Oxidative stress and genotoxicity in 1,4-dioxane liver toxicity as evidenced in a mouse model of glutathione deficiency.
Oxidative stress and genotoxicity in 1,4-dioxane liver toxicity as evidenced in a mouse model of glutathione deficiency.
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DOI：
10.1016/j.scitotenv.2021.150703
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发表时间：
2022-02-01
期刊：
影响因子：
--
通讯作者：
Vasiliou V
中科院分区：
文献类型：
--
作者：
Chen Y;Wang Y;Charkoftaki G;Orlicky DJ;Davidson E;Wan F;Ginsberg G;Thompson DC;Vasiliou V
1，4-二恶烷(DX)是一种合成化学品，用作工业溶剂的稳定剂。最近的发生数据显示，在美国，饮用水受到DX的广泛和严重污染。DX被国际癌症研究机构归类为2B类致癌物质，在动物研究中，主要的靶器官是肝脏。尽管存在暴露和癌症风险，但美国环保局尚未建立DX的饮用水最高污染物水平(MCL)，美国各地和加拿大卫生部已经制定了广泛的饮用水目标。DX的致癌机制尚不清楚；这种信息差距导致了对其进行调控的不同方法。我们最近的小鼠研究表明，高剂量DX(5000ppm)在饮用水中的早期改变是伴随DNA损伤的氧化应激反应的改变。在此，我们报道了一项后续研究，我们使用谷胱甘肽(GSH)缺乏的谷氨酸-半胱氨酸连接酶修饰亚单位(GCLM)缺失的小鼠来研究氧化还原稳态在DX诱导的肝脏细胞毒性和遗传毒性中的作用。GCLM缺失型和野生型小鼠分别给予DX 1周(1,000 mg/kg/d经口灌胃)或3个月(5000ppm饮用水)染毒。亚慢性暴露大剂量DX可引起轻度肝细胞毒性。DX在肝脏中诱导了各种分子变化，包括：(1)早期(一周)的代偿性核因子红系2相关因子(NRF2)抗氧化反应，(2)渐进性的CYP2E1诱导，(3)氧化应激的发展，表现为持续的NRF2诱导，GSH池的氧化，以及脂质过氧化副产物4-羟基壬烯醛的积累，以及(4)氧化DNA损伤和DNA修复反应的升高。这些由DX引起的变化在GSH缺乏的小鼠中被夸大了。总之，目前的研究提供了更多的证据，将氧化还原失调与DX肝的遗传毒性联系起来，暗示氧化应激是DX肝致癌的一个候选机制。
1,4-Dioxane (DX) is a synthetic chemical used as a stabilizer for industrial solvents. Recent occurrence data show widespread and significant contamination of drinking water with DX in the US. DX is classified by the International Agency for Research on Cancer as a group 2B carcinogen with the primary target organ being the liver in animal studies. Despite the exposure and cancer risk, US EPA has not established a drinking water Maximum Contaminant Level (MCL) for DX and a wide range of drinking water targets have been established across the US and by Health Canada. The DX carcinogenic mechanism remains unknown; this information gap contributes to the varied approaches to its regulation. Our recent mice study indicated alterations in oxidative stress response accompanying DNA damage as an early change by high dose DX (5,000 ppm) in drinking water. Herein, we report a follow-up study, in which we used glutathione (GSH)-deficient glutamate-cysteine ligase modifier subunit (Gclm)-null mice to investigate the role of redox homeostasis in DX-induced liver cytotoxicity and genotoxicity. Gclm-null and wild-type mice were exposed to DX for one week (1,000 mg/kg/day by oral gavage) or three months (5,000 ppm in drinking water). Subchronic exposure of high dose DX caused mild liver cytotoxicity. DX induced assorted molecular changes in the liver including: (i) a compensatory nuclear factor erythroid 2-related factor 2 (NRF2) anti-oxidative response at the early stage (one week), (ii) progressive CYP2E1 induction, (iii) development of oxidative stress, as evidenced by persistent NRF2 induction, oxidation of GSH pool, and accumulation of the lipid peroxidation by-product 4-hydroxynonenal, and (iv) elevations in oxidative DNA damage and DNA repair response. These DX-elicited changes were exaggerated in GSH-deficient mice. Collectively, the current study provides additional evidence linking redox dysregulation to DX liver genotoxicity, implying oxidative stress as a candidate mechanism of DX liver carcinogenicity.
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