Transcriptional Profiles of Select Histone Deacetylase Inhibitors in Human HepaRG Cells

Biomarkers including GENOMARK and TGx-DDI enable high-throughput transcriptomic analysis and accurate genotoxicant classification. Histone deacetylase inhibitors (HDACi), a class of epigenotoxicants, disrupt chromatin structure and gene expression, which may lead to impaired DNA repair, apoptosis, and cell cycle perturbation.

A transcriptomic biomarker (TGx-HDACi) was previously developed in human TK6 cells to classify HDACi; however, its performance in other cell types is suboptimal. Herein, we conducted a biomarker discovery study to identify a transcriptomic signature capable of discriminating HDACi from non-HDACi compounds in human HepaRG cells, a metabolically competent hepatic cell line increasingly used in genotoxicity testing. HepaRG cells were exposed to 22 reference chemicals (8 HDACi, 14 non-HDACi) at five increasing concentrations in a 72-hour repeated exposure design, and whole transcriptome profiling was performed using TempO-Seq with maximum concentrations selected based on cytotoxicity and solubility thresholds.