Time course gene expression using laser capture microscopy-extracted bile ducts, but not hepatic parenchyma, reveals acute alpha-naphthylisothiocyanate toxicity.
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.
Cullen
John Michael
JM
North Carolina State University, College of Veterinary Medicine, Raleigh, North Carolina 27606, USA. john_cullen@ncsu.edu
Falls
James Greg
JG
Brown
Harlan Roger
HR
Yoon
Lawrence Wonsik
LW
Cariello
Neal Foster
NF
Faiola
Brenda
B
Kimbrough
Carie Lynette
CL
Jordan
Holly Lynn
HL
Miller
Richard Thomas
RT
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
D015058:1-Naphthylisothiocyanate