title: Time course gene expression using laser capture microscopy-extracted bile ducts, but not hepatic parenchyma, reveals acute alpha-naphthylisothiocyanate toxicity.
abstract: Acute toxic responses to a 50-mg/kg oral dose of 1-naphthylisothiocyanate (ANIT) were evaluated by microarray analysis of laser capture-microdissected rat biliary epithelium or hepatic parenchyma obtained 2 and 6 hours postdose. Distinct differences in gene expression patterns between biliary epithelium and hepatic parenchyma were noted at the 2-hour postdose time point, where 375 genes were altered in biliary epithelium but only 38 genes were altered in hepatic parenchyma. Endoplasmic reticulum stress genes were uniquely expressed in biliary epithelial cells at 2 hours postdose. By 6 hours postdose, 620 genes were altered in biliary epithelium, but only 32 genes were altered in hepatic parenchyma. In biliary epithelium, expression of genes involved in the unfolded protein response had decreased compared with the 2-hour time point, while expression of genes involved in protein degradation such as proteasome-ubquination pathways and cell death pathways had increased. At this same time, hepatic parenchymal gene expression changed little. Within 6 hours following oral exposure to ANIT, prior to morphologic changes, specific biliary epithelial gene expression changes, indicative of a vigorous unfolded protein response with protein destruction and cell death pathway activation were noted, in contrast to minor changes in the hepatic parenchyma.
authors.affiliation: North Carolina State University, College of Veterinary Medicine, Raleigh, North Carolina 27606, USA. john_cullen@ncsu.edu
authors.forename: John Michael
authors.initials: JM
authors.lastname: Cullen
authors.forename: James Greg
authors.initials: JG
authors.lastname: Falls
authors.forename: Harlan Roger
authors.initials: HR
authors.lastname: Brown
authors.forename: Lawrence Wonsik
authors.initials: LW
authors.lastname: Yoon
authors.forename: Neal Foster
authors.initials: NF
authors.lastname: Cariello
authors.forename: Brenda
authors.initials: B
authors.lastname: Faiola
authors.forename: Carie Lynette
authors.initials: CL
authors.lastname: Kimbrough
authors.forename: Holly Lynn
authors.initials: HL
authors.lastname: Jordan
authors.forename: Richard Thomas
authors.initials: RT
authors.lastname: Miller
mesh_terms: D015058:1-Naphthylisothiocyanate / Q000633:toxicity*; D000818:Animals; D001652:Bile Ducts / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D008099:Liver / Q000187:drug effects*; D008297:Male; D018613:Microscopy, Confocal; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013995:Time; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D015058:1-Naphthylisothiocyanate