Role Of The NF-κB Signaling Pathway In Hexavalent Chromium-induced Hepatotoxicity

Background: Hexavalent chromium Cr(Ⅵ)is a primary human carcinogen with damaging toxic effects on multiple organs,with the liver being the main target one.Cr(Ⅵ)exposure can induce hepatotoxicity through oxidative stress(Reactive Oxygen Species,ROS),but its exact mechanism of action is still unclear.This project took Cr(Ⅵ)-exposed mouse liver tissue as the research object and,via RNA-seq,Western Blot,and other biological techniques,revealed the mechanism of Cr(Ⅵ)liver toxicity.Methods: A model of acute Cr(Ⅵ)liver injury was established by exposing mice to different concentrations(0,40,80,160,and 320 mg/kg.Bw)of Cr(Ⅵ);RNA-seq was used to characterize the changes in the liver tissue transcriptome of C57BL/6 mice exposed to 160mg/kg.Bw of Cr(Ⅵ).Changes in liver tissue structure were observed by H&E,protein expression was detected by Western Blot and immunohistochemistry,and gene expression levels were detected by quantitative PCR(RT-q PCR).Results: After Cr(Ⅵ)exposure,abnormal liver tissue structure,hepatocyte injury,and hepatic inflammatory response were observed in mice,and this,in a dose-dependent manner.RNA-seq transcriptome results indicated that oxidative stress,apoptosis,and inflammatory response pathways were increased after Cr(Ⅵ)exposure;KEGG pathway analysis found that the activity of the NF-κB signaling pathway was significantly upregulated.Consistent with the RNA-seq results,immunohistochemistry showed that Cr(Ⅵ)exposure resulted in an infiltration of Kupffer cells and neutrophils,and increased expression of inflammatory factors(TNF-α,IL-6,IL-1β),as well as NF-κB signaling pathways activation(p-IKKα/β and p-p65).However,treatment with the ROS inhibitor N-acetylcysteine(NAC)reduced the number of infiltrated Kupffer cells and neutrophils,reduced the expression of inflammatory factors(TNF-α,IL-6,IL-1β),inhibited NF-κB signaling pathway(p-IKKα/β and p-p65),and rescued Cr(Ⅵ)-induced liver tissue damage.Conclusion: This project revealed for the first time that Cr(Ⅵ)induced liver tissue damage through the inflammatory response mediated by the NF-κB signaling pathway.The results of this study will lay a good foundation for the in-depth disclosure of the toxic mechanism of Cr(Ⅵ)and the clinical preventive treatment.