Molecular insights into 4-nitrophenol-induced hepatotoxicity in zebrafish: Transcriptomic, histological and targeted gene expression analyses

• Published in: Biochimica et biophysica acta Vol. 1830; no. 10; pp. 4778 - 4789
• Main Authors: Lam, Siew Hong, Ung, Choong Yong, Hlaing, Mya Myintzu, Hu, Jing, Li, Zhi-Hua, Mathavan, Sinnakaruppan, Gong, Zhiyuan
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.10.2013
• Subjects: 4-Nitrophenol; adults; Animals; apoptosis; cell adhesion; cell cycle; Danio rerio; DNA damage; gene expression; Gene Expression Profiling; gene expression regulation; genes; hepatitis; hepatotoxicity; interleukins; Liver; Liver - drug effects; males; methionine; Microarray; microarray technology; nitrophenols; Nitrophenols - toxicity; Oxidative Phosphorylation; oxidative stress; p-nitrophenol; pollutants; proteasome endopeptidase complex; quantitative polymerase chain reaction; reverse transcriptase polymerase chain reaction; Toxicity; Transcriptome; Transcriptomic; transcriptomics; Zebrafish; Zebrafish; 4-Nitrophenol; Transcriptomic; Microarray; Toxicity; Liver
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2013.06.008

4-Nitrophenol (4-NP) is a prioritized environmental pollutant and its toxicity has been investigated using zebrafish, advocated as an alternative toxicological model. However, molecular information of 4-NP induced hepatotoxicity is still limited. This study aimed to obtain molecular insights into 4-NP-induced hepatotoxicity using zebrafish as a model. Adult male zebrafish were exposed to 4-NP for 8, 24, 48 and 96h. Livers were sampled for microarray experiment, qRT-PCR and various histological analyses. Transcriptomic analysis revealed that genes associated with oxidative phosphorylation and electron transport chain were significantly up-regulated throughout early and late stages of 4-NP exposure due to oxidative phosphorylation uncoupling by 4-NP. This in turn induced oxidative stress damage and up-regulated pathways associated with tumor suppressors Rb and p53, cell cycle, DNA damage, proteasome degradation and apoptosis. Pathways associated with cell adhesion and morphology were deregulated. Carbohydrate and lipid metabolisms were down-regulated while methionine and aromatic amino acid metabolisms as well as NFKB pathway associated with chronic liver conditions were up-regulated. Up-regulation of NFKB, NFAT and interleukin pathways suggested hepatitis. Histological analyses with specific staining methods and qRT-PCR analysis of selected genes corroborated with the transcriptomic analysis suggesting 4-NP induced liver injury. Our findings allowed us to propose a plausible model and provide a broader understanding of the molecular events leading to 4-NP induced acute hepatotoxicity for future studies involving other nitrophenol derivatives. This is the first transcriptomic report on 4-NP induced hepatotoxicity. •Hepatotoxicity induced by 4-nitrophenol was investigated using adult male zebrafish.•Transcriptomic, histological and qRT-PCR analyses revealed liver toxicity and injury.•A plausible model for molecular events leading to hepatotoxicity is proposed.•This is the first transcriptomics report of 4-nitrophenol induced hepatotoxicity.•Highlight potential of zebrafish as an alternative model for hepatotoxicity studies