DNA ADDUCT FORMATION IN RELATION TO LYMPHOCYTE MUTATIONS AND LUNG-TUMOR INDUCTION IN F344 RATS TREATED WITH THE ENVIRONMENTAL-POLLUTANT 1,6-DINITROPYRENE

Epidemiological studies suggest an association between exposure to die sel emissions and an increased incidence of lung and bladder cancer in humans. Of the compounds associated with diesel emissions, 1,6-dinitr opyrene is a particularly potent mutagen and carcinogen. In these expe riments we administered [4,5,9,10-H-3]1,6-dinitropyrene (30 or 100 mug ) directly to the lungs of F344 rats according to a protocol known to induce lung tumors and characterized the DNA adducts present in the ta rget tissue. In addition, we examined the adducts present in spleen ly mphocytes and assayed for the induction of mutations at the hypoxanthi ne-guanine phosphoribosyltransferase locus in these cells as measured by the frequency of 6-thioguanine-resistant (TG(r)) T-lymphocytes. Add uct formation was detected in both lung and spleen lymphocyte DNA, wit h the extent of binding being dose-dependent in the lymphocytes but no t the lung. P-32-Postlabeling analyses indicated the formation of a ma jor DNA adduct, N-(deoxyguanosin-8-yl)-1-amino-6-nitropyrene, in both tissues. 1,6-Dinitropyrene treatment resulted in a dose-dependent incr ease in TG(r) T-lymphocytes, with the increase being detected for at l east 21 weeks after treatment. These data indicate that 1,6-dinitropyr ene is metabolically activated by nitroreduction to form DNA adducts i n both the target tissue and spleen lymphocytes and that a tumorigenic dose results in a significant induction of TG(r) T-lymphocytes.