Comparative tumorigenicity of the environmental pollutant 6-nitrochrysene and its metabolites in the rat mammary gland

Karam El-Bayoumy, Dhimant Desai, Telih Boyiri, Jose Rosa, Jacek Krzeminski, Arun Sharma, Brian Pittman, Shantu Amin

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Abstract

Human exposure to the class of nitropolynuclear aromatic hydrocarbons is via inhalation and/or ingestion. Therefore, one of the goals of this study was to determine the propensity of the environmental contaminant 6-nitrochrysene (6-NC) for inducing mammary cancer following its oral administration to female CD rats. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), an established mammary carcinogen in the same animal model, was used as a positive control and trioctanoin as a negative control. Thirty-day-old female CD rats were gavaged once weekly for 8 weeks with 6-NC at 50, 25, or 12.5 μmol/rat or PhIP at 50 μmol/rat in 500 μL of trioctanoin. Twenty-three weeks after the last carcinogen administration, rats were decapitated, necropsied, and evaluated histologically. The most common mammary tumors were adenocarcinomas, followed by adenomas and fibroadenomas. The incidence and multiplicity (mean ± standard deviation) of mammary adenocarcinomas induced by these two carcinogens at the highest dose (6-NC: 90%, 3.73 ± 2.74; PhIP: 83%, 2.62 ± 2.58) were significantly higher than those in control rats (10%, 0.10 ± 0.31). However, there were no statistically significant differences between groups treated with 6-NC and PhIP or among groups receiving various doses of 6-NC. Following its metabolic activation, 6-NC is known to bind covalently to DNA; however, it remains to be determined whether it can also induce DNA base oxidation. Thus, employing the same route of administration, our studies revealed no effect of 6-NC on the basal level of 8-hydroxy-2′-deoxyguanosine (8-OHdG) in the mammary gland in tests at 6, 24, and 48 h after 6-NC treatment and at termination of the carcinogenesis assay in the normal, noninvolved tissue and in mammary tumors. This result suggests that covalent DNA binding of 6-NC metabolites is important in the induction of mammary cancer in rats. Therefore, the other goal of this study was to compare the tumorigenic activities of 6-NC and its metabolites in the rat mammary gland by intramammary administration. This route has also been used in our laboratory to induce mammary cancer in the rat by 6-NC and is employed here to avoid systemic effects and to determine the role of the mammary gland in the metabolic activation of 6-NC and its metabolites. Toward this end, a new method was developed to obtain ample materials of trans-1,2-dihydroxy-1,2-dihydro-6-aminochrysene (1,2- DHD-6-AC); other metabolites were synthesized as reported previously. On the basis of the results, the carcinogenic potency toward the mammary gland is ranked in the following order: 6-NC > 1,2-DHD-6-NC > 6-AC > 6-NCDE > 1,2-DHD-6-AC. Among the metabolites tested, 1,2-DHD-6-NC was the most potent carcinogen. It was significantly more active than its: reduced product 1,2-DHD-6-AC. However, the potency of 1,2-DHD-6-NC was not significantly different from 6-AC, a metabolite derived from simple nitroreduction, or from 6-NCDE. Collectively, these results suggest that metabolites derived from both ring-oxidation and nitroreduction contribute to the overall carcinogenicity of 6-NC in the rat mammary gland.

Original languageEnglish (US)
Pages (from-to)972-978
Number of pages7
JournalChemical research in toxicology
Volume15
Issue number7
DOIs
StatePublished - Jul 25 2002

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Environmental Pollutants
Human Mammary Glands
Metabolites
Rats
Carcinogens
Breast Neoplasms
6-nitrochrysene
Tumors
DNA
Adenocarcinoma
Breast
Chemical activation
Rat control
Fibroadenoma
Aromatic Hydrocarbons
Oxidation

All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

@article{6110c7b0e5b4496f82fc3e4c905e8716,
title = "Comparative tumorigenicity of the environmental pollutant 6-nitrochrysene and its metabolites in the rat mammary gland",
abstract = "Human exposure to the class of nitropolynuclear aromatic hydrocarbons is via inhalation and/or ingestion. Therefore, one of the goals of this study was to determine the propensity of the environmental contaminant 6-nitrochrysene (6-NC) for inducing mammary cancer following its oral administration to female CD rats. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), an established mammary carcinogen in the same animal model, was used as a positive control and trioctanoin as a negative control. Thirty-day-old female CD rats were gavaged once weekly for 8 weeks with 6-NC at 50, 25, or 12.5 μmol/rat or PhIP at 50 μmol/rat in 500 μL of trioctanoin. Twenty-three weeks after the last carcinogen administration, rats were decapitated, necropsied, and evaluated histologically. The most common mammary tumors were adenocarcinomas, followed by adenomas and fibroadenomas. The incidence and multiplicity (mean ± standard deviation) of mammary adenocarcinomas induced by these two carcinogens at the highest dose (6-NC: 90{\%}, 3.73 ± 2.74; PhIP: 83{\%}, 2.62 ± 2.58) were significantly higher than those in control rats (10{\%}, 0.10 ± 0.31). However, there were no statistically significant differences between groups treated with 6-NC and PhIP or among groups receiving various doses of 6-NC. Following its metabolic activation, 6-NC is known to bind covalently to DNA; however, it remains to be determined whether it can also induce DNA base oxidation. Thus, employing the same route of administration, our studies revealed no effect of 6-NC on the basal level of 8-hydroxy-2′-deoxyguanosine (8-OHdG) in the mammary gland in tests at 6, 24, and 48 h after 6-NC treatment and at termination of the carcinogenesis assay in the normal, noninvolved tissue and in mammary tumors. This result suggests that covalent DNA binding of 6-NC metabolites is important in the induction of mammary cancer in rats. Therefore, the other goal of this study was to compare the tumorigenic activities of 6-NC and its metabolites in the rat mammary gland by intramammary administration. This route has also been used in our laboratory to induce mammary cancer in the rat by 6-NC and is employed here to avoid systemic effects and to determine the role of the mammary gland in the metabolic activation of 6-NC and its metabolites. Toward this end, a new method was developed to obtain ample materials of trans-1,2-dihydroxy-1,2-dihydro-6-aminochrysene (1,2- DHD-6-AC); other metabolites were synthesized as reported previously. On the basis of the results, the carcinogenic potency toward the mammary gland is ranked in the following order: 6-NC > 1,2-DHD-6-NC > 6-AC > 6-NCDE > 1,2-DHD-6-AC. Among the metabolites tested, 1,2-DHD-6-NC was the most potent carcinogen. It was significantly more active than its: reduced product 1,2-DHD-6-AC. However, the potency of 1,2-DHD-6-NC was not significantly different from 6-AC, a metabolite derived from simple nitroreduction, or from 6-NCDE. Collectively, these results suggest that metabolites derived from both ring-oxidation and nitroreduction contribute to the overall carcinogenicity of 6-NC in the rat mammary gland.",
author = "Karam El-Bayoumy and Dhimant Desai and Telih Boyiri and Jose Rosa and Jacek Krzeminski and Arun Sharma and Brian Pittman and Shantu Amin",
year = "2002",
month = "7",
day = "25",
doi = "10.1021/tx020019a",
language = "English (US)",
volume = "15",
pages = "972--978",
journal = "Chemical Research in Toxicology",
issn = "0893-228X",
publisher = "American Chemical Society",
number = "7",

}

TY - JOUR

T1 - Comparative tumorigenicity of the environmental pollutant 6-nitrochrysene and its metabolites in the rat mammary gland

AU - El-Bayoumy, Karam

AU - Desai, Dhimant

AU - Boyiri, Telih

AU - Rosa, Jose

AU - Krzeminski, Jacek

AU - Sharma, Arun

AU - Pittman, Brian

AU - Amin, Shantu

PY - 2002/7/25

Y1 - 2002/7/25

N2 - Human exposure to the class of nitropolynuclear aromatic hydrocarbons is via inhalation and/or ingestion. Therefore, one of the goals of this study was to determine the propensity of the environmental contaminant 6-nitrochrysene (6-NC) for inducing mammary cancer following its oral administration to female CD rats. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), an established mammary carcinogen in the same animal model, was used as a positive control and trioctanoin as a negative control. Thirty-day-old female CD rats were gavaged once weekly for 8 weeks with 6-NC at 50, 25, or 12.5 μmol/rat or PhIP at 50 μmol/rat in 500 μL of trioctanoin. Twenty-three weeks after the last carcinogen administration, rats were decapitated, necropsied, and evaluated histologically. The most common mammary tumors were adenocarcinomas, followed by adenomas and fibroadenomas. The incidence and multiplicity (mean ± standard deviation) of mammary adenocarcinomas induced by these two carcinogens at the highest dose (6-NC: 90%, 3.73 ± 2.74; PhIP: 83%, 2.62 ± 2.58) were significantly higher than those in control rats (10%, 0.10 ± 0.31). However, there were no statistically significant differences between groups treated with 6-NC and PhIP or among groups receiving various doses of 6-NC. Following its metabolic activation, 6-NC is known to bind covalently to DNA; however, it remains to be determined whether it can also induce DNA base oxidation. Thus, employing the same route of administration, our studies revealed no effect of 6-NC on the basal level of 8-hydroxy-2′-deoxyguanosine (8-OHdG) in the mammary gland in tests at 6, 24, and 48 h after 6-NC treatment and at termination of the carcinogenesis assay in the normal, noninvolved tissue and in mammary tumors. This result suggests that covalent DNA binding of 6-NC metabolites is important in the induction of mammary cancer in rats. Therefore, the other goal of this study was to compare the tumorigenic activities of 6-NC and its metabolites in the rat mammary gland by intramammary administration. This route has also been used in our laboratory to induce mammary cancer in the rat by 6-NC and is employed here to avoid systemic effects and to determine the role of the mammary gland in the metabolic activation of 6-NC and its metabolites. Toward this end, a new method was developed to obtain ample materials of trans-1,2-dihydroxy-1,2-dihydro-6-aminochrysene (1,2- DHD-6-AC); other metabolites were synthesized as reported previously. On the basis of the results, the carcinogenic potency toward the mammary gland is ranked in the following order: 6-NC > 1,2-DHD-6-NC > 6-AC > 6-NCDE > 1,2-DHD-6-AC. Among the metabolites tested, 1,2-DHD-6-NC was the most potent carcinogen. It was significantly more active than its: reduced product 1,2-DHD-6-AC. However, the potency of 1,2-DHD-6-NC was not significantly different from 6-AC, a metabolite derived from simple nitroreduction, or from 6-NCDE. Collectively, these results suggest that metabolites derived from both ring-oxidation and nitroreduction contribute to the overall carcinogenicity of 6-NC in the rat mammary gland.

AB - Human exposure to the class of nitropolynuclear aromatic hydrocarbons is via inhalation and/or ingestion. Therefore, one of the goals of this study was to determine the propensity of the environmental contaminant 6-nitrochrysene (6-NC) for inducing mammary cancer following its oral administration to female CD rats. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), an established mammary carcinogen in the same animal model, was used as a positive control and trioctanoin as a negative control. Thirty-day-old female CD rats were gavaged once weekly for 8 weeks with 6-NC at 50, 25, or 12.5 μmol/rat or PhIP at 50 μmol/rat in 500 μL of trioctanoin. Twenty-three weeks after the last carcinogen administration, rats were decapitated, necropsied, and evaluated histologically. The most common mammary tumors were adenocarcinomas, followed by adenomas and fibroadenomas. The incidence and multiplicity (mean ± standard deviation) of mammary adenocarcinomas induced by these two carcinogens at the highest dose (6-NC: 90%, 3.73 ± 2.74; PhIP: 83%, 2.62 ± 2.58) were significantly higher than those in control rats (10%, 0.10 ± 0.31). However, there were no statistically significant differences between groups treated with 6-NC and PhIP or among groups receiving various doses of 6-NC. Following its metabolic activation, 6-NC is known to bind covalently to DNA; however, it remains to be determined whether it can also induce DNA base oxidation. Thus, employing the same route of administration, our studies revealed no effect of 6-NC on the basal level of 8-hydroxy-2′-deoxyguanosine (8-OHdG) in the mammary gland in tests at 6, 24, and 48 h after 6-NC treatment and at termination of the carcinogenesis assay in the normal, noninvolved tissue and in mammary tumors. This result suggests that covalent DNA binding of 6-NC metabolites is important in the induction of mammary cancer in rats. Therefore, the other goal of this study was to compare the tumorigenic activities of 6-NC and its metabolites in the rat mammary gland by intramammary administration. This route has also been used in our laboratory to induce mammary cancer in the rat by 6-NC and is employed here to avoid systemic effects and to determine the role of the mammary gland in the metabolic activation of 6-NC and its metabolites. Toward this end, a new method was developed to obtain ample materials of trans-1,2-dihydroxy-1,2-dihydro-6-aminochrysene (1,2- DHD-6-AC); other metabolites were synthesized as reported previously. On the basis of the results, the carcinogenic potency toward the mammary gland is ranked in the following order: 6-NC > 1,2-DHD-6-NC > 6-AC > 6-NCDE > 1,2-DHD-6-AC. Among the metabolites tested, 1,2-DHD-6-NC was the most potent carcinogen. It was significantly more active than its: reduced product 1,2-DHD-6-AC. However, the potency of 1,2-DHD-6-NC was not significantly different from 6-AC, a metabolite derived from simple nitroreduction, or from 6-NCDE. Collectively, these results suggest that metabolites derived from both ring-oxidation and nitroreduction contribute to the overall carcinogenicity of 6-NC in the rat mammary gland.

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