Assessment of TGx-DDI genes for genotoxicity in a comprehensive panel of chemicals

Abstract

Background

The TGx-DDI biomarker identifies transcripts specifically induced by primary DNA damage. Profiling similarity of TGx-DDI signatures can allow clustering compounds by genotoxic mechanism. This transcriptomics-based approach complements conventional toxicology testing by enhancing mechanistic resolution.

Methods

Unsupervised hierarchical clustering and t-distributed stochastic neighbor embedding (tSNE) were utilized to assess similarity of publicly-available per- and polyfluoroalkyl substances (PFAS) and ToxCast chemicals based on TGx-DDI modulation. TempO-seq transcriptomic data after highest chemical concentrations were analyzed.

Results

Clustering discriminated between genotoxic and non-genotoxic compounds while drawing similarity among chemicals with shared mechanisms. PFAS largely clustered distinctly from classical mutagens. However, dynamic range across PFAS types and durations indicated variable potential for DNA damage. tSNE visualization reinforced phenotypic groupings, with genotoxins clustering separately from non-DNA damaging agents.

Discussion

Unsupervised learning approaches applied to TGx-DDI profiles effectively categorizes chemical genotoxicity potential, aiding elucidation of biological response pathways. This transcriptomics-based strategy gives further insight into the role and effect of individual TGx-DDI biomarker genes and complements existing assays by enhancing mechanistic resolution. Overall, TGx-DDI biomarker profiling holds promise for predictive safety screening.

Keywords:

• TGx-DDI
• unsupervised clustering
• tSNE
• PFAS
• ToxCast

Acknowledgments

The author would like to thank Dr. Melvin Andersen for his constructive input on this manuscript.

Disclosure statement

ARB is employed by ScitoVation LLC.

Data availability statement

All the codes and data in the manuscript are available upon request.

Additional information

Funding

This work was supported by the American Chemistry Council’s Long-range Research Initiative.