Low-level arsenic causes proteotoxic stress and not oxidative stress

• Published in: Toxicology and applied pharmacology Vol. 341; pp. 106 - 113
• Main Authors: Dodson, Matthew, de la Vega, Montserrat Rojo, Harder, Bryan, Castro-Portuguez, Raul, Rodrigues, Silvia D., Wong, Pak Kin, Chapman, Eli, Zhang, Donna D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.02.2018
• Subjects: Animals; Arsenic; Arsenic - administration & dosage; Arsenic - toxicity; Autophagy - drug effects; Autophagy - physiology; Autophagy inhibitor; Cell Survival - drug effects; Cell Survival - physiology; ER stress; HEK293 Cells; HeLa Cells; Humans; Mice; NIH 3T3 Cells; Oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - physiology; Proteostasis; Reactive Oxygen Species - metabolism; Oxidative stress; Proteostasis; EIF2S1/eIF2α; Arsenic; DCF; ER stress; H2DCFDA; IRE-1; PERK; MTT; SQSTM1/p62; Autophagy inhibitor; ROS; ATF6; LC3; XBP1s
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2018.01.014

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. •Acute, low-level arsenite does not induce oxidative stress.•Low-level arsenite inhibits autophagy.•Restoring autophagy may be a viable therapy to treat arsenic-linked disease.