Evaluating Thiram-Induced Embryotoxicity Using Integrated In Silico, In Vitro, and Transcriptomic Approaches

Area of Science:

• Toxicology
• Developmental Biology
• Computational Toxicology

Background:

• Food contact materials (FCMs) exposure raises concerns for developmental toxicity.
• A computational model identified 127 high-concern FCMs for developmental toxicity.

Purpose of the Study:

• To evaluate the embryotoxicity of selected FCMs using the mouse embryonic stem cell test (mEST).
• To investigate the mechanism of thiram-induced embryotoxicity in mouse embryonic stem cells (mESCs) and human NT2 cells.

Main Methods:

• Weight-of-evidence computational modeling to prioritize FCMs.
• Mouse embryonic stem cell test (mEST) for embryotoxicity screening.
• Transcriptome analysis to identify disrupted pathways.

Main Results:

• Thiram most potently inhibited cardiac differentiation in mEST.
• Thiram suppressed markers for three germ layers but increased neurectoderm markers in mESCs.
• Thiram disrupted neural crest differentiation pathway in mESCs and NT2 cells.

Conclusions:

• Disruption of neural crest differentiation is a key mechanism in thiram-induced embryotoxicity.
• This study provides a framework for mechanism-based biomarker identification for chemical safety assessment.