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.

中文翻译：

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用1,4-二恶烷治疗的大鼠肝脏中的DNA加合物的全面分析（DNA加合物分析）。

1,4-二恶烷是一种遗传毒性致癌物，最近在鸟嘌呤磷酸核糖基转移酶（gpt）δ转基因大鼠的肝脏中观察到了其诱变特性。但是，其遗传毒性的机制仍不清楚。我们分析了1,4-二恶烷处理后大鼠肝脏中DNA加合物的形成。在饮用水中以0、20、200和5,000 ppm的剂量施用1,4-二恶烷后，通过DNA内标法分析肝脏加合物的形成。与对照组相比，经治疗的大鼠肝脏中的加合物剂量依赖性增加。主成分分析-判别分析（PCA-DA）清楚地显示了两簇DNA加合物，分别与0 ppm和低剂量（20 ppm）1,4-二恶烷处理相对于中，高剂量（200，5,000 ppm） ）处理的大鼠。确认每种加合物的强度后，筛选出3种加合物作为1，4-二恶烷处理的特征。这三个候选物中的两个包含胸腺嘧啶或胞苷/尿嘧啶部分。根据质量碎裂以及高分辨率精确质量（HRAM）质谱数据，另一种候选物被鉴定为8-oxo-dG。氧化应激反应可能部分解释了1,4-二恶烷治疗后gpt三角洲大鼠肝脏中突变增加的机制。