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ToxSci Advance Access originally published online on January 10, 2008
Toxicological Sciences 2008 102(2):262-277; doi:10.1093/toxsci/kfm308
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Protective Response of the Ah Receptor to ANIT-Induced Biliary Epithelial Cell Toxicity in See-Through Medaka

David C. Volz*,1, Seth W. Kullman{dagger}, Deanna L. Howarth*, Ron C. Hardman* and David E. Hinton*,2

* Integrated Toxicology Program and Nicholas School of the Environment and Earth Sciences, Duke University, Durham, North Carolina 27708 {dagger} Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina 27606

2 To whom correspondence should be addressed at Duke University, Nicholas School of the Environment and Earth Sciences, Box 90328, Durham, NC 27708. Fax: (919) 684-8741. E-mail: dhinton{at}duke.edu.

Received September 9, 2007; accepted December 17, 2007


  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.

Key Words: see-through medaka; AHR; liver; nuclear receptor; bile; ANIT.

1 Present Address: Syngenta Crop Protection, Inc., Environmental Safety—Americas, P.O. Box 18300, Greensboro, NC 27419.


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