Hexavalent chromium induces hepatocyte apoptosis via regulation of apoptosis signal‐regulating kinase 1/c‐Jun amino‐terminal kinase signaling. Issue 6 (15th February 2022)

• Record Type: Journal Article
• Authors: Jin, Lifang; Kom, Merveille Chancelle; Fu, Guoquan; Xie, Yixia; Gao, Yue; Shen, Jiayuan; Huang, Huarong; Hu, Baowei; Yan, Junyan
• Is Part Of: Environmental toxicology. Volume 37:Issue 6(2022)
• Page Start: 1288
• Page End: 1296
• Publication Date: 2022-02-15
• Subjects: ASK1 -- GS‐444217 -- hepatocytes -- hexavalent chromium [Cr(VI)] -- JNK; Water quality bioassay -- Periodicals; Water -- Pollution -- Toxicology -- Periodicals; Microbiological assay -- Periodicals; Toxicity testing -- Periodicals; Environmental toxicology -- Periodicals; Environmental Pollution -- Periodicals; Environmental Pollutants -- Periodicals; Environmental Monitoring -- Periodicals; Écotoxicologie -- Périodiques; Pollution -- Périodiques; 615.902
• DOI: 10.1002/tox.23483
• Languages: English
• ISSNs: 1520-4081

Abstract

Abstract: With the spread of hexavalent chromium (Cr(VI)) contamination, Cr(VI)‐induced hepatotoxicity has attracted increasing attention in recent years. To date, however, the exact mechanism of Cr(VI) toxicity remains unclear. In this study, we investigated the role of apoptosis signal‐regulating kinase 1 (ASK1)/c‐Jun amino‐terminal kinase (JNK) in Cr(VI)‐induced hepatic toxicity and the possible related mechanisms. AML‐12 hepatocyte cell‐lines were treated with 0, 1, 4, and 16 μmol/Lof Cr(VI) with or without GS‐444271 (an ASK1 inhibitor). Adult male mice were administered with 0, 2, 8, and 32 mg/kg body mass (BM)/day of Cr(VI) for 5 days. The level of hepatocyte apoptosis/proliferation, generation of reactive oxygen species (ROS), and expression levels of mRNAs and proteins related to ASK1/JNK and nuclear factor‐E2‐related factor 2 (Nrf2) signaling were assessed. Results showed that high Cr(VI) exposure induced hepatocyte apoptosis and liver injury by generation of ROS and down‐regulation of Nrf2 signaling. In addition, ASK1/JNK signaling activity was upregulated in the Cr(VI)‐treated group. Furthermore, GS‐444217 treatment significantly rescued Cr(VI)‐induced hepatocyte apoptosis and liver dysfunction in vitro and in vivo by down‐regulation of ASK1/JNK signaling. Thus, ASK1/JNK signaling appears to play an important role in Cr(VI)‐induced hepatocyte apoptosis and liver injury. This study should help improve our understanding of the mechanism of Cr(VI)‐induced liver injury and provide support for future investigations on liver disease therapy.