DNA damage and estrogenic activity induced by the environmental pollutant 2-nitrotoluene and its metabolite

Watanabe, Chiemi; Egami, Takashi; Midorikawa, Katsumi; Hiraku, Yusuke; Oikawa, Shinji; Kawanishi, Shosuke; Murata, Mariko

doi:10.1007/s12199-010-0146-1

Cited by 15 publications

(6 citation statements)

References 25 publications

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“…Estrogen antagonist can induce conformational modifications of the ER that do not preclude its binding to the estrogen response element but fail to promote the sequence events needed for gene transcription [30].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Estrogenic Potential of Flavonoids Using a Recombinant Yeast Strain and MCF7/BUS Cell Proliferation Assay

et al. 2013

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Phytoestrogens are of interest because of their reported beneficial effects on many human maladies including cancer, neurodegeneration, cardiovascular disease and diabetes. Furthermore, there is a search for compounds with estrogenic activity that can replace estrogen in hormone replacement therapy during menopause, without the undesirable effects of estrogen, such as the elevation of breast cancer occurrence. Thus, the principal objective of this study was to assess the estrogenic activity of flavonoids with different hydroxylation patterns: quercetin, kaempferol, luteolin, fisetin, chrysin, galangin, flavone, 3-hydroxyflavone, 5-hydroxyflavone and 7-hydroxyflavone via two different in vitro assays, the recombinant yeast assay (RYA) and the MCF-7 proliferation assay (E-screen), since the most potent phytoestrogens are members of the flavonoid family. In these assays, kaempferol was the only compound that showed ERα-dependent transcriptional activation activity by RYA, showing 6.74±1.7 nM EEQ, besides acting as a full agonist for the stimulation of proliferation of MCF-7/BUS cells. The other compounds did not show detectable levels of interaction with ER under the conditions used in the RYA. However, in the E-screen assay, compounds such as galangin, luteolin and fisetin also stimulated the proliferation of MCF-7/BUS cells, acting as partial agonists. In the evaluation of antiestrogenicity, the compounds quercetin, chrysin and 3-hydroxyflavone significantly inhibited the cell proliferation induced by 17-β-estradiol in the E-screen assay, indicating that these compounds may act as estrogen receptor antagonists. Overall, it became clear in the assay results that the estrogenic activity of flavonoids was affected by small structural differences such as the number of hydroxyl groups, especially those on the B ring of the flavonoid.

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Section: Discussionmentioning

confidence: 99%

Evaluation of Estrogenic Potential of Flavonoids Using a Recombinant Yeast Strain and MCF7/BUS Cell Proliferation Assay

et al. 2013

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“…Mechanistic studies suggest that o -nitrotoluene carcinogenicity may also involve oxidative mechanisms (Watanabe et al . , 2010). …”

Section: Application Of the Mode Of Action Frameworkmentioning

confidence: 99%

Assessment of the mode of action underlying development of rodent small intestinal tumors following oral exposure to hexavalent chromium and relevance to humans

Thompson

Proctor

Suh

et al. 2013

Critical Reviews in Toxicology

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Chronic exposure to high concentrations of hexavalent chromium (Cr(VI)) in drinking water causes intestinal adenomas and carcinomas in mice, but not in rats. Cr(VI) causes damage to intestinal villi and crypt hyperplasia in mice after only one week of exposure. After two years of exposure, intestinal damage and crypt hyperplasia are evident in mice (but not rats), as are intestinal tumors. Although Cr(VI) has genotoxic properties, these findings suggest that intestinal tumors in mice arise as a result of chronic mucosal injury. To better understand the mode of action (MOA) of Cr(VI) in the intestine, a 90-day drinking water study was conducted to collect histological, biochemical, toxicogenomic and pharmacokinetic data in intestinal tissues. Using MOA analyses and human relevance frameworks proposed by national and international regulatory agencies, the weight of evidence supports a cytotoxic MOA with the following key events: (a) absorption of Cr(VI) from the intestinal lumen, (b) toxicity to intestinal villi, (c) crypt regenerative hyperplasia and (d) clonal expansion of mutations within the crypt stem cells, resulting in late onset tumorigenesis. This article summarizes the data supporting each key event in the MOA, as well as data that argue against a mutagenic MOA for Cr(VI)-induced intestinal tumors.

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“…captan and o-nitrotoluene (NTP, 2008). The latter caused tumors of the large intestine (NTP, 2002), and mechanistic studies suggest that o-nitrotoluene (2-nitrotoluene) carcinogenicity may involve oxidative DNA damage (Watanabe et al, 2010). Captan and the structurally similar folpet induce similar histopathological changes in the mouse duodenum as Cr(VI), are reactive toward thiols, and have been determined to have a nonmutagenic MOA (Cohen et al, 2010;US EPA, 2004).…”

Section: Discussionmentioning

confidence: 99%

Assessment of genotoxic potential of Cr(VI) in the mouse duodenum: An in silico comparison with mutagenic and nonmutagenic carcinogens across tissues

Thompson

Hixon

Proctor

et al. 2012

Regulatory Toxicology and Pharmacology

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In vitro studies on hexavalent chromium [Cr(VI)] indicate that reduced forms of this metal can interact with DNA and cause mutations. Recently, Cr(VI) was shown to induce intestinal tumors in mice; however, Cr(VI) elicited redox changes, cytotoxicity and hyperplasia - suggesting involvement of tissue injury rather than direct mutagenesis. Moreover, toxicogenomic analyses indicated limited evidence for DNA damage responses. Herein, we extend these toxicogenomic analyses by comparing the gene expression patterns elicited by Cr(VI) with those of four mutagenic and four nonmutagenic carcinogens. To date, toxicogenomic profiles for mutagenic and nonmutagenic duodenal carcinogens do not exist, thus duodenal gene changes in mice were compared to those elicited by hepatocarcinogens. Specifically, duodenal gene changes in mice following exposure to Cr(VI) in drinking water were compared to hepatic gene changes previously identified as potentially discriminating mutagenic and nonmutagenic hepatocarcinogens. Using multivariate statistical analyses (including logistic regression classification), the Cr(VI) gene responses clustered apart from mutagenic carcinogens and closely with nonmutagenic carcinogens. These findings are consistent with other intestinal data supporting a nonmutagenic mode of action (MOA). These findings may be useful as part of a full weight of evidence MOA evaluation for Cr(VI)-induced intestinal carcinogenesis. Limitations to this analysis will also be discussed.

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DNA damage and estrogenic activity induced by the environmental pollutant 2-nitrotoluene and its metabolite

Cited by 15 publications

References 25 publications

Evaluation of Estrogenic Potential of Flavonoids Using a Recombinant Yeast Strain and MCF7/BUS Cell Proliferation Assay

Evaluation of Estrogenic Potential of Flavonoids Using a Recombinant Yeast Strain and MCF7/BUS Cell Proliferation Assay

Assessment of the mode of action underlying development of rodent small intestinal tumors following oral exposure to hexavalent chromium and relevance to humans

Assessment of genotoxic potential of Cr(VI) in the mouse duodenum: An in silico comparison with mutagenic and nonmutagenic carcinogens across tissues

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