Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM, United States.
Division of Epidemiology, Biostatistics and Preventive Medicine, University of New Mexico, Albuquerque, NM, United States.
Toxicol Lett. 2014 Jan 30;224(3):407-15. doi: 10.1016/j.toxlet.2013.11.010. Epub 2013 Nov 21.
The rise of melanoma incidence in the United States is a growing public health concern. A limited number of epidemiology studies suggest an association between arsenic levels and melanoma risk. Arsenic acts as a co-carcinogen with ultraviolet radiation (UVR) for the development of squamous cell carcinoma and proposed mechanisms include generation of oxidative stress by arsenic and UVR and inhibition of UVR-induced DNA repair by arsenic. In this study, we investigate similarities and differences in response to arsenic and UVR in keratinocytes and melanocytes. Normal melanocytes are markedly more resistant to UVR-induced cytotoxicity than normal keratinocytes, but both cell types are equally sensitive to arsenite. Melanocytes were more resistant to arsenite and UVR stimulation of superoxide production than keratinocytes, but the concentration of arsenite necessary to inhibit the activity of the DNA repair protein poly(ADP-ribose)polymerase and enhance retention of UVR-induced DNA damage was essentially equivalent in both cell types. These findings suggest that although melanocytes are less sensitive than keratinocytes to initial UVR-mediated DNA damage, both of these important target cells in the skin share a mechanism related to arsenic inhibition of DNA repair. These findings suggest that concurrent chronic arsenic exposure could promote retention of unrepaired DNA damage in melanocytes and act as a co-carcinogen in melanoma.
美国黑色素瘤发病率的上升是一个日益严重的公共卫生问题。少数流行病学研究表明，砷水平与黑色素瘤风险之间存在关联。砷与紫外线辐射（UVR）一起作为协同致癌剂，作用于鳞状细胞癌，其提出的机制包括砷和 UVR 产生氧化应激，以及砷抑制 UVR 诱导的 DNA 修复。在这项研究中，我们研究了角质细胞和黑素细胞对砷和 UVR 的反应的异同。正常黑素细胞对 UVR 诱导的细胞毒性的抵抗力明显强于正常角质细胞，但这两种细胞类型对亚砷酸盐的敏感性相同。黑素细胞对亚砷酸盐和 UVR 刺激的超氧化物产生的抵抗力强于角质细胞，但抑制 DNA 修复蛋白聚（ADP-核糖）聚合酶活性并增强 UVR 诱导的 DNA 损伤的保留所需的亚砷酸盐浓度在这两种细胞类型中基本相同。这些发现表明，尽管黑素细胞对初始 UVR 介导的 DNA 损伤的敏感性低于角质细胞，但皮肤中这两种重要的靶细胞都具有与砷抑制 DNA 修复相关的机制。这些发现表明，同时慢性砷暴露可能会促进未修复的 DNA 损伤在黑素细胞中的保留，并作为黑色素瘤的协同致癌剂。
