Drug 12

• developmental toxicity 


  toxicity to developing embryo or foetus
• embryotoxicity 


  toxicity that causes growth retardation or delayed growth
• teratogenicity 


  the ability to induce irreversible structural alteration (irreversible birth defects)
• human teratogen 


  an agent that alters the structure or growth of developing foetus or embryo leading to birth defects
• drugs that are human teratogens

  thalidomide and alcohol
• environmental chemical that is a human teratogen

  DES
• types of human teratogens

  drugs, infectious agents, environmental chemicals, physical agents
• exposure to human teratogen in first 2 weeks


  death of embryo or embryo survives without birth defects
• exposure to human teratogen weeks 3-8

  organogenesis, most sensitive to exposure will get defects
• exposure to human teratogen week 9 to birth

  functional disturbances to fetus, e.g cognitive disturbances
• why CNS defects common

  is sensitive entire pregnancy, developing whole time
• placenta barrier


  partial limiter for prenatal exposure as drugs can cross via passive diffusion or transporters
• CYPs in placenta


  induced following exposure to inducers like smoking, alcohol
• what was thalidomide used for


  as a non addictive non barbiturate sedative to treat morning sickness, had early reports of peripheral neuropathy
• thalidomide critical period of exposure

  21-36 days post conception, a single dose enough to cause defects
• thalidomide defects


  mainly limb malformations - shortened or none to upper limbs ear

  eye damage

  internal organ
• theory of how thalidomide cause birth defects

  cereblon sd thalidomide binding protein
• cereblon


  mediates thalidomide infected teratogenicity forms complex with 3 other proteins that recognise substrate
• SALL4


  TF involved in foetal limb development, a loss of function mutation causes congenital birth defects
• what thalidomide does to SALL

  promotes degradation so substrate transcription not regulated = mutations
• why is prenatal exposure to alcohol leading cause of preventable birth defects


  wide sensitive window as brain develops over entire gestation period
• FASD


  fetal alcohol spectrum disorder - spectrum of effects due to prenatal exposure
• FAS


  fetal alcohol syndrome is most severe form of FASD
• triad of FAS


  facial defects

  pre/postnatal growth retardation

  neurodevelopment impairment
• when to FASD become evident

  neurodevelopment markers child age
• 2 key biomarkers for FASD

  ethyl glucuronide (UGT) and ethyl sulfate (SULT) in maternal urine
• mechanisms of alcohol teratogenicity

  reactive acetaldehyde, protein and DNA adducts, disruption of cell signalling = cell damage and death = birth defects