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DNA Adduct Formation and T-Lymphocyte Mutation Induction in F344 Rats Implanted with Tumorigenic Doses of 1,6-Dinitropyrene¹

National Center for Toxicological Research, Jefferson, Arkansas 72079

Diesel emissions are known to induce tumors in experimental animals and are suspected of being carcinogenic in humans. Of the compounds associated with diesel exhaust, 1,6-dinitropyrene is a particularly potent mutagen and carcinogen. In these experiments, we have investigated the use of DNA adducts and T-lymphocyte mutations of 1,6-dinitropyrene as biomarkers for exposure to diesel emissions. 1,6-Dinitropyrene (0–150 µg) was applied directly to the lungs of male F344 rats according to a protocol known to induce lung tumors. In target (lung) and surrogate (liver, WBC, and spleen lymphocytes) tissues, one major DNA adduct, N-(deoxyguanosin-8-yl)-1-amino-6-nitropyrene, was detected by HPLC and/or ³²P-post-labeling analyses. The levels of this adduct reached a maximum 1–7 days following treatment and decreased to 13–50% of the peak values by 28 days after dosing. In the lung, a 2-fold increase in dose resulted in a 2-fold increase in DNA binding up to the 30-µg dose; in the liver the same relationship was observed up to 10 µg 1,6-dinitropyrene. At higher doses, the extent of adduct formation still increased, but the rate was much lower than that occurring at lower doses. A limiting dilution clonal assay was used to measure mutation induction at the hypoxanthine-guanine phosphoribosyltransferase locus in spleen T lymphocytes. Following treatment, the mutant frequency increased until 21 weeks, remained constant until week 40, and then began to decrease. Mutant induction was dose related, with the increase in mutant frequency being significant at doses 1 µg 1,6-dinitropyrene. These data indicate that 1,6-dinitropyrene, a constituent of diesel emissions, is metabolically activated by nitroreduction to give DNA adducts in target and surrogate tissues. They further suggest that T-lymphocyte mutations may be a more sensitive and longer-lived biomarker than DNA adducts for assessing previous exposures to nitropolycyclic aromatic hydrocarbons.

¹ Part of the research described in this article was conducted under contract to the Health Effects Institute, an organization jointly funded by the United States Environmental Protection Agency under Assistance Agreement X812059 and automotive manufacturers. The contents of this article do not necessarily reflect the views of the Health Effects Institute, nor do they necessarily reflect the policies of the Environmental Protection Agency or automotive manufacturers. Preliminary accounts of this work have appeared in Environ. Health Perspect. 99: 277–280, 1993 and 102 (Suppl 6): 185–189, 1994.

² To whom requests for reprints should be addressed, at HFT-110, National Center for Toxicological Research, 3900 NCTR Road, Jefferson, AR 72079.

Received 1/ 9/95. Accepted 3/31/95.

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