Lecture 9 Teratogens

How does the incidence and severity of a defect relate to the dosage of a teratogen?

• Incidence and severity increase with increasing teratogen dose

• severity hits a max

Discuss how the timing of exposure to a teratogen affects the severity of a birth defect.

• must occur during sensitive window when the affected structure is forming

What is the threshold dose for a teratogen?

• dose below which all embryos are unaffected/safe

List the criteria used to associate a rise in birth defects with a novel potential teratogen.

• INCAPS

  • Increase in defect frequency

  • New exposure

  • Critical development stage

  • Animal evidence supports

  • can cross Placenta

  • makes biological Sense

What birth defects are caused by exposure to thalidomide?

• phocomelia (failure of long bone development)

• thumb abnormalities

• ear abnormalities (external ear development)

What is the time sensitive windows for thalidomide action?

• 4th week of development

What are the two hypotheses for how thalidomide might interfere with limb bud development?

• Thalidomide inhibits cereblon activity and prevents if from ubiquitinating a substrate, leading to inhibition of outgrowth

• When thalidomide binds to cereblon, its substrate specificity is altered, causing cereblon to ubiquitinate “neosubstrates” and tag them for degradation. these neosubstrates are necessary for limb development (p63)

What is the function of E3 ubiquitin ligases, like cereblon?

• brings the substrate to ubiquitin E2 complex

• participate in reaction that poly-ubinquitinates substrate proteins → degradation by proteasome

What are neosubstrates?

• proteins that are not normally bound but are not ubiquitinated and targeted for degradation like a normal substrate would be

Why is thalidomide still prescribed today?

• treatment for mutliple myeloma (inhibitions proliferation, increases apoptosis)

• treatment for leprosy (inhibits lesion formation)

What is microcephaly?

• smaller head than usual

How was it determined that the Zika virus causes microencephaly?

• Found in amniotic fluid of fetuses diagnosed with microencephaly in-utero

• Model systems show that ZIKV infects and kills neuronal progenitor cells

What are some reasons that no one realized that Zika virus could cause microencephaly before 2015?

• different strains of Zika virus have different pathogenecity

• herd immunity due to prior exposure of other flaviviruses

• weak health monitoring in areas where Zika was endemic

How does Zika pass through the placenta to reach the fetus

• Recognized by antibodies as DENV and taken up

• transport of maternal igG is used to build temporary passive immunity

What are the effects of Zika infection on the developing brain?

• affects proliferation of cells in cortex between 12-16 weeks gestation

• neuronal progenitor cells - S-phase arrest with Zika exposure

• arrest of proliferation of astrocytes, microglia, oligodendrocyte precursor cells

• upregulates TP53 causing apoptosis