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Title: Assessment of global and gene-specific DNA methylation in rat liver and kidney in response to non-genotoxic carcinogen exposure

Abstract

Altered expression of tumor suppressor genes and oncogenes, which is regulated in part at the level of DNA methylation, is an important event involved in non-genotoxic carcinogenesis. This may serve as a marker for early detection of non-genotoxic carcinogens. Therefore, we evaluated the effects of non-genotoxic hepatocarcinogens, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), hexachlorobenzene (HCB), methapyrilene (MPY) and male rat kidney carcinogens, d-limonene, p-dichlorobenzene (DCB), chloroform and ochratoxin A (OTA) on global and CpG island promoter methylation in their respective target tissues in rats. No significant dose-related effects on global DNA hypomethylation were observed in tissues of rats compared to vehicle controls using LC–MS/MS in response to short-term non-genotoxic carcinogen exposure. Initial experiments investigating gene-specific methylation using methylation-specific PCR and bisulfite sequencing, revealed partial methylation of p16 in the liver of rats treated with HCB and TCDD. However, no treatment related effects on the methylation status of Cx32, e-cadherin, VHL, c-myc, Igfbp2, and p15 were observed. We therefore applied genome-wide DNA methylation analysis using methylated DNA immunoprecipitation combined with microarrays to identify alterations in gene-specific methylation. Under the conditions of our study, some genes were differentially methylated in response to MPY and TCDD, whereas d-limonene, DCB and chloroform did not induce any methylation changes.more » 90-day OTA treatment revealed enrichment of several categories of genes important in protein kinase activity and mTOR cell signaling process which are related to OTA nephrocarcinogenicity. - Highlights: • Studied non-genotoxic carcinogens caused no change on global DNA hypomethylation. • d-Limonene, DCB and chloroform did not show any genome-wide methylation changes. • Some genes were differentially methylated in response to MPY, TCDD and OTA. • Protein kinase activity and mTOR cell signaling are involved in OTA carcinogenicity. • Our data highlight Cpne4 may be a potential biomarker for non-genotoxic carcinogens.« less

Authors:
 [1];  [2];  [3];  [4];  [5]; ;  [1];  [6];  [7]
  1. Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul (Turkey)
  2. Department of Molecular Biology and Genetics, Faculty of Science, Istanbul University, Istanbul (Turkey)
  3. Department of Biostatistics and Medical Informatics, Acibadem University, Istanbul (Turkey)
  4. Biological Sciences and Bioengineering, Faculty of Engineering and Natural Sciences, Sabancı University, Istanbul (Turkey)
  5. Department of Toxicology, School of Public Health, Soochow University, Suzhou (China)
  6. School of Biosciences, The University of Birmingham, Birmingham (United Kingdom)
  7. Department of Toxicology, University of Würzburg, Würzburg (Germany)
Publication Date:
OSTI Identifier:
22687826
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 289; Journal Issue: 2; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANIMAL TISSUES; BIOLOGICAL MARKERS; CARCINOGENS; CHLOROFORM; DIOXIN; DNA; GROWTH FACTORS; INSULIN; KIDNEYS; LIQUID COLUMN CHROMATOGRAPHY; LIVER; MASS SPECTROSCOPY; METHYLATION; NUCLEOTIDES; ONCOGENES; PHOSPHOTRANSFERASES; POLYMERASE CHAIN REACTION; RATS

Citation Formats

Ozden, Sibel, Turgut Kara, Neslihan, Sezerman, Osman Ugur, Durasi, İlknur Melis, Chen, Tao, Demirel, Goksun, Alpertunga, Buket, Chipman, J. Kevin, and Mally, Angela. Assessment of global and gene-specific DNA methylation in rat liver and kidney in response to non-genotoxic carcinogen exposure. United States: N. p., 2015. Web. doi:10.1016/J.TAAP.2015.09.023.
Ozden, Sibel, Turgut Kara, Neslihan, Sezerman, Osman Ugur, Durasi, İlknur Melis, Chen, Tao, Demirel, Goksun, Alpertunga, Buket, Chipman, J. Kevin, & Mally, Angela. Assessment of global and gene-specific DNA methylation in rat liver and kidney in response to non-genotoxic carcinogen exposure. United States. doi:10.1016/J.TAAP.2015.09.023.
Ozden, Sibel, Turgut Kara, Neslihan, Sezerman, Osman Ugur, Durasi, İlknur Melis, Chen, Tao, Demirel, Goksun, Alpertunga, Buket, Chipman, J. Kevin, and Mally, Angela. Tue . "Assessment of global and gene-specific DNA methylation in rat liver and kidney in response to non-genotoxic carcinogen exposure". United States. doi:10.1016/J.TAAP.2015.09.023.
@article{osti_22687826,
title = {Assessment of global and gene-specific DNA methylation in rat liver and kidney in response to non-genotoxic carcinogen exposure},
author = {Ozden, Sibel and Turgut Kara, Neslihan and Sezerman, Osman Ugur and Durasi, İlknur Melis and Chen, Tao and Demirel, Goksun and Alpertunga, Buket and Chipman, J. Kevin and Mally, Angela},
abstractNote = {Altered expression of tumor suppressor genes and oncogenes, which is regulated in part at the level of DNA methylation, is an important event involved in non-genotoxic carcinogenesis. This may serve as a marker for early detection of non-genotoxic carcinogens. Therefore, we evaluated the effects of non-genotoxic hepatocarcinogens, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), hexachlorobenzene (HCB), methapyrilene (MPY) and male rat kidney carcinogens, d-limonene, p-dichlorobenzene (DCB), chloroform and ochratoxin A (OTA) on global and CpG island promoter methylation in their respective target tissues in rats. No significant dose-related effects on global DNA hypomethylation were observed in tissues of rats compared to vehicle controls using LC–MS/MS in response to short-term non-genotoxic carcinogen exposure. Initial experiments investigating gene-specific methylation using methylation-specific PCR and bisulfite sequencing, revealed partial methylation of p16 in the liver of rats treated with HCB and TCDD. However, no treatment related effects on the methylation status of Cx32, e-cadherin, VHL, c-myc, Igfbp2, and p15 were observed. We therefore applied genome-wide DNA methylation analysis using methylated DNA immunoprecipitation combined with microarrays to identify alterations in gene-specific methylation. Under the conditions of our study, some genes were differentially methylated in response to MPY and TCDD, whereas d-limonene, DCB and chloroform did not induce any methylation changes. 90-day OTA treatment revealed enrichment of several categories of genes important in protein kinase activity and mTOR cell signaling process which are related to OTA nephrocarcinogenicity. - Highlights: • Studied non-genotoxic carcinogens caused no change on global DNA hypomethylation. • d-Limonene, DCB and chloroform did not show any genome-wide methylation changes. • Some genes were differentially methylated in response to MPY, TCDD and OTA. • Protein kinase activity and mTOR cell signaling are involved in OTA carcinogenicity. • Our data highlight Cpne4 may be a potential biomarker for non-genotoxic carcinogens.},
doi = {10.1016/J.TAAP.2015.09.023},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 2,
volume = 289,
place = {United States},
year = {2015},
month = {12}
}