Mammary carcinogenesis and molecular analysis of in vivo cII gene mutations in the mammary tissue of female transgenic rats treated with the environmental pollutant 6-nitrochrysene

Telih Boyiri, Joseph Guttenplan, Michael Khmelnitsky, Wieslawa Kosinska, Jyh Ming Lin, Dhimant Desai, Shantu Amin, Brian Pittman, Karam El-Bayoumy

Research output: Contribution to journalArticle

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Abstract

We determined the mutant fractions (MF) and mutational specificities in the cII gene in histologically confirmed normal, non-involved and tumor mammary tissues of female transgenic (Big Blue F344 × Sprague-Dawley)F1 rats treated with the environmental pollutant 6-nitrochrysene (6-NC). At 30 days of age, three groups were set up for oral treatment with 6-NC dissolved in trioctanoin, or trioctanoin alone once a week for 8 weeks. Two dose levels of 6-NC (100 and 200 μmol/rat) were selected on the basis of our previous carcinogenicity bioassays with CD rats. The rats were decapitated 32 weeks after the last carcinogen dose. Both incidence and multiplicity of mammary adenocarcinomas were significantly elevated in the high dose (36%, 0.57, P < 0.01) group but at the low dose these outcomes (16%, 0.23, P < 0.1) were not significantly different from those of control rats (3%, 0.03). The MF in normal, non-involved and tumor tissues from the mammary glands of 6-NC-treated rats were comparable. At the high and low doses, respectively (4.8 ± 2.0, 3.2 ± 2.1) the MF of 6-NC-treated rats, were significantly higher (P < 0.05) than that observed in control rats (1.2 ± 0.6). Control mutants consisted primarily of GC → AT transitions, whereas 6-NC-induced mutants were comprised of several major classes of mutations with GC → TA, GC → CG, AT → GC and AT → TA as the most prevalent. Further studies indicated that the structures of 6-NC-DNA adducts in the mammary tissue are consistent with the mutational specificities. This is the first report that defines the relationship between carcinogenesis and mutagenesis, as well as between structures of 6-NC-DNA adducts and mutation characteristics in the target organ in vivo.

Original languageEnglish (US)
Pages (from-to)637-643
Number of pages7
JournalCarcinogenesis
Volume25
Issue number4
DOIs
StatePublished - Apr 1 2004

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Transgenic Rats
Environmental Pollutants
Carcinogenesis
Breast
Mutation
Genes
DNA Adducts
6-nitrochrysene
Inbred F344 Rats
Human Mammary Glands
Mutagenesis
Biological Assay
Carcinogens
Sprague Dawley Rats
Neoplasms
Adenocarcinoma
Age Groups
Incidence

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

@article{86de943074e54ffb879dd7cdad04fe5d,
title = "Mammary carcinogenesis and molecular analysis of in vivo cII gene mutations in the mammary tissue of female transgenic rats treated with the environmental pollutant 6-nitrochrysene",
abstract = "We determined the mutant fractions (MF) and mutational specificities in the cII gene in histologically confirmed normal, non-involved and tumor mammary tissues of female transgenic (Big Blue F344 × Sprague-Dawley)F1 rats treated with the environmental pollutant 6-nitrochrysene (6-NC). At 30 days of age, three groups were set up for oral treatment with 6-NC dissolved in trioctanoin, or trioctanoin alone once a week for 8 weeks. Two dose levels of 6-NC (100 and 200 μmol/rat) were selected on the basis of our previous carcinogenicity bioassays with CD rats. The rats were decapitated 32 weeks after the last carcinogen dose. Both incidence and multiplicity of mammary adenocarcinomas were significantly elevated in the high dose (36{\%}, 0.57, P < 0.01) group but at the low dose these outcomes (16{\%}, 0.23, P < 0.1) were not significantly different from those of control rats (3{\%}, 0.03). The MF in normal, non-involved and tumor tissues from the mammary glands of 6-NC-treated rats were comparable. At the high and low doses, respectively (4.8 ± 2.0, 3.2 ± 2.1) the MF of 6-NC-treated rats, were significantly higher (P < 0.05) than that observed in control rats (1.2 ± 0.6). Control mutants consisted primarily of GC → AT transitions, whereas 6-NC-induced mutants were comprised of several major classes of mutations with GC → TA, GC → CG, AT → GC and AT → TA as the most prevalent. Further studies indicated that the structures of 6-NC-DNA adducts in the mammary tissue are consistent with the mutational specificities. This is the first report that defines the relationship between carcinogenesis and mutagenesis, as well as between structures of 6-NC-DNA adducts and mutation characteristics in the target organ in vivo.",
author = "Telih Boyiri and Joseph Guttenplan and Michael Khmelnitsky and Wieslawa Kosinska and Lin, {Jyh Ming} and Dhimant Desai and Shantu Amin and Brian Pittman and Karam El-Bayoumy",
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Mammary carcinogenesis and molecular analysis of in vivo cII gene mutations in the mammary tissue of female transgenic rats treated with the environmental pollutant 6-nitrochrysene. / Boyiri, Telih; Guttenplan, Joseph; Khmelnitsky, Michael; Kosinska, Wieslawa; Lin, Jyh Ming; Desai, Dhimant; Amin, Shantu; Pittman, Brian; El-Bayoumy, Karam.

In: Carcinogenesis, Vol. 25, No. 4, 01.04.2004, p. 637-643.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mammary carcinogenesis and molecular analysis of in vivo cII gene mutations in the mammary tissue of female transgenic rats treated with the environmental pollutant 6-nitrochrysene

AU - Boyiri, Telih

AU - Guttenplan, Joseph

AU - Khmelnitsky, Michael

AU - Kosinska, Wieslawa

AU - Lin, Jyh Ming

AU - Desai, Dhimant

AU - Amin, Shantu

AU - Pittman, Brian

AU - El-Bayoumy, Karam

PY - 2004/4/1

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N2 - We determined the mutant fractions (MF) and mutational specificities in the cII gene in histologically confirmed normal, non-involved and tumor mammary tissues of female transgenic (Big Blue F344 × Sprague-Dawley)F1 rats treated with the environmental pollutant 6-nitrochrysene (6-NC). At 30 days of age, three groups were set up for oral treatment with 6-NC dissolved in trioctanoin, or trioctanoin alone once a week for 8 weeks. Two dose levels of 6-NC (100 and 200 μmol/rat) were selected on the basis of our previous carcinogenicity bioassays with CD rats. The rats were decapitated 32 weeks after the last carcinogen dose. Both incidence and multiplicity of mammary adenocarcinomas were significantly elevated in the high dose (36%, 0.57, P < 0.01) group but at the low dose these outcomes (16%, 0.23, P < 0.1) were not significantly different from those of control rats (3%, 0.03). The MF in normal, non-involved and tumor tissues from the mammary glands of 6-NC-treated rats were comparable. At the high and low doses, respectively (4.8 ± 2.0, 3.2 ± 2.1) the MF of 6-NC-treated rats, were significantly higher (P < 0.05) than that observed in control rats (1.2 ± 0.6). Control mutants consisted primarily of GC → AT transitions, whereas 6-NC-induced mutants were comprised of several major classes of mutations with GC → TA, GC → CG, AT → GC and AT → TA as the most prevalent. Further studies indicated that the structures of 6-NC-DNA adducts in the mammary tissue are consistent with the mutational specificities. This is the first report that defines the relationship between carcinogenesis and mutagenesis, as well as between structures of 6-NC-DNA adducts and mutation characteristics in the target organ in vivo.

AB - We determined the mutant fractions (MF) and mutational specificities in the cII gene in histologically confirmed normal, non-involved and tumor mammary tissues of female transgenic (Big Blue F344 × Sprague-Dawley)F1 rats treated with the environmental pollutant 6-nitrochrysene (6-NC). At 30 days of age, three groups were set up for oral treatment with 6-NC dissolved in trioctanoin, or trioctanoin alone once a week for 8 weeks. Two dose levels of 6-NC (100 and 200 μmol/rat) were selected on the basis of our previous carcinogenicity bioassays with CD rats. The rats were decapitated 32 weeks after the last carcinogen dose. Both incidence and multiplicity of mammary adenocarcinomas were significantly elevated in the high dose (36%, 0.57, P < 0.01) group but at the low dose these outcomes (16%, 0.23, P < 0.1) were not significantly different from those of control rats (3%, 0.03). The MF in normal, non-involved and tumor tissues from the mammary glands of 6-NC-treated rats were comparable. At the high and low doses, respectively (4.8 ± 2.0, 3.2 ± 2.1) the MF of 6-NC-treated rats, were significantly higher (P < 0.05) than that observed in control rats (1.2 ± 0.6). Control mutants consisted primarily of GC → AT transitions, whereas 6-NC-induced mutants were comprised of several major classes of mutations with GC → TA, GC → CG, AT → GC and AT → TA as the most prevalent. Further studies indicated that the structures of 6-NC-DNA adducts in the mammary tissue are consistent with the mutational specificities. This is the first report that defines the relationship between carcinogenesis and mutagenesis, as well as between structures of 6-NC-DNA adducts and mutation characteristics in the target organ in vivo.

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