RRC ID 15505
Author Volz DC, Kullman SW, Howarth DL, Hardman RC, Hinton DE.
Title Protective response of the Ah receptor to ANIT-induced biliary epithelial cell toxicity in see-through medaka.
Journal Toxicol Sci
Abstract The adaptive role of the aryl hydrocarbon receptor (Ah receptor or AHR) in protecting against disease-related conditions remains unclear in nonmammalian models, particularly teleosts. Therefore, this study focused on the potential role of AHR in response to biliary epithelial cell toxicity and hepatobiliary alteration in medaka. See-through medaka (STII strain) were exposed for 96 h using the biliary toxicant alpha-naphthylisothiocyanate (ANIT) as a reagent, and fish were evaluated daily using histological and ultrastructural analysis, and by imaging directly through the body wall of living fish. Brightfield and transmission electron microscopy showed that a single ANIT dose (40 mg/kg) specifically induced swelling and apoptosis of bile preductular epithelial cells (BPDECs) as early as 6 h after initial exposure. Following ANIT-induced BPDEC toxicity, in vivo imaging of STII medaka showed significant gallbladder discoloration from 48-72 h. Collectively, these pathologic data suggested that ANIT exposure resulted in acute hepatobiliary changes, lasting < 96 h following initial exposure. We then tested the potential role of AHR in response to ANIT-induced hepatobiliary alteration. Overall, we demonstrated that (1) transient AHR activation and cytochrome P450 1A (CYP1A) induction in livers occurred during ANIT-induced hepatobiliary impairment, (2) pretreatment with an AHR agonist partially protected against acute hepatobiliary alteration, and (3) using a luciferase-based reporter assay, the bile pigment bilirubin weakly activated mouse AHR and binding to medaka-specific CYP1A promoter, resulting in AHR element-driven transcription. Given that bile acids and pigments are present in mammalian and fish liver, these studies collectively suggest that bile-induced AHR activation may be conserved between teleosts and rodents.
Volume 102(2)
Pages 262-77
Published 2008-4-1
DOI 10.1093/toxsci/kfm308
PII kfm308
PMID 18187559
MeSH 1-Naphthylisothiocyanate / toxicity* Animals Apoptosis / drug effects Bile Ducts, Intrahepatic / drug effects* Bile Ducts, Intrahepatic / metabolism Bile Ducts, Intrahepatic / pathology Bilirubin / pharmacology Cell Line, Tumor Cholestasis, Intrahepatic / metabolism Cholestasis, Intrahepatic / prevention & control* Cloning, Molecular Cytochrome P-450 CYP1A1 / biosynthesis Cytochrome P-450 CYP1A1 / genetics Disease Models, Animal Drug Antagonism Enzyme Induction Epithelial Cells / drug effects Epithelial Cells / metabolism Epithelial Cells / ultrastructure Gallbladder / drug effects Gallbladder / pathology Gene Expression / drug effects Injections, Intraperitoneal Liver / drug effects Liver / metabolism Liver / pathology Male Mice Oryzias / physiology* Pigmentation / genetics Polychlorinated Dibenzodioxins / pharmacology RNA, Messenger / metabolism Receptors, Aryl Hydrocarbon / agonists* Receptors, Aryl Hydrocarbon / drug effects Receptors, Aryl Hydrocarbon / metabolism*
IF 3.703
Times Cited 8
Medaka STII