Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA.
Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA 16802, USA.
Toxicol Appl Pharmacol. 2018 Feb 15;341:106-113. doi: 10.1016/j.taap.2018.01.014. Epub 2018 Feb 3.
Prolonged exposure to arsenic has been shown to increase the risk of developing a number of diseases, including cancer and type II diabetes. Arsenic is present throughout the environment in its inorganic forms, and the level of exposure varies greatly by geographical location. The current recommended maximum level of arsenic exposure by the EPA is 10μg/L, but levels>50-1000μg/L have been detected in some parts of Asia, the Middle East, and the Southwestern United States. One of the most important steps in developing treatment options for arsenic-linked pathologies is to understand the cellular pathways affected by low levels of arsenic. Here, we show that acute exposure to non-lethal, low-level arsenite, an environmentally relevant arsenical, inhibits the autophagy pathway. Furthermore, arsenite-induced autophagy inhibition initiates a transient, but moderate ER stress response. Significantly, low-level arsenite exposure does not exhibit an increase in oxidative stress. These findings indicate that compromised autophagy, and not enhanced oxidative stress occurs early during arsenite exposure, and that restoring the autophagy pathway and proper proteostasis could be a viable option for treating arsenic-linked diseases. As such, our study challenges the existing paradigm that oxidative stress is the main underlying cause of pathologies associated with environmental arsenic exposure.
长期接触砷已被证明会增加多种疾病的风险，包括癌症和 2 型糖尿病。砷以无机形式存在于整个环境中，暴露水平因地理位置的不同而有很大差异。美国环保署目前建议的砷暴露最高水平为 10μg/L，但在亚洲、中东和美国西南部的一些地区已经检测到超过 50-1000μg/L 的水平。开发与砷相关的病理学治疗方案的最重要步骤之一是了解受低水平砷影响的细胞途径。在这里，我们表明急性暴露于非致死性、低水平亚砷酸盐（一种与环境相关的砷化物）会抑制自噬途径。此外，亚砷酸盐诱导的自噬抑制会引发短暂但适度的内质网应激反应。重要的是，低水平砷酸盐暴露不会导致氧化应激增加。这些发现表明，在砷酸盐暴露早期，自噬功能受损而不是氧化应激增强，恢复自噬途径和适当的蛋白质稳态可能是治疗与砷相关疾病的可行选择。因此，我们的研究挑战了现有的观点，即氧化应激是与环境砷暴露相关的病理学的主要潜在原因。
