L15

• 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


  An agent that alters the structure or growth of the developing embryo or fetus, leading to birth defects
• Types of human teratogens

  • Drugs (e.g. thalidomide, alcohol, antibiotics like tetracyclines)
  • Environmental chemicals (e.g. diethylstilbestrol)
  • Physical agents (e.g. ionising radiation)
  • Maternal factors (e.g. diabetes)
  • Mechanical factors (e.g. 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)
  • Week 9 to birth: functional disturbance (alcohol)
• Thalidomide effects upper or lower limbs more
• Placenta


  Acts a partial barrier to limit prenatal exposure to xenobiotics. Drugs cross via passive diffusion or drug transporters
• Transporters


  Expressed on the fetal capillary endothelium and syncytiotrophoblast. Efflux transporters on the apical membrane (e.g., MDR1) protect 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
• Thalidomide exposure during embryonic development

  Between day 21 and day 36 post conception. Single dose can cause defects.
• Thalidomide-induced defects


  • Limb malformations (phocomelia, amelia)
  • 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, limb defects.
• Cereblon


  Coded by CRBN gene in human. Forms 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


  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.
• SALL4 as thalidomide-dependent cereblon substrate


  SALL4 can mediate teratogenicity as a thalidomide-dependent cereblon substrate
• Thalidomide binds to cereblon


  1. Causes a confirmation change (its an allosteric modulator)

  2. Change in the cereblon cause E3 ubiquitin complex to recognise a new set of substrate proteins (would be different if thalidomide was absent) including SALL4(TF) that becomes ubiquitinated and degradation by proteasome

  3. Degradation causes change in signal transduction
• Thalidomide therapeutic effects


  Metabolites treat multiple myeloma (has antimyeloma effects)
• Alcohol as human teratogen

  Prenatal alcohol exposure is the leading cause of preventable birth defects. Wide sensitive window - brain development spans the major part of gestation.
• Fetal Alcohol Spectrum Disorder (FASD)


  A spectrum of effects due to prenatal alcohol exposure including facial defects, prenatal/postnatal growth retardation, and neurodevelopmental impairment.
• Diagnosis of FASD


  • Confirmation is necessary before intervention
  • Self-reporting - under-reporting is an issue
  • Neurodevelopmental impairment becomes evident around school age
  • Biomarkers
• FASD Biomarkers


  • FAEE synthase (fatty acid ethyl ester)
  • Phospholipase D
  • SULT- sulfotransferases
  • UGT-Glucuronosyltransferase
• FASD Biomarkers: ethyl glucuronide and ethyl sulfate


  Detected in maternal urine when someone consumes alcohol, showing alcohol consumption.
• FASD Biomarkers metabolites


  • FAEE (detected in neonatal meconium)
  • Phosphatidylethanol (detected in maternal blood)
  • Ethyl sulfate
  • Ethyl glucuronide
• Mechanisms of alcohol teratogenicity (FAEE)

  1. Alcohol

  2. FAEE synthase

  3. FAEE

  4. Damage and cell death

  5. Birth defects
• Mechanisms of alcohol teratogenicity (Phospholipase D)

  1. Alcohol

  2. Phospholipase D

  3. Phosphatidylethanol

  4. Disrupt cell signalling

  5. Birth defects