L15 Prenatal Toxicity

Question 1

embryology

Answer 1

The science of studying embryos, including the embryonic and fetal period

Question 2

teratology

Answer 2

The science of studying abnormal development of embryos

Question 3

developmental toxicity

Answer 3

Toxicity to the developing embryo or fetus

Question 4

Embryotoxicity

Answer 4

Toxicity that causes growth retardation or delayed growth

Question 5

embryolethality

Answer 5

Lethal embryotoxicity that leads to the death of embryos

Question 6

teratogenicity

Answer 6

The ability to induce irreversible structural alterations.

Question 7

Human teratogen

Answer 7

A human teratogen is an agent that alters the structure or growth of the developing embryo or fetus, leading to birth defects

Question 8

Types of human teratogens

Answer 8

Drugs
* thalidomide
* alcohol
* antibiotics like tetracyclines
Environmental chemicals
* diethylstilbestrol
Physical agents
* ionising radiation
Maternal factors
* * diabetes
Mechanical factors
* restriction of fetal movement

Question 9

Timing of exposure and teratogenicity

Answer 9

First two weeks: all or nothing (dies or survives with no harm)
Weeks 3-8: most sensitive to teratogens (heart, liver, limb defects) organogenesis
Week 9 to birth: functional disturbance (alcohol)

Question 10

Thalidomide effects upper or lower limbs more

Answer 10

Upper

Question 11

Placenta acts a partial barrier to limit prenatal exposure to xenobiotics. Drugs cross via

Answer 11

drugs cross the placenta via passive diffusion or drug transporters

Question 12

Transporters are expressed on the fetal (what) and efflux transporters are on the (what) side

Answer 12

fetal capillary endothelium and syncytiotrophoblast

efflux transporters on the apical membrane (e.g.,
MDR1) protects fetus by exporting drugs

Question 13

CYPs in fetuses

Answer 13

• expressed in placenta - a minor role in drug metabolism
• induced following maternal exposure to inducers, e.g.,
  smoking, alcohol

Question 14

TGA category safe

Answer 14

A and B

Question 15

TGA category unsafe

Answer 15

D and X

Question 16

What is the critical period of thalidomide exposure during embryonic development and what how many doses needed to cause a response.

Answer 16

Between day 21 and day 36 post conception.
Single dose can cause defects.

Question 17

What are the thalidomide-induced defects

Answer 17

Limb malformations
* Phocomelia (short limbs)
* Amelia (no limbs)
Also eye/ear damage and internal organ defects but these are minor.

Question 18

Cereblon as a thalidomide-binding protein (antiangiogenesis theory)

Answer 18

Causes antiangiogenesis (inhibit new blood vessel formation). This means that the body cannot support the development of limbs as there are no new blood vessels for it therefore, limb defects.

Question 19

Cereblon as a thalidomide-binding protein (reactive oxygen theory)

Answer 19

Causes reactive oxygen species formation and cell death therefore, lib defects.

Question 20

Cereblon coded by what and forms what type of complex with DDB1, Cullin 4 and Roc1

Answer 20

CRBN gene in human
E3 ubiquitin ligase complex that is involved in the proteolysis of substrate proteins.

Question 21

Thalidomide and Cereblon experiments in fish

Answer 21

Thalidomide cause fin defects but cereblon can rescue it.

Question 22

SALL4 name

Answer 22

Spalt-like transcription factor 4

Question 23

SALL4 foetal involvement and mutation; model

Answer 23

it is involved in foetal limb development and if a loss-of-function mutation happens then congenital birth defects.
There is an inter-species difference as rodents are resistant. (difference in 1 aa)

Question 24

Thalidomide and SALL4

Answer 24

Thalidomide promotes degradation of SALL4, a
transcription factor implicated in Duane Radial Ray syndrome.

Question 25

SALL4 can mediate teratogenicity as what type of substrate

Answer 25

thalidomide-dependent cereblon substrate

Question 26

Thalidomide binds to cereblon and causes a confirmation change (its an allosteric modulator) then what happens

Answer 26

Change in the cereblon cause E3 ubiquitin complex to recognise a new set of substrate proteins (would be different if thalidomide was absent) including SALL4(TF) that becomes ubiquitinated and degradation by proteasome.
Degradation causes change in signal transduction.

Question 27

Thalidomide therapeutic effects

Answer 27

Metabolites treat multiple myeloma (has antimyeloma effects)

Question 28

Human teratogen (II) - alcohol

Answer 28

Prenatal alcohol exposure is the leading cause of preventable birth defects
* wide sensitive window - brain development spans the major part of gestation
* Cause fetal alcohol spectrum disorder

Question 29

Fetal Alcohol Spectrum Disorder (FASD)

Answer 29

a spectrum of effects due to prenatal alcohol exposure
*facial defects
* prenatal/postnatal growth retardation
* neurodevelopmental impairment

Question 30

Diagnosis of FASD

Answer 30

• confirmation is necessary before intervention
• self-reporting - under-reporting is an issue
• neurodevelopmental impairment becomes evident around school age
• biomarkers

Question 31

FASD (4) Biomarkers

Answer 31

FAEE synthase (fatty acid ethyl ester)
Phospholipase D
SULT- sulfotransferases
UGT-Glucuronosyltransferase

Question 32

FASD Biomarkers: ethyl glucuronide and ethyl sulfate are detected when

Answer 32

It’s only form when someone consumes alcohol so its shows alcohol consumption.
Detected in maternal urine

Question 33

FASD (4) Biomarkers metabolites

Answer 33

SYN: FAEE (detected in neonatal meconium)
lipaseD: phosphatidylethanol (detected in maternal blood)
SULT: ethyl sulfate
UGT: ethyl glucuronide

Question 34

Mechanisms of alcohol teratogenicity (FAEE)

Answer 34

Alcohol
↓
FAEE synthase
↓
FAEE
↓
Damage and cell death
↓
Birth defects

Question 35

Mechanisms of alcohol teratogenicity (Phospholipase D)

Answer 35

Alcohol
↓
Phospholipase D
↓
Phosphatidylethanol
↓
Disrupt cell signalling
↓
Birth defects