Adverse outcome pathway-driven identification of rat liver tumorigens in short-term assays

• Published in: Toxicology and applied pharmacology Vol. 356; pp. 99 - 113
• Main Authors: Rooney, John, Hill, Thomas, Qin, Chunhua, Sistare, Frank D., Corton, J. Christopher
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2018
• Subjects: Adverse outcome pathway; Adverse Outcome Pathways; Animals; Aryl hydrocarbon receptor; Biomarkers, Tumor - metabolism; Body Weight - drug effects; Carcinogenicity Tests - methods; Carcinogens - classification; Carcinogens - toxicity; Clinical chemistry; Constitutive activated receptor; DNA Damage - drug effects; Estrogen receptor; Gene Expression Regulation, Neoplastic - drug effects; Genotoxicity; Key events; Liver cancer; Liver Neoplasms, Experimental - chemically induced; Liver Neoplasms, Experimental - pathology; Liver weight; Molecular initiating events; Organ Size - drug effects; Oxidative stress; p53; Peroxisome proliferator-activated receptor alpha; Rats; Rats, Sprague-Dawley; ToxPi; Transcript profiling; Oxidative stress; Estrogen receptor; Molecular initiating events; Clinical chemistry; ToxPi; Transcript profiling; Genotoxicity; Peroxisome proliferator-activated receptor alpha; Constitutive activated receptor; p53; Liver weight; Liver cancer; Aryl hydrocarbon receptor; Key events; Adverse outcome pathway
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2018.07.023

Chemicals induce liver cancer in rodents through well characterized adverse outcome pathways (AOPs). We hypothesized that measurement of molecular initiating events (MIEs) and downstream key events (KEs) in liver cancer AOPs in short-term assays will allow early identification of chemicals and their associated doses that are likely to be tumorigenic in the liver in two-year bioassays. We tested this hypothesis using the rat in vivo TG-GATES study data to measure MIEs (genotoxicity, cytotoxicity, AhR, CAR, ER, PPARα) and associated KEs (oxidative stress, cell proliferation, liver to body weights) across 77 chemicals that could be linked to doses with previously established effects on rat liver tumor induction. Gene expression biomarkers for MIEs generally considered to be rodent specific and human irrelevant (CAR, PPARα) and for MIEs that would be considered of greater risk at human relevant exposures (ER, AhR) were built using microarray comparisons from the livers of rats treated with prototypical activators of the receptors. The genotoxicity biomarker, also a potentially human relevant MIE, was comprised of 7 p53-responsive genes known to be induced upon DNA damage. The ability of the biomarkers to accurately predict MIE activation ranged from 91% to 98%. The Toxicological Priority Index (ToxPi) was used to rank chemicals based on their ability to activate MIEs/KEs. Chemicals administered at tumorigenic doses clearly gave the highest ranked scores. Our AOP-directed approach could be used in short term assays to identify chemicals and their doses that would be predicted to cause liver tumors in rats. •AOPs provide a framework for predictions of cancer based on early key events.•Key events for six rodent liver cancer AOPs were measured in the TG-GATES study.•Gene expression biomarkers accurately predicted nuclear receptor activation.•ToxPi was used to summarize scores for chemical-induced key events.•Measurement of effects at 4 days accurately predicted liver cancer.