2,3,7,8-Tetrachlorodibenzo-p-dioxin-Mediated Production of Reactive Oxygen Species Is An Essential Step in the Mechanism of Action to Accelerate Human Keratinocyte Differentiation
2,3,7,8-Tetrachlorodibenzo-p-dioxin-Mediated Production of Reactive Oxygen Species Is An Essential Step in the Mechanism of Action to Accelerate Human Keratinocyte Differentiation
复制标题
DOI：
10.1093/toxsci/kfs325
复制
发表时间：
2013-03-01
影响因子：
3.8
通讯作者：
Sutter, Thomas R.
中科院分区：
文献类型：
--
作者：
Kennedy, Lawrence H.;Sutter, Carrie Hayes;Sutter, Thomas R.
氯痤疮是常见于接触2，3，7，8-四氯二苯并对二恶英（TCDD）的人类;然而，毒性机制尚未完全了解。利用正常人表皮角质形成细胞，我们研究了TCDD介导的表皮分化的增强机制，整合功能基因组学，代谢组学和生化分析。TCDD增加了染色体1 q21上发现的40%的表皮分化复合体基因的表达和75%的从头神经酰胺生物合成所需的基因。脂质分析表明，九类神经酰胺中有八类被TCDD增加，改变了神经酰胺与游离脂肪酸的比例。TCDD降低了葡萄糖转运蛋白SLC 2A 1和大部分糖酵解转录物的表达，其次是糖酵解中间产物（包括丙酮酸）的减少。NADH和Krebs循环中间产物减少，而NAD增加。线粒体谷胱甘肽（GSH）还原酶活性和GSH/谷胱甘肽二硫键比降低TCDD，最终导致线粒体功能障碍，其特征是线粒体内膜电位和ATP产生减少，活性氧（ROS），过氧化氢的产生增加。芳烃受体（AHR）拮抗剂阻断了许多转录本对TCDD的反应，以及ATP产生和分化减少的终点，表明AHR的调节。用化学抗氧化剂或过氧化氢酶共同处理细胞，阻断了TCDD介导的角质形成细胞皮质包膜形成的加速，这是终末分化的终点。因此，TCDD介导的ROS产生是这种化学物质加速角质形成细胞分化的机制中的关键步骤。
Chloracne is commonly observed in humans exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); yet, the mechanism of toxicity is not well understood. Using normal human epidermal keratinocytes, we investigated the mechanism of TCDD-mediated enhancement of epidermal differentiation by integrating functional genomic, metabolomic, and biochemical analyses. TCDD increased the expression of 40% of the genes of the epidermal differentiation complex found on chromosome 1q21 and 75% of the genes required for de novo ceramide biosynthesis. Lipid analysis demonstrated that eight of the nine classes of ceramides were increased by TCDD, altering the ratio of ceramides to free fatty acids. TCDD decreased the expression of the glucose transporter, SLC2A1, and most of the glycolytic transcripts, followed by decreases in glycolytic intermediates, including pyruvate. NADH and Krebs cycle intermediates were decreased, whereas NAD was increased. Mitochondrial glutathione (GSH) reductase activity and the GSH/glutathione disulfide ratio were decreased by TCDD, ultimately leading to mitochondrial dysfunction, characterized by decreased inner mitochondrial membrane potential and ATP production, and increased production of the reactive oxygen species (ROS), hydrogen peroxide. Aryl hydrocarbon receptor (AHR) antagonists blocked the response of many transcripts to TCDD, and the endpoints of decreased ATP production and differentiation, suggesting regulation by the AHR. Cotreatment of cells with chemical antioxidants or the enzyme catalase blocked the TCDD-mediated acceleration of keratinocyte cornified envelope formation, an endpoint of terminal differentiation. Thus, TCDD-mediated ROS production is a critical step in the mechanism of this chemical to accelerate keratinocyte differentiation.