title: 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 micromol/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/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.
authors.affiliation: Veterans Affairs Medical Center, Minneapolis, MN 55417, USA. malej001@umn.edu
authors.forename: Danuta
authors.initials: D
authors.lastname: Malejka-Giganti
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Parkin
authors.forename: Richard W
authors.initials: RW
authors.lastname: Decker
authors.forename: Gloria A
authors.initials: GA
authors.lastname: Niehans
authors.forename: Robin L
authors.initials: RL
authors.lastname: Bliss
authors.forename: Mona I
authors.initials: MI
authors.lastname: Churchwell
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Beland
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D002274:Carcinogens, Environmental / Q000378:metabolism / Q000633:toxicity*; D002851:Chromatography, High Pressure Liquid; D018736:DNA Adducts / Q000187:drug effects / Q000378:metabolism; D003849:Deoxyguanosine / Q000378:metabolism; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D005449:Fluorenes / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D015994:Incidence; D007274:Injections, Intraperitoneal; D053208:Kaplan-Meier Estimate; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity*; D009603:Nitroso Compounds / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry
chemical_list: C527359:2-nitroso-7-nitro-9-oxofluorene; C527358:2-nitroso-7-nitrofluorene; D002274:Carcinogens, Environmental; D018736:DNA Adducts; D004785:Environmental Pollutants; D005449:Fluorenes; D009153:Mutagens; D009603:Nitroso Compounds; C085049:2,7-dinitrofluorene; D003849:Deoxyguanosine; D001205:Ascorbic Acid