L15 Prenatal Toxicity Flashcards
(35 cards)
embryology
The science of studying embryos, including the embryonic and fetal period
teratology
The science of studying abnormal development of embryos
developmental toxicity
Toxicity to the developing embryo or fetus
Embryotoxicity
Toxicity that causes growth retardation or delayed growth
embryolethality
Lethal embryotoxicity that leads to the death of embryos
teratogenicity
The ability to induce irreversible structural alterations.
Human teratogen
A human teratogen is an agent that alters the structure or growth of the developing embryo or fetus, leading to birth defects
Types of human teratogens
Drugs
* thalidomide
* alcohol
* antibiotics like tetracyclines
Environmental chemicals
* diethylstilbestrol
Physical agents
* ionising radiation
Maternal factors
* * diabetes
Mechanical factors
* restriction of fetal movement
Timing of exposure and teratogenicity
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)
Thalidomide effects upper or lower limbs more
Upper
Placenta acts a partial barrier to limit prenatal exposure to xenobiotics. Drugs cross via
drugs cross the placenta via passive diffusion or drug transporters
Transporters are expressed on the fetal (what) and efflux transporters are on the (what) side
fetal capillary endothelium and syncytiotrophoblast
efflux transporters on the apical membrane (e.g.,
MDR1) protects fetus by exporting drugs
CYPs in fetuses
- expressed in placenta - a minor role in drug metabolism
- induced following maternal exposure to inducers, e.g.,
smoking, alcohol
TGA category safe
A and B
TGA category unsafe
D and X
What is the critical period of thalidomide exposure during embryonic development and what how many doses needed to cause a response.
Between day 21 and day 36 post conception.
Single dose can cause defects.
What are the thalidomide-induced defects
Limb malformations
* Phocomelia (short limbs)
* Amelia (no limbs)
Also eye/ear damage and internal organ defects but these are minor.
Cereblon as a thalidomide-binding protein (antiangiogenesis theory)
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.
Cereblon as a thalidomide-binding protein (reactive oxygen theory)
Causes reactive oxygen species formation and cell death therefore, lib defects.
Cereblon coded by what and forms what type of complex with DDB1, Cullin 4 and Roc1
CRBN gene in human
E3 ubiquitin ligase complex that is involved in the proteolysis of substrate proteins.
Thalidomide and Cereblon experiments in fish
Thalidomide cause fin defects but cereblon can rescue it.
SALL4 name
Spalt-like transcription factor 4
SALL4 foetal involvement and mutation; model
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)
Thalidomide and SALL4
Thalidomide promotes degradation of SALL4, a
transcription factor implicated in Duane Radial Ray syndrome.
