23 - Repro tox Flashcards
(33 cards)
What is Teratology
Investigation of causes and mechanisms of congenital developmental disorders (CDD)
Congenital developmental disorders caused by…
- Genetic (Down’s syndrome)
- Injury (birth)
- Chem (Thalidomide)
- Infection
James G. Wilson’s 6 principles of teratology
- Genotype of conceptus
- Developmental stage at time of exposure
- MOA abnormal developmental events
- Nature of influence
- 4 manifestations of deviant devel.
- Frequency and Dose
The 4 manifestations of deviant development
- Death
- Malformation,
- Growth retardation
- Impaired function.
What is Thalidomide?
Released as sedative
* Caused severe birth defects and death
* Marketed as safe and non-addictive
CDD caused by Thalidomide
Effects to eyes, ears, limbs (phocomelia), facial palsies, mental effects
Biochemistry of thalidomide
2x linked rings (glutarimide and pthalimid)
* Chiral carbon ➔ unstable, allows 2 enantiomers to coexist
* Interchange rapidly in body fluid, water
Thalidomide enantiomers
S-enantiomer is teratogenic, R-enantiomer is sedative
* Was sold as a racemic mix
* Non-teratogenic form possible
Critical period for Thalidomide-induced birth abnormalities
Occur from day 21 post conception to day 36
* Early use could be ok
* Morning sickness > development of important structures (critical)
Thalidomide Mechanism of Teratogenicity
- Bind to cereblon (CRBN)
- Disrupt E3 ubiquitin ligase complex function
- ↓-reg of fibroblast growth factor genes (esp. fgf8 → key in limb devel. abnormalities)
Toxicant exposure and timing in repro cycle
Weeks 1 & 2 not susceptible to teratogens but spontaneous abortions common
* 1st trimester very sensitive
Sexual differentiation during gestation
Wk ~7 sex morphology develops
* rely on Y chromosomal control
* SRY codes protein ➔ testicular organogenesios
* Absent ➔ ovaries
* Male repro devel hormone-dependent ➔ susceptible to endocrine disruption
How can toxicants effect ovarian histology?
- Poly-ovular follicles
- Oocyte depletion
- Interstitial cell hyperplasia
- Corpora albanicas
- Absense of corpora lutea
Sites of action for reproductive (cycle) toxicants
Centrally acting catecholaminergic drugs can interfere with neuroendocrine reg.
* Hypothalamic-pituitary-gonadal (HPG) target in both sexes
* Disrupted by exogenous estrogens + PCBs
How can toxicants effect testicle histology?
- Cadmium ➔ disrupts blood supply from internal spermatic artery
- Melatonin ➔ regression of testes, ↓ testi steroids + mating behaviours
- CCl4 ➔ tox to liver → disrupt metabolism of sex steroids
Can we use animal models to predict teratology?
Understanding of animal repro facilitates use to investigate potential human effects
* Comparable stages exist in non-clinical species
* Rat and Rabbit
Two main sources of info for human repro data/effects
- Registries of cogenital abnormalities (drug/chem exposure in patient history)
- Teratology info services (TIS)
EUROCAT
EU cogenital register
* Evaluate efficacy of safety measures (pregnancy prevention programs) for thalidomide (myeloma), isotretinoin (acne), acitretin (psoriasis)
How can registers be used to study teratology?
Rates of abnormalities compared to prescribing databases
* Used to construct cohort & case-control studies
* Other exposures hard to measure
Vitamin K antagonists
Required for producing clotting factors
* Antagonists (warfarin) prevent clots and strokes
* AVOID during 1st trimester
TIS observed effects of Vit K Ant.
- Inhibit bone growth
- Bleeding foetus
- Spontaneous abortion
- Defects
- Premature and low birth weight
TIS observed effects of Isotretinoin
Accidental exposure in **1st 2 weeks **after conception doesn‘t necessarily call for termination
* Ultrasound at 12 and 20 wk ➔ assess foetal condition
TIS observed effects of AT-II antagonists
Impairs perfusion of foetal organs + ↓ amniotic fluid
* Not a major teratogen
Mothersafe NSW
TIS for NSW
* Provide evidence-based info
* Support mothers
* Prevent termination due to misled concerns
