Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85724, USA.
Toxicol Lett. 2010 Nov 30;199(2):153-9. doi: 10.1016/j.toxlet.2010.08.017. Epub 2010 Sep 9.
Chronic exposure to inorganic arsenic is associated with diverse, complex diseases, making the identification of the mechanism underlying arsenic-induced toxicity a challenge. An increasing body of literature from epidemiological and in vitro studies has demonstrated that arsenic is an immunotoxicant, but the mechanism driving arsenic-induced immunotoxicity is not well established. We have previously demonstrated that in human lymphoblastoid cell lines (LCLs), arsenic-induced cell death is strongly associated with the induction of autophagy. In this study we utilized genome-wide gene expression analysis and functional assays to characterize arsenic-induced effects in seven LCLs that were exposed to an environmentally relevant, minimally cytotoxic, concentration of arsenite (0.75 μM) over an eight-day time course. Arsenic exposure resulted in inhibition of cellular growth and induction of autophagy (measured by expansion of acidic vesicles) over the eight-day exposure duration. Gene expression analysis revealed that arsenic exposure increased global lysosomal gene expression, which was associated with increased functional activity of the lysosome protease, cathepsin D. The arsenic-induced expansion of the lysosomal compartment in LCL represents a novel target that may offer insight into the immunotoxic effects of arsenic.
慢性接触无机砷与多种复杂疾病有关，因此确定砷诱导毒性的机制是一个挑战。越来越多的流行病学和体外研究文献表明，砷是一种免疫毒素，但砷诱导免疫毒性的确切机制尚不清楚。我们之前的研究表明，在人类淋巴母细胞系（LCL）中，砷诱导的细胞死亡与自噬的诱导密切相关。在这项研究中，我们利用全基因组基因表达分析和功能测定，在 7 个 LCL 中对环境相关的、最小细胞毒性浓度（0.75 μM）的亚砷酸盐暴露 8 天的时间过程进行了砷诱导效应的特征描述。砷暴露导致细胞生长抑制和自噬诱导（通过酸性囊泡的扩张来衡量），持续 8 天。基因表达分析显示，砷暴露增加了溶酶体的全局基因表达，这与溶酶体蛋白酶组织蛋白酶 D 的功能活性增加有关。LCL 中溶酶体区室的砷诱导扩张代表了一个新的靶点，可能为砷的免疫毒性作用提供深入了解。
