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.

What is the threshold dose for a teratogen?

The dose below which all embryos are unaffected/safe.

What factors are included in the INCAPS criteria for associating birth defects with a teratogen?

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, thumb abnormalities, ear abnormalities.

What is the time-sensitive window for thalidomide action?

4th week of development.

What are the two hypotheses on how thalidomide interferes with limb bud development?

1. Thalidomide inhibits cereblon activity, preventing ubiquitination of substrate and outgrowth

2. Alters substrate specificity of cereblon leading to ubiquitination of 'neosubstrates' necessary for limb development.

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

They bring the substrate to the ubiquitin E2 complex and participate in reactions that poly-ubiquitinate substrate proteins for degradation.

What are neosubstrates?

Proteins that are not normally bound, but are ubiquitinated and targeted for degradation like a normal substrate.

Why is thalidomide still prescribed today?

It is used to treat multiple myeloma and leprosy.

What is microcephaly?

A condition characterized by a smaller than usual head.

How was it determined that the Zika virus causes microcephaly?

Zika was found in the amniotic fluid of fetuses diagnosed with microcephaly and model systems showed ZIKV infects and kills neuronal progenitor cells.

What are some reasons Zika virus was not associated with microcephaly before 2015?

Different strains of Zika have different pathogenicity, herd immunity from prior flavivirus exposure, weak health monitoring in endemic areas.

How does Zika pass through the placenta to reach the fetus?

Maternal antibodies enter placenta to build passive immunity in fetus, Zika recognized by antibodies as DENV and taken up, brought across placenta unknowingly

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

Affects cell proliferation in the cortex, S-phase arrest in neuronal progenitor cells, infection of astrocytes, microglia, oligodendrocyte precursor cells, and upregulation of P53 causing apoptosis.

What happens to neuronal progenitor cells during Zika infection?

S-phase arrest occurs in neuronal progenitor cells.

When should teratogen exposure ideally not occur to prevent defects?

During sensitive windows when the affected structure is forming.

How does Zika cause apoptosis in developing brain cells?

Zika infection upregulates P53, leading to apoptosis.

What can excessive teratogen exposure lead to in a developing embryo?

Increased incidence and severity of defects.