Differentially expressed and alternately spliced genes as a novel tool for genotoxicity: a computerized study in ATT-myc transgenic mice for the recognition of genotoxic and non-genotoxic chemical.

Background: Transgenic mice and gene expression in analyses were employed to evaluate hazardous chemicals. Methods: Mice received weekly doses of NDEA (75 mg/kg) for six weeks and twice-weekly doses of BHT (300 mg/kg) for eight weeks. Gene expression and splicing alterations in the livers of six transgenic mice for each treatment of NDEA and BHT were examined using the MouseExon10ST array. Results: Six hybridizations revealed 645 genes with significant expression changes, and 181 genes showed both expression and splicing alterations (p < 0.01). Furthermore, 2021 genes demonstrated significant exon-group interactions, indicating potential alternative splicing. Pathway analysis identified enriched groups in GOMolFn, GOProcess, GOCellLoc, and Pathway classes, with a higher representation of alternatively spliced and expressed genes (p < 0.01). Discussion: Among the top expressed genes was TAT, which encodes the mitochondrial enzyme tyrosine aminotransferase, involved in tyrosine metabolism and recognized as a novel tumor suppressor gene linked to hepatocellular carcinoma (HCC). Additionally, HNF-4, a transcription factor, plays a crucial role in TAT expression. Conclusions: This method can be used to identify genotoxic compounds in the att-myc model for short-term toxicity.