In vivo positive mutagenicity of 1,4-dioxane and quantitative analysis of its mutagenicity and carcinogenicity in rats
In vivo positive mutagenicity of 1,4-dioxane and quantitative analysis of its mutagenicity and carcinogenicity in rats
复制标题
DOI：
10.1007/s00204-018-2282-0
复制
发表时间：
2018-10-01
影响因子：
6.1
通讯作者：
Fukushima, Shoji
中科院分区：
文献类型：
--
作者：
Gi, Min;Fujioka, Masaki;Fukushima, Shoji
1,4-二恶烷是一种广泛使用的合成工业化学品，其对饮用水和食品的污染是一个潜在的健康问题。当将其加入到大鼠和小鼠的饮用水中时，会诱发肝脏肿瘤。然而，1,4-二氧杂环己烷致癌性的作用方式（MOA）仍不清楚。重要的是，目前尚不清楚 1,4-二恶烷是否具有遗传毒性，这是风险评估的一个关键考虑因素。为了确定 1,4-二恶烷的体内致突变性，gpt delta 转基因 F344 大鼠在饮用水中加入不同剂量的 1,4-二恶烷 16 周。通过施用 5000 ppm 1,4-二恶烷，gpt 转基因中的总体突变频率 (MF) 和 A:T-to G:C 转变以及 A:T-to T:A 颠换显着增加。通过施用 1000 ppm 1,4-二恶烷，A:T-至 T:A 的颠换也显着增加。此外，DNA修复酶MGMT在5000 ppm 1,4-二恶烷下被显着诱导，这意味着广泛的遗传损伤超出了肝脏细胞的修复能力，从而导致肝癌发生。没有发现任何证据支持其他 MOA，包括诱导氧化应激、细胞毒性或核受体激活，可能导致 1,4-二恶烷的致癌作用。这些研究结果表明，1,4-二恶烷是一种遗传毒性肝癌物质，并通过致突变 MOA 诱导大鼠肝癌发生。由于我们的数据表明1,4-二恶烷是一种遗传毒性致癌物，因此我们使用未观察到的效应水平方法和基准剂量方法来估计1,4-二恶烷的致突变性和致癌性的出发点，以表征其在低剂量下的剂量-反应关系。
1,4-Dioxane is a widely used synthetic industrial chemical and its contamination of drinking water and food is a potential health concern. It induces liver tumors when administered in the drinking water to rats and mice. However, the mode of action (MOA) of the hepatocarcinogenicity of 1,4-dioxane remains unclear. Importantly, it is unknown if 1,4-dioxane is genotoxic, a key consideration for risk assessment. To determine the in vivo mutagenicity of 1,4-dioxane, gpt delta transgenic F344 rats were administered 1,4-dioxane at various doses in the drinking water for 16 weeks. The overall mutation frequency (MF) and A:T-to G:C transitions and A:T-to T:A transversions in the gpt transgene were significantly increased by administration of 5000 ppm 1,4-dioxane. A:T-to T:A transversions were also significantly increased by administration of 1000 ppm 1,4-dioxane. Furthermore, the DNA repair enzyme MGMT was significantly induced at 5000 ppm 1,4-dioxane, implying that extensive genetic damage exceeded the repair capacity of the cells in the liver and consequently led to liver carcinogenesis. No evidence supporting other MOAs, including induction of oxidative stress, cytotoxicity, or nuclear receptor activation, that could contribute to the carcinogenic effects of 1,4-dioxane were found. These findings demonstrate that 1,4-dioxane is a genotoxic hepatocarcinogen and induces hepatocarcinogenesis through a mutagenic MOA in rats. Because our data indicate that 1,4-dioxane is a genotoxic carcinogen, we estimated the point of departure of the mutagenicity and carcinogenicity of 1,4-dioxane using the no-observed effect-level approach and the Benchmark dose approach to characterize its dose-response relationship at low doses.