Anchoring Hepatic Gene Expression with Development of Fibrosis and Neoplasia in a Toxicant-induced Fish Model of Liver Injury

Wettere, Arnaud J. Van; Law, J. Mac; Hinton, David E.; Kullman, Seth W.

doi:10.1177/0192623312464308

Cited by 17 publications

(9 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Tgfb1 encodes a multifunctional peptide which regulates proliferation, differentiation, adhesion, migration, and many other physiological and pathological functions (Causey et al, 2012;Massague and Gomis, 2006). In the liver, Tgfb1 encodes a master regulator of ECM production and hepatic stellate cell activation after toxic chemical injury (Ghosh and Vaughan, 2012;Liu, 2008;Van Wettere et al, 2013). In contrast, the inducible form of TGF-b (Tgfbi) was downregulated in the livers with microscopic evidence of fibrosis in this study (Figure 11; Supplementary Table 1).…”

Section: Gene Signatures In Hepatotoxic Injurymentioning

confidence: 64%

Gene Expression Patterns Associated With Histopathology in Toxic Liver Fibrosis

et al. 2015

View full text Add to dashboard Cite

Toxic industrial chemicals induce liver injury, which is difficult to diagnose without invasive procedures. Identifying indicators of end organ injury can complement exposure-based assays and improve predictive power. A multiplexed approach was used to experimentally evaluate a panel of 67 genes predicted to be associated with the fibrosis pathology by computationally mining DrugMatrix, a publicly available repository of gene microarray data. Five-day oral gavage studies in male Sprague Dawley rats dosed with varying concentrations of 3 fibrogenic compounds (allyl alcohol, carbon tetrachloride, and 4,4'-methylenedianiline) and 2 nonfibrogenic compounds (bromobenzene and dexamethasone) were conducted. Fibrosis was definitively diagnosed by histopathology. The 67-plex gene panel accurately diagnosed fibrosis in both microarray and multiplexed-gene expression assays. Necrosis and inflammatory infiltration were comorbid with fibrosis. ANOVA with contrasts identified that 51 of the 67 predicted genes were significantly associated with the fibrosis phenotype, with 24 of these specific to fibrosis alone. The protein product of the gene most strongly correlated with the fibrosis phenotype PCOLCE (Procollagen C-Endopeptidase Enhancer) was dose-dependently elevated in plasma from animals administered fibrogenic chemicals (P < .05). Semiquantitative global mass spectrometry analysis of the plasma identified an additional 5 protein products of the gene panel which increased after fibrogenic toxicant administration: fibronectin, ceruloplasmin, vitronectin, insulin-like growth factor binding protein, and α2-macroglobulin. These results support the data mining approach for identifying gene and/or protein panels for assessing liver injury and may suggest bridging biomarkers for molecular mediators linked to histopathology.

show abstract

Section: Gene Signatures In Hepatotoxic Injurymentioning

confidence: 64%

Gene Expression Patterns Associated With Histopathology in Toxic Liver Fibrosis

et al. 2015

View full text Add to dashboard Cite

show abstract

“…All medaka embryos used were at stage 21 because our previous study had revealed that this stage was more sensitive than other stages to SNC (Kashiwada et al, 2012). Japanese medaka is commonly used as a typical freshwater fish model in toxicology (Van Wettere et al, 2013) and ecotoxicology (Kashiwada et al, 2008). Although Japanese medaka is a freshwater fish, it can live in not only freshwater but also brackish water or seawater.…”

Section: Medaka Eggsmentioning

confidence: 99%

Salinity‐dependent toxicity of water‐dispersible, single‐walled carbon nanotubes to Japanese medaka embryos

Kataoka

Nakahara

Shimizu

et al. 2016

J of Applied Toxicology

View full text Add to dashboard Cite

To investigate the effects of salinity on the behavior and toxicity of functionalized single-walled carbon nanotubes (SWCNTs), which are chemical modified nanotube to increase dispersibility, medaka embryos were exposed to non-functionalized single-walled carbon nanotubes (N-SWCNTs), water-dispersible, cationic, plastic-polymer-coated, single-walled carbon nanotubes (W-SWCNTs), or hydrophobic polyethylene glycol-functionalized, single-walled carbon nanotubes (PEG-SWCNTs) at different salinities, from freshwater to seawater. As reference nanomaterials, we tested dispersible chitin nanofiber (CNF), chitosan-chitin nanofiber (CCNF) and chitin nanocrystal (CNC, i.e. shortened CNF). Under freshwater conditions, with exposure to 10 mg l W-SWCNTs, the yolk sacks of 57.8% of embryos shrank, and the remaining embryos had a reduced heart rate, eye diameter and hatching rate. Larvae had severe defects of the spinal cord, membranous fin and tail formation. These toxic effects increased with increasing salinity. Survival rates declined with increasing salinity and reached 0.0% in seawater. In scanning electron microscope images, W-SWCNTs, CNF, CCNF and CNC were adsorbed densely over the egg chorion surface; however, because of chitin's biologically harmless properties, only W-SWCNTs had toxic effects on the medaka eggs. No toxicity was observed from N-SWCNT and PEG-SWCNT exposure. We demonstrated that water dispersibility, surface chemistry, biomedical properties and salinity were important factors in assessing the aquatic toxicity of nanomaterials. Copyright © 2016 John Wiley & Sons, Ltd.

show abstract

“…The changes in the liver of DMN-exposed fish were similar to those described by Hobbie et al ., (2011) and Van Wettere et al . (2012).…”

Section: Resultsmentioning

confidence: 96%

“…However, in this study, exposure to DMN was used to induce oval cell hyperplasia (Thoolen et al ., 2010; Hobbie et al ., 2011; Van Wettere et al ., 2012). The subset of DMN-exposed livers that exhibited prominent oval cell hyperplasia was selected and evaluated by IHC and TEM.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Immunohistochemical Characterization of the Hepatic Progenitor Cell Compartment in Medaka (Oryzias latipes) following Hepatic Injury

Wettere

Kullman

Hinton

et al. 2013

Journal of Comparative Pathology

View full text Add to dashboard Cite

Summary Laboratory fish species are used increasingly in biomedical research and are considered robust models for the study of regenerative processes. Studies investigating the response of the fish liver to injury have demonstrated the presence of a ductular reaction and oval-like cells in injured and regenerating liver. To date, however, it is unclear if this cell population is the piscine equivalent of oval cells or intermediate hepatobiliary cells identified in rodents and man, respectively. The present study defines the process of oval cell differentiation in fish liver using histopathology, immunohistochemistry and transmission electron microscopy. To generate oval cell proliferation in Japanese medaka (Oryzias latipes), hepatic injury was induced by exposure of adult fish to either microcystin LR or dimethylnitrosamine. A transgenic strain of medaka expressing a red fluorescent protein (RFP) exclusively in hepatocytes was used. The morphological response to injury was characterized by a ductular reaction comprised of cytokeratin (CK) AE1/AE3+ oval cells progressing to intermediate hepatobiliary cells variably positive for CK and RFP, and finally mature RFP+ hepatocytes and CK+ cholangiocytes. These observations support a bipotential differentiation pathway of fish oval cells towards hepatocytes and cholangiocytes. Ultrastructural morphology confirmed the presence of oval cells and differentiation towards hepatocytes. These results demonstrated clear similarities between patterns of reaction to injury in fish and mammalian livers. They also confirm the presence of and support the putative bipotential lineage capabilities of the fish oval cell.

show abstract

Anchoring Hepatic Gene Expression with Development of Fibrosis and Neoplasia in a Toxicant-induced Fish Model of Liver Injury

Cited by 17 publications

References 69 publications

Gene Expression Patterns Associated With Histopathology in Toxic Liver Fibrosis

Gene Expression Patterns Associated With Histopathology in Toxic Liver Fibrosis

Salinity‐dependent toxicity of water‐dispersible, single‐walled carbon nanotubes to Japanese medaka embryos

Immunohistochemical Characterization of the Hepatic Progenitor Cell Compartment in Medaka (Oryzias latipes) following Hepatic Injury

Contact Info

Product

Resources

About