Lecture 4: Reproductive Toxicology Flashcards
What is a repro toxicant (makeup/produced by)?
protein produced by organism as defense mechanism
3 main endpoints (harmful/AEs) for repro toxicants?
- Fertility
- Pregnancy outcome (birth defects, others)
- Lactation
What can Parvovirus B19 cause?
What does it not cause?
Can cause hydrops
Does not cause birth defects (structural malformation)
How does exposure level relate to repro toxicology?
EVERYTHING toxic at high enough dose level
NO reproductive toxicants only toxic exposure scenarios
Mutagenesis
Test for it?
changing genetic code (depends on dose)
AMES test - identifies chemicals mutagenic–> cause birth defects
How to do AMES test
- bacteria (Salmonella) altered to be independent of AA nutrient
- observed for back mutation to natural state
(growth = back mutated)
Can mutagenesis or carcinogenesis predict reproductive toxicity?
NO
3 mechanisms for defining repro toxicant?
- Mutagenesis
- Carcinogenesis
- Endocrine activity
not good way to define it…cant predict repro toxicity and endo activ not spp
What is the radiation dose that is considered the counseling threshold?
5 rads
What does counseling threshold mean?
Abn outcome = same chance as general population
What is the radiation dose that definitely causes bad outcomes (microcephaly, retardation)
50 rads
What 2 circumstances is withholding Tx worse for fetus? (reason to give meds in preg)
Why?
- DM –> incr in fetal malformations
2. Asthma –> growth prob
What does category X in pregnancy mean?
Not mean?
Categ X = CI in pregnancy
DOES NOT MEAN CAUSES BIRTH DEFECTS
What is an example of 2 meds CI in preg (Categ X)
- Accutane
2. OCPs
Why is Accutane CI in preg (Categ X)?
causes malformation in high % of exposed embryos or other developmental abnormality
Why are OCPs CI in preg (Categ X)?
CI NOT b/c causes birth defects
CI b/c not effective/indicated in preg
What med is in Categ D?
pt decides whether benefit > risk
Valproic acid
What is included in new labels of drugs (3)?
- Risk summary (of human + animal studies)
- Clinical considerations (risk of untreated dz, dose adjustment in preg)
- Summary of data
What type of study typically done before drug 1st marketed
Experimental animal studies `
Why are monkeys worse than rats for experimental animal studies?
monkeys = less offspring per preg –> less opportunities for fetal malformations
ACE inhibitor toxicity leads to what?
Absence of scalp/skill
poison fetal RAAS –> HoTN –> dont urinate–> absensce of amniotic fluid –> pressure necrosis of scalp
When does the fetal RAAS develop?
fetal RAAS dev in 2nd trimester
What does Diethylstilbestrol (DES) cause (2 things)?
Clear cell carcinoma & malformations of developing genital tract
What are the 2 malformations of developing genital tract caused by Diethylstilbestrol?
- T shaped uterine cavity (instead of triangular)
2. Norm vaginal epithelium replaced by columnar epithelium –> more risk for CA as adolescent
Why was Diethylstilbestrol prescribed originally?
Given to pregnant women to prevent miscarriage, premature labor, and related complications
What drug causes Phocomelia?
what is Phocomelia?
Thalidomide
Malformations of the arms and legs
What is selective embryotoxicity?
What drug exhibits this?
at certain doses the drug is selectively toxic to embryo (not mother)
Thalidomide
What are 2 future types of testing for repro toxicity adverse outcome pathways?
In vitro/silico screening
3 molecular initiating events in the adverse outcome pathway
- Receptor activation
2/3. protein or DNA binding
3 key events in the adverse outcome pathway
- Gene activation, Protein production
- Altered signaling
- Altered tissue, disrupted homeostasis
3 Adverse outcomes in the adverse outcome pathway
- malformations
- organ dysfxn
- lethality
