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

Abstract

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 lmol/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 5 0.003) or 9-oxo-2,7-diNF-treated (p 5 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 5 0.02 vs. vehicletreated), 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/10 8 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/10 8 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.Key words: environmental nitroaromatic; rat; mammary cancer; genotoxicity Nitrated polycyclic aromatic hydrocarbons (nitro-PAHs) are widespread environmental pollutants resulting from the incomplete combustion of fossil fuels and atmospheric nitration. [1][2][3] Potential harmful effects of several nitro-PAHs are ascribed to their metabolic activation via nitroreduction to genotoxic species. 4,5 The risks associated with exposure of human populations to mutagenic and carcinogenic nitro-PAHs through inhalation, ingestion or dermal exposure are recognized. 3,[6][7][8][9][10] Nitrofluorenes and their C9-oxidized derivatives constitute a significant fraction of environmental nitro-PAHs. 3,6,7,11,12 2-Nitrofluorene (2-NF) is an abundant compound in diesel, gasoline and kerosene exhausts, and is present in urban air particles at especially high levels (310-5,220 pg/m 3 ) during winter, due to coal and kerosene heating. 6,12 The concentration of 2,7-dinitrofluorene (2,7-diNF; Fig. 1) in the air of Tokyo has been reported to be $30-and $10-fold greater than that of 2-NF and 1-nitropyrene, respectively. 6,13 Administration of 2,7-diNF, 2-NF and 2,5-diNF to female Sprague-Dawley rats at 1.62 mmol/kg of diet for 8 months yielded chi...

Mass spectrometry for the assessment of the occurrence and biological consequences of DNA adducts

“…4-aminobiphenyl, 4-ABP), 50 nitroaromatic compounds ( e.g. 2-nitrofluorene), 51 and heterocyclic aromatic amines found in cooked fish and meats, such as 2-amino-3-methylimidazo[4,5- f ]quinoline (IQ), 52 2-amino-1-methyl-6-phenylimidazo[4,5- b ]pyridine (PhIP), 53 and 2-amino-3,8-dimethylimidazo-[4,5- f ]quinoxaline (MeIQx). 54 Although the sites of substitution on nucleobases vary substantially, it appears that the C8 atom and the exocyclic amino nitrogen of the purine bases, particularly of guanine, are the major targets for arylamination.…”

Interaction of Nitrate and Folate on the Risk of Breast Cancer Among Postmenopausal Women

“…Exposure to industrial NOCs was associated with DNA adduct formation and benign and malignant tumor incidence in mammary glands in animal studies, suggesting potential relevance for risk of breast cancer (5–7). Nitrate is a natural component of the diet, and nitrate and nitrite are added as preservatives to meats.…”

Design, synthesis, and mechanistic study of 2-piperazineone-bearing peptidomimetics as novel HIV capsid modulators

“…NACs are known to have genotoxic activity and can seriously threaten humans and the environment. 53–57 NACs can directly interact with the human genome via DNA interactions. Fortunately, those interactions can be computationally described with physicochemical properties within the molecule.…”