Mechanistic Toxicology II Flashcards
(20 cards)
Reproductive Toxicity Definition
Effects on sexual behaviour and fertility in males and non-pregnant females
Developmental Toxicity Definition
Abnormal structural or functional development after exposure of pregnant or lactating females
Teratogenicity Definition
Ability to cause gross structural malformations
Stages of Reproductive Cycle
- Sexual maturation, 2. Gamete production & release, 3. Fertilisation, 4. Zygote transport, 5. Implantation, 6. Embryogenesis, 7. Fetal Development, 8. Parturition, 9. Lactation & postnatal development 10. Growth & development
Placenta Functions
- Gas exchange, transfer of nutrients + waste products
- Transfer of immunity between (Igs)
- Secretion of hormones for foetal growth
Properties to cross placenta from maternal blood
-Uncharged
-MW less than 1000
-Not highly bound to proteins
Different placenta barrier structures
Humans, guinea pigs, chinchillas - hemomonochorial (syncytiotrophoblast)
Rabbits - hemodichorial (cytotrophoblast + syn)
Mice, rat - hemotrichorial
Sheep, pig - epitheliochorial
Placenta Development
Foetal - chorionic sac
Maternal - endometrium
Types of drug transfer across placenta
Complete (type 1 drugs) - e.g. thiopental
Exceeding (type 2 drugs) - e.g. ketamine
Incomplete (type 3 drugs) - e.g. suxamethonium
Movement of drug from mother to foetus
Intervillous space through syncytiotrophoblast, foetal CT, foetal capillary endothelium
DES (diethylstilbestrol) - prescription
1940-1970
-7-8 weeks prevent miscarriage through progesterone deficiency
-later stages prevent early labour or to treat breakthrough bleeding
- toxic at lower doses
Consequences of DES
- Increased rate of miscarriages before first term delivery
- Possibly increased premature labour and definitely didn’t prevent spontaneous labour
- Mother 10% increased neoplasia chance, 30-50% chance breast cancer
DES daughters troubles
- 40X increase in clear cell vaginal adenocarcinoma in daughters
- 2X breast cancer risk over 40
- infertility, reproductive organs structural abnormalities, ectopic pregnancy, miscarriage
DES Sons
-testicular cancer
- hypospadias
- CV disease, diabetes, osteoporosis
DES mechanisms
- interferes with hormone functions (endocrine disrupting)
- Enterohepatic circulation, long half life (2-3d days)
- Chromosome aberrations (aneuploidy), disrupts miotic spindles
DES Estrogen receptors
- targets areas with high estrogen receptor expression
- in mice effects on development of reproductive systems dependant or ERs ( regardless of gender)
DES low affinity for estrogen binding proteins
Proteins protect from high levels of estrogens by binding them (thus inactivating) , protecting foetus.
DES affinity for a-fetoproteins 100 less than other estrogens like estradiol.
DES reduction of gene expression
Estrogen binding to ERs usually leads to the expression of genes. DES can reduce expression of Hox (60%) and Wnt genes.(80%).
HOX
-Uterine organogenesis (a10)
-Embryogenesis (reproductive tract) (a11)
DES - DNA methylation
DES changes the expression of DNA methylation transferases (DNMTs) causing hyper and hypomethylation of DNA - cell cycle arrest and apoptosis
