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Author Ozden, Sibel ♦ Turgut Kara, Neslihan ♦ Sezerman, Osman Ugur ♦ Durasi, İlknur Melis ♦ Chen, Tao ♦ Demirel, Goksun ♦ Alpertunga, Buket ♦ Chipman, J. Kevin ♦ Mally, Angela
Source United States Department of Energy Office of Scientific and Technical Information
Content type Text
Language English
Subject Keyword 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
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. 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.
ISSN 0041008X
Educational Use Research
Learning Resource Type Article
Publisher Date 2015-12-01
Publisher Place United States
Journal Toxicology and Applied Pharmacology
Volume Number 289
Issue Number 2


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