Integrating Transcriptomic and Targeted New Approach Methodologies into a Tiered Framework for Chemical Bioactivity...

Area of Science:

• Environmental toxicology
• Chemical safety assessment
• Molecular profiling

Background:

• Identifying chemical hazards is crucial due to the vast number of chemicals in commerce and the environment.
• High-throughput transcriptomics (HTTr) and receptor screening assays offer potential for improved hazard identification.

Purpose of the Study:

• To link transcriptomic data to specific molecular targets.
• To integrate transcriptomic predictions with orthogonal receptor assays for chemical hazard prioritization.

Main Methods:

• Developed gene expression signatures for molecular targets using TempO-Seq in U-2 OS and HepaRG cells.
• Screened 1,126 chemicals using HTTr and assessed selective bioactivity against signatures.
• Validated predictions using EPA ToxCast data and prospective receptor-level assays.

Main Results:

• 201 out of 1,126 chemicals showed selective bioactivity; 57 were confirmed as selective nuclear receptor agonists.
• Transcriptomic signatures accurately predicted orthogonal assay bioactivity.
• Prospective testing confirmed predicted receptor activity in 49% of chemicals lacking prior data.

Conclusions:

• Integrating transcriptomics with targeted orthogonal assays supports Next Generation Risk Assessment.
• This tiered framework effectively identifies putative molecular targets and prioritizes chemicals for further testing.