Early formation of DNA adducts compared with tumor formation in a long-term tumor study in rats after administration of 2-nitrofluorene

Abstract

2-Nitrofluorene (NF) is a model compound for nitroarenes which has been identified in diesel exhaust and in urban air. The current study was carried out to observe the carcinogenicity of different doses of NF to rats and DNA adduct formation in different organs at an early stage of NF administration. One group of rats was fed basal diet as a control, whereas the other three groups of rats were fed basal diet supplemented with different amounts of NF (0.24, 0.95 and 2.37 mmol NF/kg diet, referred to as low, medium and high dose, respectively). The rats were exposed to NF continuously for 11 months, after which all groups of rats were fed basal diet without NF for another 13 months. In the high dose group hepatocellular carcinomas were found in all rats (20/20), forestomach squamous carcinomas in 11 and cortical kidney carcinomas in 10 rats. Fifteen out of 19 rats fed the medium dose of NF had hepatocellular carcinomas, 16 had forestomach squamous carcinomas and 15 had cortical kidney carcinomas. The major tumors of the rats fed the low dose of NF were forestomach squamous carcinomas (10/18). DNA adducts formed in tumor target organs after 1, 2, 6 and 10 days NF administration were dose- and time-dependent. Ten days after the start of NF administration DNA adduct levels were found to be 54, 11 and 6 DNA adducts/10(8) normal nucleotides in forestomach, liver and kidney respectively. In the non-tumor target organs levels in the range 1.7-4.8 DNA adducts/10(8) normal nucleotides were found. DNA adduct formation in this study showed a good correlation with the localization of tumors, although there is a need for additional factors for tumor formation. The results indicate that DNA adduct formation is an important factor for tumor formation and suggest that DNA adducts could be used as biomarkers for genotoxic risk.

Mechanistic relationships between hepatic genotoxicity and carcinogenicity in male B6C3F1 mice treated with polycyclic aromatic hydrocarbon mixtures

“…DNA adducts and their levels are important for tumor formation in rats after exposure to 2-nitrofluorene (Cui et al 1995) and our results also confirmed that DNA adducts could be useful biomarkers for tumor risk in mice after exposure to complex PAH mixtures. However, there are many factors involved in chemical carcinogenesis between formation of DNA adducts and tumor formation.…”

Hypothesis: chemical carcinogenesis mediated by a transiently active carcinogen receptor

“…Evidence suggests that adducts could be formed endogenously and may not have a direct role in transformation (Milo and Casto, 1986;Cui et al, 1995;Shimizu et al, 2000). Thus, from the above discussion, the following scenario of genotoxically active carcinogens in oncogenesis may be drawn: Carcinogens enter the cell by passive diffusion.…”

DNA damage and acute toxicity caused by the urban air pollutant 3‐nitrobenzanthrone in rats; Characterization of DNA adducts in eight different tissues and organs with synthesized standards

“…In a chronic exposure study of 2-nitrofluorene (2-NF) in rats, the tissue DNA adduct formation during the first days of exposure was correlated with tumor formation up to two years later [Cui et al, 1995]. These observations are similar to the results obtained in our previous study, in which treatment of rats with 3-NBA gave rise to a rapid increase in DNA adducts of the lung during the first few days after administration, followed by the development of squamous cell carcinoma in the lungs within 18 months [Nagy et al, 2005b].…”

“…Studies on the pathways of 3-NBA metabolism indicate that the metabolite, N-acetoxy-N-acetyl-aminobenzanthrone ], induces DNA base substitutions, similar to the mutations induced by aminofluorene (2-AF), acetylaminofluorene (2-AAF), and nitro-and nitroso-PAHs [Shelton and DeMarini, 1995;Shibutani and Grollman, 1997], suggesting that these compounds are metabolized through similar pathways. In a chronic exposure study of 2-nitrofluorene (2-NF) in rats, the tissue DNA adduct formation during the first days of exposure was correlated with tumor formation up to two years later [Cui et al, 1995]. These observations are similar to the results obtained in our previous study, in which treatment of rats with 3-NBA gave rise to a rapid increase in DNA adducts of the lung during the first few days after administration, followed by the development of squamous cell carcinoma in the lungs within 18 months [Nagy et al, 2005b].…”