Network toxicology-assisted experiments to explore 2,7-dibromocarbazole's hepatotoxic mechanism
The environmental pollutant 2,7-dibromocarbazole(27-BCZ)significantly induces liver toxicity,thus identification of its molecular mechanism on liver toxicity play a vital role in ecological risk assessment and the development of therapeutics.This study confirmed that 0.05 μmol/L or 0.15 μmol/L 27-BCZ can induce liver damage in zebrafish due to partial cell lysis,nuclear pyknosis and denaturation,and an increase in ALT and AST in the liver.The network toxicology predicted that the key targets of 27-BCZ in inducing liver damage were RXRα,MAPK1,HSP90AA1,etc.,and the mechanisms involved PI3K-Akt signaling pathways.The molecular docking results indicated that the core target RXRα associated with the PI3K-Akt signaling pathway had strong binding activity with 27-BCZ.To verify the feasibility of network toxicology prediction,RT-qPCR was used to detect apoptosis-related genes mediated by the PI3K-Akt signaling pathway in the liver.The results showed that 27-BCZ significantly reduced the transcriptional levels of genes pi3k,akt,and bcl-2,and significantly increased transcriptional levels of genes bax and caspase 3 which are related to cell apoptosis.The trends of decrease or increase were further enhanced with increasing concentration of 27-BCZ.Based on the network toxicological and experimental results,we found that 27-BCZ-induced liver damage may be related to its downregulation of the PI3K-Akt signaling pathway and promotion of liver cell apoptosis.This is the first study that attempted using the network toxicology methods to explore the hepatic toxicity mechanisms of environmental pollutants,which provides new insight into investigation of the toxicity mechanism of environmental organic pollutants.
国家科技期刊平台
NSTL
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