Classifying polycyclic aromatic hydrocarbons by carcinogenic potency using in vitro biosignatures

• Published in: Toxicology in vitro 2020-12, Vol.69, p.104991-104991, Article 104991
• Main Authors: Chang, Yvonne, Huynh, Celine Thanh Thu, Bastin, Kelley M., Rivera, Brianna N., Siddens, Lisbeth K., Tilton, Susan C.
• Format: Article
• Language: English
• Subjects: Angiogenesis; Aromatic compounds; Bayesian analysis; Benzo(a)pyrene; Biocompatibility; Biological activity; Carcinogenicity; Carcinogens; Cell cycle; Classification; Epithelial cells; Gene expression; Hazard assessment; Mesenchyme; Mode of action; Polycyclic aromatic hydrocarbons; Pyrene; Risk assessment; Toxicology; Transcription
• ISSN: 0887-2333; 1879-3177
• DOI: 10.1016/j.tiv.2020.104991

One of the most difficult challenges for risk assessment is evaluation of chemicals that predominately co-occur in mixtures like polycyclic aromatic hydrocarbons (PAHs). We previously developed a classification model in which systems biology data collected from mice short-term after chemical exposure accurately predict tumor outcome. The present study demonstrates translation of this approach into a human in vitro model in which chemical-specific bioactivity profiles from 3D human bronchial epithelial cells (HBEC) classify PAHs by carcinogenic potency. Gene expression profiles were analyzed from HBEC exposed to carcinogenic and non-carcinogenic PAHs and classification accuracies were identified for individual pathway-based gene sets. Posterior probabilities of best performing gene sets were combined via Bayesian integration resulting in a classifier with four gene sets, including aryl hydrocarbon receptor signaling, regulation of epithelial mesenchymal transition, regulation of angiogenesis, and cell cycle G2-M. In addition, transcriptional benchmark dose modeling of benzo[a]pyrene (BAP) showed that the most sensitive gene sets to BAP regulation were largely dissimilar from those that best classified PAH carcinogenicity challenging current assumptions that BAP carcinogenicity (and subsequent mode of action) is reflective of overall PAH carcinogenicity. These results illustrate utility of using systems toxicology approaches to analyze global gene expression towards carcinogenic hazard assessment. •Global gene expression from 3D human bronchial epithelium was compared across multiple PAHs.•Classification model developed to predict PAH carcinogenic potency using in vitro biosignatures.•Transcriptional benchmark dose modeling revealed most sensitive processes regulated by benzo[a]pyrene.