Gene Expression Biomarkers for Predicting Lung Tumors in Two-Year Rodent Bioassays

Two-year rodent bioassays play a central role in evaluating both the carcinogenic potential of a chemical and generating quantitative information on the dose-response behavior for chemical risk assessments. The bioassays involved are expensive and time-consuming, requiring nearly lifetime exposures (two years) in mice and rats and costing $2 to $4 million per chemical. Since there are approximately 80,000 chemicals registered for commercial use in the United States and 2,000 more are added each year, applying animal bioassays to all chemicals of concern is clearly impossible. To efficiently and economically identify carcinogens prior to widespread use and human exposure, alternatives to the two-year rodent bioassay must be developed. In this study, animals were exposed for 13 weeks to two chemicals that were positive for lung tumors in the two-year rodent bioassay, two chemicals that were negative for tumors, and two vehicle controls. Gene expression analysis was performed on the lungs of the animals to assess the potential for identifying gene expression biomarkers that can predict tumor formation in a two-year bioassay following a 13 week exposure. Keywords: toxicology, chemical carcinogenesis, lung Five week old female B6C3F1 mice were exposed for 13 weeks to the following treatments: 1) 1,5-Naphthalenediamine, CAS No. 2243-62-1, feed, 2000 ppm, positive lung carcinogen; 2) 2,3-Benzofuran, CAS No. 271-89-6, gavage, 240 mg/kg, positive lung carcinogen; 3) N-(1-naphthyl)ethylenediamine dihydrochloride, CAS No. 1465-25-4, feed, 2000 ppm, negative lung carcinogen; 4) Pentachloronitrobenzene, CAS No. 82-68-8, feed, 8187 ppm, negative lung carcinogen; 5) Feed control; 6) Corn oil gavage control. Feed animals were exposed 7 days/week and gavage animals were exposed 5 days/week (5 ml/kg). Microarray analysis was performed on the lungs of three mice per treatment group.