Cr(VI) induces cytotoxicity in vitro through activation of ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction via the PI3K/Akt signaling pathway.
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.
Department of Toxicology, Xiangya School of Public Health, Central South University, Changsha 410078, PR China.
Yujing
Y
Zhang
Department of Toxicology, Xiangya School of Public Health, Central South University, Changsha 410078, PR China.
Fang
F
Xiao
Department of Toxicology, Xiangya School of Public Health, Central South University, Changsha 410078, PR China.
Xinmin
X
Liu
Department of Toxicology, Xiangya School of Public Health, Central South University, Changsha 410078, PR China.
Kaihua
K
Liu
Department of Toxicology, Xiangya School of Public Health, Central South University, Changsha 410078, PR China.
Xiaoxin
X
Zhou
Department of Toxicology, Xiangya School of Public Health, Central South University, Changsha 410078, PR China. Electronic address: zcg54@csu.edu.cn.
Caigao
C
Zhong
D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002857:Chromium / Q000633:toxicity*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D017382:Reactive Oxygen Species; D002857:Chromium; C074702:chromium hexavalent ion; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
Apoptosis; Cr(VI); ER stress; Mitochondrial dysfunction; PI3K/Akt; ROS