Teratogenicity and Embryotoxicity of Thalidomide and 3-Aza-Thalidomide in Mice

Abstract

The molecules of thalidomide (I) and 3-azathalidomide (II) have the characteristic aromatic six-membered ring 1,2-dicarboximide structure which is regarded as necessary for effecting teratogenicity. Pregnant SWS mice were given single i.p. injections of I and II on day 9 of gestation. A mixture of physiological saline and Tween 20 (3:1) was used as solvent. II showed a much higher teratogenic and embryotoxic effect than I. This variation is assumed to be caused by a different ability of the two substances to intercalate between base pairs of the double helix of DNA.

Controversy regarding the functional conservation of cereblon CUL4-type E3 ligase substrate receptor

“…The drug was approved for cancer treatment under an FDA directive requiring routine pregnancy testing with distribution of written and verbal warnings to inform patients of the detrimental impact of thalidomide on fetal development [8]. Many studies have confirmed the relationship between thalidomide, and its related class of compounds (also known as immunomodulatory drugs, IMiD®) and teratogenicity in humans, zebrafish, chickens and in rodents when given during specific periods of gestation [1,[9][10][11][12] Fifty years after the thalidomide tragedy, Takumi Ito and colleagues revealed the molecular mechanism of this drug through elegant studies conducted in zebrafish and chickens [12]. Cereblon (CRBN) was identified as the direct target of immunomodulatory compounds and one of many DDB1 and CUL4-associated factors (DCAFs) that directs protein turnover by ubiquitination and subsequent proteasome recognition.…”