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.

2.50
Hdl Handle:
http://hdl.handle.net/10146/25512
Title:
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.
Authors:
Nagy, Eszter; Adachi, Shuichi; Takamura-Enya, Takeji; Zeisig, Magnus; Moller, Lennart
Abstract:
3-Nitrobenzanthrone (3-NBA) is an urban air pollutant and rat lung carcinogen that is among the most potent mutagens yet tested in the Salmonella reversion assay. In the present study, 1 mg 3-NBA was administered orally to female F344 rats and DNA adduct formation was examined in liver, lung, kidney and five sections of the gastrointestinal (GI) tract at 6 hr, and 1, 2, 3, 5, and 10 days after administration. The DNA adduct patterns, analyzed by (32)P-postlabelling followed by HPLC separation, were similar in all tissues and organs. Five of the adduct peaks cochromatographed with synthesized DNA adduct standards. Three of these unequivocally determined standards, dGp-C8-N-ABA, dGp-N2-C2-ABA, and dAp-N6-C2-ABA, were of the nonacetylated type, suggesting that at least part of the pathway for activation of 3-NBA proceeds through O-acetylation of the hydroxylamine intermediate. The two other DNA adduct standards, dGp-C8-C2-N-Ac-ABA, and dGp-N2-C2-N-Ac-ABA, were of the acetylated type, but there was some ambiguity in the characterization of these DNA adducts, since they varied inconsistently between samples and they also aligned with peaks found in controls. At 6 hr after treatment, the level of DNA adducts was highest in glandular stomach (relative adduct labeling (RAL), approximately 70 adducts/10(8) normal nucleotides (NN)); adduct levels in this organ decreased at 24 hr, but increased afterwards. DNA adduct levels in the majority of organs were characterized by an early increase (from 6 hr to 3 days), which was followed by a decrease at 5 days and a maximum level 10 days after administration (RAL approximately 120 adducts/10(8) NN for the lung, kidney and glandular stomach, approximately 80 adducts/10(8) NN for the forestomach and ceacum, and approximately 40 adducts/10(8) NN for the liver, small intestine, and colon). This pattern was consistent with pathological observations during autopsy showing high levels of tissue damage in the GI tract; the tissue damage included hemorrhages, loss of villous surface structure in the small intestine, as well as intestine fragility and oedema of the adipose tissue around the GI-tract. Tissue damage decreased and DNA adduct levels increased at 10 days after administration. These observations suggest that 3-NBA not only exerts acute toxic effects, but that the bioavailability is affected by storage in tissues and later becomes available, resulting in the increased DNA adduct levels at the later time points of collection.
Citation:
Environ. Mol. Mutagen. 2006, 47 (7):541-552
Journal:
Environmental and Molecular Mutagenesis
Issue Date:
Aug-2006
URI:
http://hdl.handle.net/10146/25512
DOI:
10.1002/em.20227
PubMed ID:
16795088
Additional Links:
http://www3.interscience.wiley.com/journal/112659311/abstract
Type:
Article
Language:
en
ISSN:
0893-6692
Sponsors:
The authors of this paper would like to express their gratitude to Prof. Lennart C. Eriksson for his help in interpreting histopathological features and Mary-Ann Zetterqvist for her skilful technical assistance. The authors of this paper are partners of the EU Network of Excellence ECNIS (Environmental Cancer, Nutrition and Individual Susceptibility).
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Articles

Full metadata record

DC FieldValue Language
dc.contributor.authorNagy, Eszter-
dc.contributor.authorAdachi, Shuichi-
dc.contributor.authorTakamura-Enya, Takeji-
dc.contributor.authorZeisig, Magnus-
dc.contributor.authorMoller, Lennart-
dc.date.accessioned2008-05-12T10:49:10Z-
dc.date.available2008-05-12T10:49:10Z-
dc.date.issued2006-08-
dc.identifier.citationEnviron. Mol. Mutagen. 2006, 47 (7):541-552en
dc.identifier.issn0893-6692-
dc.identifier.pmid16795088-
dc.identifier.doi10.1002/em.20227-
dc.identifier.urihttp://hdl.handle.net/10146/25512-
dc.description.abstract3-Nitrobenzanthrone (3-NBA) is an urban air pollutant and rat lung carcinogen that is among the most potent mutagens yet tested in the Salmonella reversion assay. In the present study, 1 mg 3-NBA was administered orally to female F344 rats and DNA adduct formation was examined in liver, lung, kidney and five sections of the gastrointestinal (GI) tract at 6 hr, and 1, 2, 3, 5, and 10 days after administration. The DNA adduct patterns, analyzed by (32)P-postlabelling followed by HPLC separation, were similar in all tissues and organs. Five of the adduct peaks cochromatographed with synthesized DNA adduct standards. Three of these unequivocally determined standards, dGp-C8-N-ABA, dGp-N2-C2-ABA, and dAp-N6-C2-ABA, were of the nonacetylated type, suggesting that at least part of the pathway for activation of 3-NBA proceeds through O-acetylation of the hydroxylamine intermediate. The two other DNA adduct standards, dGp-C8-C2-N-Ac-ABA, and dGp-N2-C2-N-Ac-ABA, were of the acetylated type, but there was some ambiguity in the characterization of these DNA adducts, since they varied inconsistently between samples and they also aligned with peaks found in controls. At 6 hr after treatment, the level of DNA adducts was highest in glandular stomach (relative adduct labeling (RAL), approximately 70 adducts/10(8) normal nucleotides (NN)); adduct levels in this organ decreased at 24 hr, but increased afterwards. DNA adduct levels in the majority of organs were characterized by an early increase (from 6 hr to 3 days), which was followed by a decrease at 5 days and a maximum level 10 days after administration (RAL approximately 120 adducts/10(8) NN for the lung, kidney and glandular stomach, approximately 80 adducts/10(8) NN for the forestomach and ceacum, and approximately 40 adducts/10(8) NN for the liver, small intestine, and colon). This pattern was consistent with pathological observations during autopsy showing high levels of tissue damage in the GI tract; the tissue damage included hemorrhages, loss of villous surface structure in the small intestine, as well as intestine fragility and oedema of the adipose tissue around the GI-tract. Tissue damage decreased and DNA adduct levels increased at 10 days after administration. These observations suggest that 3-NBA not only exerts acute toxic effects, but that the bioavailability is affected by storage in tissues and later becomes available, resulting in the increased DNA adduct levels at the later time points of collection.en
dc.description.sponsorshipThe authors of this paper would like to express their gratitude to Prof. Lennart C. Eriksson for his help in interpreting histopathological features and Mary-Ann Zetterqvist for her skilful technical assistance. The authors of this paper are partners of the EU Network of Excellence ECNIS (Environmental Cancer, Nutrition and Individual Susceptibility).en
dc.language.isoenen
dc.relation.urlhttp://www3.interscience.wiley.com/journal/112659311/abstracten
dc.subject3-nitrobenzanthroneen
dc.subjectair pollutanten
dc.subjectoral administrationen
dc.subjectacute toxicityen
dc.subjectDNA adductsen
dc.subjectF344 ratsen
dc.subject.meshAcute Toxicity Tests-
dc.subject.meshAdministration, Oral-
dc.subject.meshAir Pollutants-
dc.subject.meshAnimals-
dc.subject.meshBenz(a)Anthracenes-
dc.subject.meshChromatography, High Pressure Liquid-
dc.subject.meshDNA Adducts-
dc.subject.meshDNA Damage-
dc.subject.meshFemale-
dc.subject.meshMolecular Structure-
dc.subject.meshOrgan Specificity-
dc.subject.meshRats-
dc.subject.meshRats, Inbred F344-
dc.subject.meshTime Factors-
dc.titleDNA 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.en
dc.typeArticleen
dc.identifier.journalEnvironmental and Molecular Mutagenesisen

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