Prenatal toxicity

Question 1

Embryotoxicity

Answer 1

Is toxicity which can cause growth retardation or delayed growth

Question 2

Embryolethality

Answer 2

Is lethal embryotoxicity which can lead to the embryo’s death

Question 3

Teratogenicity

Answer 3

Is the ability to induce irreversible structural alteration in the embryo

Question 4

What is human teratogen?

Answer 4

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

Question 5

why is the timing of exposure important in drug-induced teratogenicity?

Answer 5

it can determine the outcome

Question 6

what happens in the first 2 weeks of exposure to teratogen?

Answer 6

death of the embryo or embryo survives without defects

this is the period of cell division in the embryo

Question 7

what happens during weeks 3-8 if exposed to a teratogen?

Answer 7

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

Question 8

what happens in week 9 to birth if exposed to a teratogen?

Answer 8

Functional disturbance, not structural malformation

this is where the organ systems grow and mature

Question 9

What is the role of the placenta in prenatal exposure to xenobiotics?

Answer 9

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.

Question 10

When is the critical period for thalidomide exposure?

Answer 10

Day 21-36 in which a single dose can cause defects in 50% of pregnancies

Question 11

Thalidomide induced defects are…

Answer 11

Limb malformations, shortened limbs (phocomelia), lack of limbs (amelia)

Upper limbs more commonly affected

Ear & eye damage

Internal organ defects (heart, kidneys)

Question 12

What and thalidomide form a complex that induces teratogenicity?

Answer 12

Cereblon

Question 13

What is cereblon?

Answer 13

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

Question 14

How does thalidomide cause teratogenicity?

Answer 14

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)

Question 15

What is SALL4

Answer 15

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

Question 16

Interspecies differences is not important in the case of thalidomide induced teratogenicity. True or False?

Answer 16

False, it is important as rodents are resistant to thalidomide induced teratogenicity, whilst humans are not

Question 17

Outline the therapeutic use of thalidomide and its derivatives

Answer 17

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

Question 18

How is alcohol a human teratogen

Answer 18

Alcohol has a wide spectrum window as brain development spans from week 3 to birth

Question 19

What is foetal alcohol spectrum disorder (FASD)

Answer 19

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)

Question 20

What are some important biomarkers for the diagnosis of FASD following maternal alcohol consumption

Answer 20

FAEE
Phosphatidylethanol 
Ethyl glucoronide
Ethyl sulfate
(both are phase II metabolites)

Question 21

How do non-oxidative mechanisms of alcohol teratogenicity work?

Answer 21

FAEE synthase metabolises alcohol into FAEE (toxic)

Phospholipase D converts alcohol into phosphatidylethanol which disrupts cell signalling and then leads to birth defects

Question 22

How do oxidative mechanisms of teratogenicity work?

Answer 22

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