Correlation between induction of unscheduled DNA synthesis in the liver and excretion of mutagenic metabolites in the urine of rats exposed to the carcinogenic air pollutant 2-nitrofluorene

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Abstract
The genotoxic effects of 2-nitrofluorene (NF) have been studied in vivo by measuring the induction of DNA repair, i.e. unscheduled DNA synthesis (UDS), in hepatocytes from male rats pretreated by oral gavage with NF. During the NF exposure, urine was collected for 24 h, and its mutagenicity was investigated in the plate incorporation assay, using Salmonella TA98 as tester strain. The urine samples were also used for the identification of excreted metabolities of NF. Rats treated with 2-acetylaminofluorene (AAF) were studied simultaneously. A positive UDS response was observed 12 and 24 h following a single gavage exposure to 12.5, 25 and 50 mg/kg NF, with the response returning to near control levels by 36 h. The positive control AAF induced approximately twice the response observed with NF, and both compounds gave a UDS response that was 2-3 times higher in Wistar rats relative to Sprague-Dawley rats. A potent direct-acting mutagenic effect was observed in urine samples after NF treatment, while AAF exposure only gave rise to a weak mutagenic effect, the NA/AAF ratio being 10/1. The stronger urinary mutagenicity after NF treatment relative to AAF treatment was associated with the presence of hydroxylated NFs. The genotoxic effect observed in the liver after NF treatment is, on the other hand, more likely due to the same AAF metabolities that are also formed after in vivo treatment with AAF.