The mechanistic basis of arsenicosis: pathogenesis of skin cancer.
The mechanistic basis of arsenicosis: pathogenesis of skin cancer.
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砷中毒的机制基础：皮肤癌的发病机制。
DOI：
10.1016/j.canlet.2014.08.016
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发表时间：
2014-11-28
期刊：
影响因子：
9.7
通讯作者：
Athar, Mohammad
中科院分区：
文献类型：
--
作者：
Hunt, Katherine M.;Srivastava, Ritesh K.;Elmets, Craig A.;Athar, Mohammad
在许多国家的地下水中发现了大量的砷，包括阿根廷，孟加拉国，智利，中国，印度，墨西哥和美国，估计有2亿人面临有毒物质暴露的风险。虽然慢性砷中毒会损害许多器官系统，但它通常首先出现在皮肤中，表现包括色素沉着过度、角化过度、鲍温病、鳞状细胞癌和基底细胞癌。砷通过上调烟酰胺腺嘌呤二核苷酸磷酸氧化酶，解偶联一氧化氮合酶，以及通过消耗天然抗氧化剂如一氧化氮和谷胱甘肽以及靶向负责维持氧化还原稳态的其他蛋白质来促进氧化应激。它引起免疫功能障碍和组织炎症反应，这可能涉及未折叠蛋白反应信号通路的激活。此外，其他分子靶点如核因子κ B、Hippo信号蛋白雅普和矿物粉尘诱导的原癌基因的失调可能协调砷介导的健康效应的发病机制。类金属降低肿瘤抑制分子的表达，并增加促炎性丝裂原活化蛋白激酶途径的表达，从而导致肿瘤促进组织微环境。上调的信号转导分子与DNA损伤的合作可以消除凋亡，促进增殖，并提高细胞存活。通过直接DNA损伤和几种细胞DNA修复机制的减弱导致的基因组不稳定性也可能是砷暴露人群中重要的癌症发展机制。因此，砷通过产生氧化应激、引起免疫功能障碍、促进遗传毒性、阻碍DNA修复和破坏信号转导来介导其毒性，这可以解释砷中毒中所见的复杂疾病表现。
Significant amounts of arsenic have been found in the groundwater of many countries including Argentina, Bangladesh, Chile, China, India, Mexico, and the United States with an estimated 200 million people at risk of toxic exposure. Although chronic arsenic poisoning damages many organ systems, it usually first presents in the skin with manifestations including hyperpigmentation, hyperkeratoses, Bowen’s disease, squamous cell carcinoma, and basal cell carcinoma. Arsenic promotes oxidative stress by upregulating nicotinamide adenine dinucleotide phosphate oxidase, uncoupling nitric oxide synthase, and by depleting natural antioxidants such as nitric oxide and glutathione in addition to targeting other proteins responsible for the maintenance of redox homeostasis. It causes immune dysfunction and tissue inflammatory responses, which may involve activation of the unfolded protein response signaling pathway. In addition, the dysregulation of other molecular targets such as nuclear factor kappa B, Hippo signaling protein Yap, and the mineral dust-induced proto-oncogene may orchestrate the pathogenesis of arsenic-mediated health effects. The metalloid decreases expression of tumor suppressor molecules and increases expression of pro-inflammatory mitogen-activated protein kinase pathways leading to a tumor-promoting tissue microenvironment. Cooperation of upregulated signal transduction molecules with DNA damage may abrogate apoptosis, promote proliferation, and enhance cell survival. Genomic instability via direct DNA damage and weakening of several cellular DNA repair mechanisms could also be important cancer development mechanisms in arsenic-exposed populations. Thus, arsenic mediates its toxicity by generating oxidative stress, causing immune dysfunction, promoting genotoxicity, hampering DNA repair, and disrupting signal transduction, which may explain the complex disease manifestations seen in arsenicosis.
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DOI：
10.1186/1476-069x-12-73
发表时间：
2013-09-02
期刊：
Environmental health : a global access science source
影响因子：
--
作者：
Dangleben NL;Skibola CF;Smith MT
通讯作者：
Smith MT
影响因子：
10.4
作者：
Gilbert-Diamond D;Li Z;Perry AE;Spencer SK;Gandolfi AJ;Karagas MR
通讯作者：
Karagas MR
影响因子：
5
作者：
Chen, Yu;Wu, Fen;Ahsan, Habibul
通讯作者：
Ahsan, Habibul
影响因子：
10.4
作者：
Burns FJ;Uddin AN;Wu F;Nádas A;Rossman TG
通讯作者：
Rossman TG
影响因子：
3.8
作者：
Banerjee, Nilanjana;Paul, Somnath;Giri, Ashok K.
通讯作者：
Giri, Ashok K.