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ToxSci Advance Access originally published online on August 14, 2009
Toxicological Sciences 2009 112(1):229-244; doi:10.1093/toxsci/kfp189
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Comparative Analysis of AhR-Mediated TCDD-Elicited Gene Expression in Human Liver Adult Stem Cells

Suntae Kim*,{dagger},{ddagger}, Edward Dere*,{dagger}, Lyle D. Burgoon*,{dagger},§, Chia-Cheng Chang{dagger},¶ and Timothy R. Zacharewski*,{dagger},{ddagger},1

* Department of Biochemistry & Molecular Biology {dagger} National Food Safety & Toxicology Center {ddagger} Center for Integrative Toxicology § Gene Expression in Development and Disease Initiative Department of Pediatrics & Human Development, Michigan State University, East Lansing, Michigan 48824

1 To whom correspondence should be addressed at Michigan State University, Department of Biochemistry & Molecular Biology, 501 Biochemistry Building, Wilson Road, East Lansing, MI 48824-1319. Fax: (517) 353-9334. E-mail: tzachare{at}msu.edu.

Received May 14, 2009; accepted July 29, 2009


  Abstract

Time course and dose-response studies were conducted in HL1-1 cells, a human liver cell line with stem cell–like characteristics, to assess the differential gene expression elicited by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) compared with other established models. Cells were treated with 0.001, 0.01, 0.1, 1, 10, or 100nM TCDD or dimethyl sulfoxide vehicle control for 12 h for the dose-response study, or with 10nM TCDD or vehicle for 1, 2, 4, 8, 12, 24, or 48 h for the time course study. Elicited changes were monitored using a human cDNA microarray with 6995 represented genes. Empirical Bayes analysis identified 144 genes differentially expressed at one or more time points following treatment. Most genes exhibited dose-dependent responses including CYP1A1, CYP1B1, ALDH1A3, and SLC7A5 genes. Comparative analysis of HL1-1 differential gene expression to human HepG2 data identified 74 genes with comparable temporal expression profiles including 12 putative primary responses. HL1-1–specific changes were related to lipid metabolism and immune responses, consistent with effects elicited in vivo. Furthermore, comparative analysis of HL1-1 cells with mouse Hepa1c1c7 hepatoma cell lines and C57BL/6 hepatic tissue identified 18 and 32 commonly regulated orthologous genes, respectively, with functions associated with signal transduction, transcriptional regulation, metabolism and transport. Although some common pathways are affected, the results suggest that TCDD elicits species- and model-specific gene expression profiles.

Key Words: human liver stem cell; TCDD; comparative; liver; human; toxicogenomics.


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