Identifying developmental toxicity pathways for a subset of ToxCast chemicals using human embryonic stem cells and...

Area of Science:

• Toxicology
• Metabolomics
• Stem Cell Biology

Background:

• Chemical screening and prioritization are crucial for identifying developmental toxicants.
• Human embryonic stem cells (hESCs) offer a valuable model for assessing developmental toxicity.
• Metabolomics can reveal cellular responses to chemical exposure.

Purpose of the Study:

• To investigate the utility of hES cell metabolomics for predicting chemical developmental toxicity.
• To identify metabolic signatures associated with developmental toxicity from EPA ToxCast chemicals.
• To evaluate the predictive accuracy of a metabolomics-based model for developmental toxicity.

Main Methods:

• Metabolomics analysis of hES cell culture supernatants exposed to 11 EPA ToxCast chemicals.
• Identification and pathway mapping of significant endogenous metabolite changes.
• Utilizing a predictive DevTox® model, incorporating ToxRefDB and experimental data.
• Assessing model performance for predicting developmental toxicity in concordance with animal data.

Main Results:

• 83 putatively annotated mass features showed significant fold changes in response to ToxCast chemicals.
• Key affected metabolic pathways include nicotinate/nicotinamide, pantothenate/CoA biosynthesis, glutathione, and arginine/proline metabolism.
• The predictive model achieved 73% accuracy initially and improved to 83% after retraining.
• Metabolomics data from hESCs provided valuable insights into developmental toxicity mechanisms.

Conclusions:

• hES cell secretome metabolomics is a promising tool for developmental toxicity prediction.
• Metabolic pathway alterations offer mechanistic understanding of chemical-induced developmental toxicity.
• This approach supports the development of more accurate predictive models for chemical safety assessment.