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Gene expression in hepatocytes and bile ducts from ANIT-treated rats

ABSTRACT: Acute toxic responses to a single 50 mg/kg oral dose of 1-napthylisothiocyanate (ANIT) were evaluated by microarray analysis of laser capture-microdissected rat biliary epithelium or hepatic parenchyma at 2 and 6 hours post-dose. Selective and dramatic differences between the biliary epithelium and the hepatic parenchyma were evident as soon as 2 hours at which time 375 genes were altered in biliary epithelium, but only a nominal 38 genes were altered in the hepatic parenchyma. Gene expression analysis revealed increased expression of genes involved in the unfolded protein response and ER stress in biliary epithelial cells, but no alteration of these genes in hepatocytes. By 6 hours post dose, 620 genes showed altered expression in biliary epithelium while there were only 32 genes altered in hepatic parenchyma. At this timepoint, analysis of the biliary epithelium revealed decreased expression of genes involved in the unfolded protein response compared to the 2 hour time point, and increased expression at 6 hours of genes involved in protein degradation such as proteasome-ubquination pathways, and genes associated with cell death. Our analysis revealed early loss of biliary epithelial integrity and attempts at repair of damage with subsequent activation of protein degradation and cell fate decisions leading to death pathways within a 6 hour time course. During this same time interval, hepatic parenchymal gene expression changed little and mainly reflected a decrease in enterohepatic circulation of bile acids and an increase in ribosomal proteins which may signal an adaptive change to reduced bile acid delivery to the liver and an increased demand for bile acids and glutathione-mediated transport of ANIT. This versatile approach provides a precise evaluation of distinct cell populations, biliary epithelium and hepatic parenchyma, in situ. (Cullen et.al., Toxicologic Pathology 2010)

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE20498 | GEO | 2010/02/24

SECONDARY ACCESSION(S): PRJNA125077

REPOSITORIES: GEO

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Project description:Acute toxic responses to a single 50 mg/kg oral dose of 1-napthylisothiocyanate (ANIT) were evaluated by microarray analysis of laser capture-microdissected rat biliary epithelium or hepatic parenchyma at 2 and 6 hours post-dose. Selective and dramatic differences between the biliary epithelium and the hepatic parenchyma were evident as soon as 2 hours at which time 375 genes were altered in biliary epithelium, but only a nominal 38 genes were altered in the hepatic parenchyma. Gene expression analysis revealed increased expression of genes involved in the unfolded protein response and ER stress in biliary epithelial cells, but no alteration of these genes in hepatocytes. By 6 hours post dose, 620 genes showed altered expression in biliary epithelium while there were only 32 genes altered in hepatic parenchyma. At this timepoint, analysis of the biliary epithelium revealed decreased expression of genes involved in the unfolded protein response compared to the 2 hour time point, and increased expression at 6 hours of genes involved in protein degradation such as proteasome-ubquination pathways, and genes associated with cell death. Our analysis revealed early loss of biliary epithelial integrity and attempts at repair of damage with subsequent activation of protein degradation and cell fate decisions leading to death pathways within a 6 hour time course. During this same time interval, hepatic parenchymal gene expression changed little and mainly reflected a decrease in enterohepatic circulation of bile acids and an increase in ribosomal proteins which may signal an adaptive change to reduced bile acid delivery to the liver and an increased demand for bile acids and glutathione-mediated transport of ANIT. This versatile approach provides a precise evaluation of distinct cell populations, biliary epithelium and hepatic parenchyma, in situ. (Cullen et.al., Toxicologic Pathology 2010) Rat were exposed to a single dose of 1-napthylisothiocyanate (ANIT) or vehicle. Laser capture-microdissection was used to isolate rat biliary epithelium or hepatic parenchyma at 2 and 6 hours post-dose. Affymetrix GeneChips and Rosetta Resolver were used to determine differential gene expression.

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Gene expression in hepatocytes and bile ducts from ANIT-treated rats

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