
Functional disturbance, not structural malformation
this is where the organ systems grow and mature
What is the role of the placenta in prenatal exposure to xenobiotics?
The placenta is a partial barrier, drugs can cross via diffusion or drug transporters (hence the placenta has a limited role in protecting the foetus from exposure to teratogens)
Efflux transporters like MDR1 on the apical membrane, protect the foetus by sending the drugs back to maternal circulation.
Placenta also expresses CYP enzymes but they play a minor role in drug metabolism, due to the ontogeny of metabolising enzymes, this is because in children, the CYP enzymes aren’t developed initially and the drug clearance and CYP metabolism capacity develops over time.
When is the critical period for thalidomide exposure?
Day 21-36 in which a single dose can cause defects in 50% of pregnancies
Thalidomide induced defects are…
Limb malformations, shortened limbs (phocomelia), lack of limbs (amelia)
Upper limbs more commonly affected
Ear & eye damage
Internal organ defects (heart, kidneys)
What and thalidomide form a complex that induces teratogenicity?
Cereblon
What is cereblon?
it forms a part of an E3 Ubiquitin ligase complex along with other parts, which is involved in the proteolysis of substrate proteins by ubiquitinating the substrate proteins
How does thalidomide cause teratogenicity?
Thalidomide binds to cereblon, and induces teratogenicity –> this interaction is necessary
Binding deficient cereblon, rescued the fish from thalidomide induced malformations
Thalidomide-cereblon binding changes the substrate specificity of the E3 ubiquitin ligase complex, such that it can no longer recognise the original substrates
as a result, the new substrates are recognised are ubiquitinated & degraded, whilst the old substrates are not
these changes cause a variety of changes in the signalling pathways leading to a range of effects (teratogenic and theraputic)
What is SALL4
it is a transcription factor which is involved in foetal limb development
Mutations in this TF, leads to birth defects
Thalidomide promotes the degradation of this TF, hence, leading to birth defects
Interspecies differences is not important in the case of thalidomide induced teratogenicity. True or False?
False, it is important as rodents are resistant to thalidomide induced teratogenicity, whilst humans are not
Outline the therapeutic use of thalidomide and its derivatives
1) ability to treat multiple myeloma
2) anti-inflammatory effects as it reduces TNF-a expression (cytokine produces by macrophages during acute inflammation)
c) Antiangiogenic effects & anti-proliferative effects used for cancer treatment
the production of reactive oxygen species can also be used as therapy
How is alcohol a human teratogen
Alcohol has a wide spectrum window as brain development spans from week 3 to birth
What is foetal alcohol spectrum disorder (FASD)
It is a spectrum of effects due to prenatal alcohol exposure
FAS (foetal alcohol syndrome) is the most severe form it leads to facial defect, pre/postnatal growth retardation Neurodevelopmental impairment (learning, behaviour)
What are some important biomarkers for the diagnosis of FASD following maternal alcohol consumption
FAEE Phosphatidylethanol Ethyl glucoronide Ethyl sulfate (both are phase II metabolites)
How do non-oxidative mechanisms of alcohol teratogenicity work?
FAEE synthase metabolises alcohol into FAEE (toxic)
Phospholipase D converts alcohol into phosphatidylethanol which disrupts cell signalling and then leads to birth defects
How do oxidative mechanisms of teratogenicity work?
All work by the creation of DNA/protein adducts which lead to birth defects
Alcohol is metabolised by either alcohol dehydrogenase or CYP2E1 into acetaldehyde which is a toxic and reactive metabolite, that leads to the creation of DNA/protein adducts which then lead to cell damage/death and that leads to birth defects
Alcohol is also metabolised by CYP2E1 to create hydroxyethyl radicals which directly create DNA/proteins adducts
Alcohol is also metabolised by CYP2E1 to create reactive oxygen species (ROS) which cause lipid peroxidation, and that results in reactive aldehydes, which again work by creating protein and DNA adducts
at the end the damage and death of cells, causes birth defects
