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Teratogenicity

Teratogenicity

The ability of a drug to produce structural deformations and functional abnormalities in the developing embryo or the fetus is called teratogenicity, and the drug producing this effect is known as a teratogen. Teratogenic effects include stillbirth, miscarriage, intrauterine growth restriction, and neurocognitive delay. A teratogen may affect the embryo at different stages of development, which is important in determining the type and extent of the damage. During blastocyst formation, the early...

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Related Experiment Video

Updated: May 20, 2025

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs

Published on: May 15, 2019

Thalidomide-induced limb malformations: an update and reevaluation.

Michael D Collins¹, William J Scott²

¹Department of Environmental Health Sciences and Molecular Toxicology Interdisciplinary Program, UCLA School of Public Health, CHS 46-078, 650 Charles E. Young Drive South, Los Angeles, CA, 90095, USA. mdc@ucla.edu.

Archives of Toxicology

|April 8, 2025

Summary

This summary is machine-generated.

Thalidomide causes limb malformations in developing embryos, primarily affecting forelimbs and left limbs. The cereblon-binding mechanism explains this embryopathy, with SALL4 as a key neosubstrate.

Keywords:

Enantiomers Limb Phenocopy Phocomelia SALL4 Species-specificity Thalidomide

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Analysis of Craniomaxillofacial Malformations in Mice Using Three-dimensional Microcomputed Tomography

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Last Updated: May 20, 2025

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs

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Published on: May 15, 2019

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Analysis of Craniomaxillofacial Malformations in Mice Using Three-dimensional Microcomputed Tomography

Analysis of Craniomaxillofacial Malformations in Mice Using Three-dimensional Microcomputed Tomography

Published on: January 17, 2025

Area of Science:

Developmental toxicology
Teratology
Pharmacology

Background:

Thalidomide is a historical example of chemical teratogenicity, causing severe congenital malformations, notably phocomelia.
Understanding thalidomide's teratogenic effects is crucial for developmental toxicology and drug safety.
The precise mechanisms and species-specific responses to thalidomide remain areas of active research.

Purpose of the Study:

To describe the human thalidomide-induced limb phenotype and compare it across species.
To review mechanistic insights into thalidomide embryopathy, focusing on cereblon binding.
To highlight the importance of toxicokinetics and species-specificity in understanding teratogenic effects.

Main Methods:

Review of historical data and unpublished findings on thalidomide-induced limb malformations in humans and non-human primates.
Analysis of mechanistic studies involving cereblon (CRBN) binding and protein ubiquitination.
Comparative analysis of thalidomide's effects across different laboratory animal models.

Main Results:

Thalidomide induces a longitudinal limb phenotype, preferentially affecting forelimbs, preaxial structures, and left limbs.
Non-human primates and rabbits exhibit malformations anatomically similar to humans.
Cereblon binding to thalidomide leads to ubiquitination of neosubstrates like SALL4, implicated in the embryopathy.

Conclusions:

The cereblon-CRL4CRBN complex and its neosubstrates (e.g., SALL4) offer a partial mechanistic explanation for thalidomide limb defects.
Species-specific responses and toxicokinetic parameters are critical for understanding thalidomide's teratogenicity.
Further research into candidate neosubstrates and traditional mechanisms like anti-angiogenesis may fully elucidate thalidomide embryopathy.