An Evaluation of Human Induced Pluripotent Stem Cells to Test for Cardiac Developmental Toxicity

Area of Science:

• Toxicology
• Stem Cell Biology
• Developmental Biology

Background:

• Maternal exposure to chemicals can cause congenital defects, necessitating pre-market toxicity screening.
• Current animal models for developmental toxicity testing have limitations in predicting human risk.
• The established embryonic stem cell test (EST) using mouse cells has improved screening but may not fully represent human responses.

Purpose of the Study:

• To develop a human-relevant developmental toxicity screening approach.
• To update the traditional mouse embryonic stem cell test (EST) using human induced pluripotent stem cells (hiPSCs).
• To assess the utility of hiPSCs and early molecular endpoints for predicting embryotoxicity.

Main Methods:

• Utilized human induced pluripotent stem cells (hiPSCs) and human fibroblasts to update the three endpoints of the classic mouse EST.
• Exposed hiPSCs to selected test chemicals to evaluate differentiation inhibition.
• Assessed the expression of the early cardiac gene TBX5 as a molecular endpoint.

Main Results:

• hiPSCs demonstrated inhibition of differentiation at lower chemical concentrations compared to the mouse EST.
• The hiPSC-based test identified adverse developmental outcomes from novel environmental toxicants.
• The TBX5 gene evaluation showed toxicity patterns consistent with the full hiPSC-EST.

Conclusions:

• hiPSCs provide a more biologically relevant model for embryotoxicity screening.
• Early molecular endpoints, like TBX5, can complement full hiPSC-EST assessments.
• These findings support the development of hiPSC-based assays for chemical and mixture safety evaluations.