Comprehensive analysis of DNA adducts (DNA adductome analysis) in the liver of rats treated with 1,4-dioxane

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  • TOTSUKA Yukari
    Division of Carcinogenesis & Cancer Prevention, National Cancer Center Research Institute
  • MAESAKO Yuya
    Division of Carcinogenesis & Cancer Prevention, National Cancer Center Research Institute Department of Life Sciences, Graduate School of Life Sciences, Toyo University
  • ONO Hanako
    Department of Bioinformatics, National Cancer Center Research Institute
  • NAGAI Momoko
    Department of Bioinformatics, National Cancer Center Research Institute
  • KATO Mamoru
    Department of Bioinformatics, National Cancer Center Research Institute
  • GI Min
    Department of Environmental Risk Assessment, Osaka City University, Graduate School of Medicine
  • WANIBUCHI Hideki
    Department of Environmental Risk Assessment, Osaka City University, Graduate School of Medicine
  • FUKUSHIMA Shoji
    Japan Bioassay Research Center, Japan Organization of Occupational Health and Safety Association for Promotion of Research on Risk Assessment
  • SHIIZAKI Kazuhiro
    Department of Life Sciences, Graduate School of Life Sciences, Toyo University
  • NAKAGAMA Hitoshi
    National Cancer Center

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Abstract

<p>1,4-Dioxane is a genotoxic carcinogen, and its mutagenic properties were recently observed in the liver of guanine phosphoribosyl transferase (gpt) delta transgenic rats. However, the mechanisms of its genotoxicity remain unclear. We analyzed DNA adduct formation in rat livers following 1,4-dioxane treatment. After administering 1,4-dioxane in drinking water at doses of 0, 20, 200, and 5,000 ppm, liver adduct formation was analyzed by DNA adductome analysis. Adducts in treated rat livers were dose-dependently increased compared with those in the control group. Principal component analysis-discriminant analysis (PCA-DA) clearly revealed two clusters of DNA adducts, associated with 0 ppm and low-dose (20 ppm) 1,4-dioxane-treatment versus middle- and high-dose (200, 5,000 ppm)-treated rats. After confirming the intensity of each adduct, three adducts were screened as characteristic of 1,4-dioxane treatment. Two of the three candidates contained thymine or cytidine/uracil moieties. Another candidate was identified as 8-oxo-dG based on mass fragmentation together with high-resolution accurate-mass (HRAM) mass spectrometry data. Oxidative stress responses may partly explain the mechanisms of increased mutations in the liver of gpt delta rats following 1,4-dioxane treatment.</p>

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