Cr(VI) induces cytotoxicity in vitro through activation of ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction via the PI3K/Akt signaling pathway

• Published in: Toxicology in vitro 2017-06, Vol.41, p.232-244
• Main Authors: Zhang, Yujing, Xiao, Fang, Liu, Xinmin, Liu, Kaihua, Zhou, Xiaoxin, Zhong, Caigao
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Acetylcysteine; AKT protein; Apoptosis; Apoptosis - drug effects; Cell cycle; Cell Cycle - drug effects; Cell Line; Cell Proliferation - drug effects; Cell Survival - drug effects; Chromium; Chromium - toxicity; Cr(VI); Cytotoxicity; Endoplasmic reticulum; Endoplasmic Reticulum Stress - drug effects; ER stress; Hepatocytes; Hepatocytes - drug effects; Hepatocytes - metabolism; Hepatotoxicity; Hexavalent chromium; Homology; Humans; Inhibition; Insulin-like growth factor I; Liver; Membrane Potential, Mitochondrial - drug effects; Mitochondria; Mitochondria, Liver - drug effects; Mitochondria, Liver - metabolism; Mitochondrial DNA; Mitochondrial dysfunction; Molecular modelling; Phosphatidylinositol 3-Kinases - metabolism; PI3K/Akt; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Reactive oxygen species; Reactive Oxygen Species - metabolism; ROS; Signal transduction; Signal Transduction - drug effects; Signaling; siRNA; Stress; Stresses; Time dependence; Toxicity; Toxicology
• ISSN: 0887-2333; 1879-3177
• DOI: 10.1016/j.tiv.2017.03.003

The occupational and environmental toxicant hexavalent chromium [Cr(VI)] can cause severe damage to the liver; however, the exact mechanisms associated with its toxicity have not been thoroughly demonstrated. In the present study, the underlying mechanisms of Cr(VI)-induced hepatotoxicity were investigated. Our results showed that Cr(VI) inhibited the growth and proliferation of L-02 hepatocytes. Further study revealed that Cr(VI) significantly induced S-phase cell cycle arrest and apoptosis accompanying with the overproduction of reactive oxygen species (ROS). Cr(VI)-induced apoptosis could be prevented by inhibiting ROS with N-acetyl-l-cysteine (NAC). Additionally, our data showed that Cr(VI)-induced endoplasmic reticulum (ER) stress and mitochondrial dysfunction were concentration- and time-dependent. Moreover, inhibition of C/EBA homologous protein (CHOP) expression by siRNA partially prevented Cr(VI)-induced cell apoptosis, mitochondrial dysfunction and ROS generation. We also found that Cr(VI) treatment inhibited the PI3K/Akt pathway in a concentration- and time-dependent manner. After using IGF-1 (50ng/mL), the specific agonist of the PI3K/AKT signaling pathway, the facilitating effects of Cr(VI) were depressed. This finding demonstrated the relationship between the PI3K/Akt pathway, ER stress and mitochondrial dysfunction. Collectively, these findings indicated that Cr(VI) increased ROS production. Increased ROS production may account for inhibition of the PI3K/Akt pathway and lead to ER stress and mitochondrial dysfunction, which consequently induces apoptosis in L-02 hepatocytes. This study provides novel insights into the molecular mechanisms of Cr(VI)-induced cytotoxicity. •Cr(VI) caused change in expression of CHOP and cytochrome c in L-02 hepatocytes.•The formation of ROS may account for ER stress and mitochondrial dysfunction.•Inhibition of CHOP suppressed the formation of ROS and mitochondrial dysfunction.•Activation of PI3K can ameliorate Cr(VI)-induced cytotoxicity in L-02 hepatocytes.