Tumorigenicity and genotoxicity of an environmental pollutant 2,7‐dinitrofluorene after systemic administration at a low dose level to female rats

• Published in: International journal of cancer 2008-05, Vol.122 (9), p.1958-1965
• Main Authors: Malejka‐Giganti, Danuta, Parkin, Daniel R., Decker, Richard W., Niehans, Gloria A., Bliss, Robin L., Churchwell, Mona I., Beland, Frederick A.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Ascorbic Acid - pharmacology; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Carcinogens, Environmental - metabolism; Carcinogens, Environmental - toxicity; Chemical agents; Chromatography, High Pressure Liquid; Deoxyguanosine - metabolism; DNA Adducts - drug effects; DNA Adducts - metabolism; environmental nitroaromatic; Environmental Pollutants - administration & dosage; Environmental Pollutants - metabolism; Environmental Pollutants - toxicity; Female; Fluorenes - administration & dosage; Fluorenes - metabolism; Fluorenes - toxicity; genotoxicity; Incidence; Injections, Intraperitoneal; Kaplan-Meier Estimate; Liver Neoplasms, Experimental - chemically induced; Liver Neoplasms, Experimental - metabolism; mammary cancer; Mammary Neoplasms, Experimental - chemically induced; Mammary Neoplasms, Experimental - metabolism; Medical sciences; Mutagens - metabolism; Mutagens - toxicity; Nitroso Compounds - toxicity; rat; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry; Tumors
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.23352

Environmental pollution with nitroaromatic compounds may pose health hazards. We have examined the tumorigenicity in female Sprague‐Dawley rats of 2,7‐dinitrofluorene (2,7‐diNF) and 9‐oxo‐2,7‐diNF administered by intraperitoneal (i.p.) and oral routes at 10 μmol/kg body weight, 3 times per week for 4 weeks. After i.p. treatment, the estimated median latency for the combined malignant and benign mammary tumors was decreased in 2,7‐diNF‐ (p = 0.003) or 9‐oxo‐2,7‐diNF‐treated (p = 0.007), relative to vehicle‐treated rats (42 or 64 vs. 80 weeks, respectively), whereas after oral dosing, there were no significant differences. At 90 weeks, the malignant mammary tumor incidence in 2,7‐diNF‐, 9‐oxo‐2,7‐diNF‐ and vehicle‐i.p. treated rats was 44 (p = 0.02 vs. vehicle‐treated), 25 and 6%, respectively. Liver and mammary gland DNA was analyzed by HPLC combined with electrospray tandem mass spectrometry for the presence of a deoxyguanosine (dG‐2,7‐diNF) adduct and a deoxyadenosine (dA‐2,7‐diNF) adduct derived from 2,7‐diNF, and a deoxyguanosine (dG‐9‐oxo‐2,7‐diNF) adduct derived from 9‐oxo‐2,7‐diNF. Both dG‐2,7‐diNF and dA‐2,7‐diNF were detected in DNA of 2,7‐diNF‐treated rats, whereas only very low levels of dG‐9‐oxo‐2,7‐diNF were detected in DNA of 9‐oxo‐2,7‐diNF‐treated rats. After i.p. treatment, the dA‐2,7‐diNF level was higher (p < 0.01) in the mammary gland than liver (13.6 vs. 7.8 adducts/108 nucleotides). In the mammary gland, the dG‐2,7‐diNF level was higher (p < 0.05) after i.p. than oral dosing and also higher (p < 0.05) than in the liver (36 vs. 8.6 and vs. 9.1 adducts/108 nucleotides, respectively). The preferential display of carcinogenicity and genotoxicity in the mammary gland by low doses of 2,7‐diNF signifies its potential relevance for environmental breast cancer. © 2008 Wiley‐Liss, Inc.