title: Molecular insights into 4-nitrophenol-induced hepatotoxicity in zebrafish: transcriptomic, histological and targeted gene expression analyses.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  This is the first transcriptomic report on 4-NP induced hepatotoxicity.
authors.affiliation: Department of Biological Sciences, National University of Singapore, Singapore, Singapore. dbslsh@nus.edu.sg
authors.forename: Siew Hong
authors.initials: SH
authors.lastname: Lam
authors.forename: Choong Yong
authors.initials: CY
authors.lastname: Ung
authors.forename: Mya Myintzu
authors.initials: MM
authors.lastname: Hlaing
authors.forename: Jing
authors.initials: J
authors.lastname: Hu
authors.forename: Zhi-Hua
authors.initials: ZH
authors.lastname: Li
authors.forename: Sinnakaruppan
authors.initials: S
authors.lastname: Mathavan
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Gong
mesh_terms: D000818:Animals; D020869:Gene Expression Profiling; D008099:Liver / Q000187:drug effects*; D009596:Nitrophenols / Q000633:toxicity*; D010085:Oxidative Phosphorylation; D059467:Transcriptome; D015027:Zebrafish
chemical_list: D009596:Nitrophenols; C024836:4-nitrophenol
keywords: 4-Nitrophenol; Liver; Microarray; Toxicity; Transcriptomic; Zebrafish