Detection of thalidomide embryotoxicity by in vitro embryotoxicity testing based on human iPS cells

Area of Science:

• Developmental toxicology
• Stem cell biology
• Drug safety assessment

Background:

• The mouse embryonic stem cell test (mEST) assesses drug embryotoxicity by examining effects on stem cell cardiac differentiation.
• Thalidomide's embryotoxicity has not been previously reported using the mEST.
• Existing methods may lack predictive power for certain drug toxicities.

Purpose of the Study:

• To adapt the mEST using human induced pluripotent stem cells (hiPSCs) for improved embryotoxicity detection.
• To evaluate the embryotoxic potential of thalidomide using this modified assay.
• To compare the predictive ability of the hiPSC-based test with the traditional mEST.

Main Methods:

• Human induced pluripotent stem cells (hiPSCs) were used instead of mouse embryonic stem cells.
• Three endpoints were assessed: inhibition of cardiac differentiation, cytotoxicity to hiPSCs, and cytotoxicity to human dermal fibroblasts.
• Embryotoxicity was classified into classes based on IC50 values and established criteria, with valproate as a positive control and ascorbic acid as a negative control.

Main Results:

• Thalidomide was classified as a Class 2 agent (weak embryotoxicity) by mEST criteria and Category 3 by study criteria.
• Ascorbic acid was classified as Class 1 / Category 1 (non-embryotoxic) by both criteria.
• The hiPSC-based test detected thalidomide's embryotoxicity, indicating its effectiveness.

Conclusions:

• The hiPSC-based embryonic stem cell test demonstrates a greater predictive ability for drug embryotoxicity compared to the mEST.
• This modified assay provides a valuable tool for assessing the developmental toxicity of drug candidates.
• The study highlights the potential of human stem cells in advancing drug safety evaluations.