[Transcriptomics-driven Evaluation on Liver Toxicity Using Adverse Outcome Pathways (AOP)].

Area of Science:

• Toxicology
• Genomics
• In vitro and In silico methods

Background:

• The liver is a primary target for chemical and pharmaceutical toxicity.
• Non-animal testing methods are crucial for animal welfare and cost reduction.
• Mechanistic interpretation of non-animal test data is increasingly important.

Purpose of the Study:

• To investigate evaluating liver toxicity using the adverse outcome pathway (AOP) concept.
• To apply gene set enrichment analysis (GSEA) to gene expression (GEx) data for toxicity assessment.
• To demonstrate the utility of transcriptome-driven AOP evaluation for predicting hepatocellular fatty degeneration (HFD).

Main Methods:

• Compared GEx data from rat primary hepatocytes (in vitro) and rat liver (in vivo) treated with an HFD-inducing chemical.
• Identified in vitro detectable events by comparing in vitro and in vivo GEx data.
• Calculated GSEA scores using established gene sets for HFD-related events.

Main Results:

• Mechanistic information leading to HFD was successfully obtained from GSEA scores.
• The study demonstrated the potential for transcriptome-driven evaluation using AOP.
• Hepatocellular fatty degeneration was accurately predicted.

Conclusions:

• The AOP concept combined with GSEA of GEx data is a viable method for evaluating liver toxicity.
• This approach provides mechanistic insights into toxicity.
• Non-animal testing for liver toxicity assessment can be advanced using this transcriptome-driven AOP strategy.