ToxSci Advance Access published online on March 6, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp050
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Phenobarbital (PB) Elicits Unique, Early Changes in the Expression of Hepatic Genes That Affect Critical Pathways in Tumor-Prone B6C3F1 Mice
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* Department of Biochemistry and Molecular Biology
Gene Expression in Development and Disease Initiative
Department of Pharmacology and Toxicology, and Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824
1 Corresponding Author: Jay I. Goodman, Michigan State University, B-440 Life Sciences Bldg., East Lansing, MI 48824, Email: goodman3{at}msu.edu, Tel: 517-353-9346, Fax: 517-353-8915
Received January 12, 2009; revision received February 18, 2009; accepted March 3, 2009
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Abstract |
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At 2 and 4 weeks following treatment with Phenobarbital (PB), the classical nongenotoxic rodent liver carcinogen, we elucidated unique gene expression changes (both induction and repression) in liver tumor-susceptible B6C3F1 mice, as compared to the relatively resistant C57BL/6. Based on their cancer-related roles, we believe that altered expression of at least some of these genes might underlie PB-induced liver tumorigenesis. Putative constitutive active/androstane (CAR) response elements (CAREs), a subset of PB response elements, were present within multiple genes whose expression was uniquely altered in the B6C3F1 mice, suggesting a role for CAR in their regulation. Additionally, 3 DNA methyltransferase genes (Dnmt1, Dnmt3a, and Dnmt3b) were repressed uniquely in the tumor-prone B6C3F1 mice, and all possess putative CAREs, providing a potential direct link between PB and expression of key genes that regulate DNA methylation status.
Previously, we demonstrated that PB elicited unique regions of altered methylation (RAMs) in B6C3F1 mice, as compared to the relatively resistant C57BL/6, at 2 and 4 weeks (Bachman et al., 2006), and annotation of the regions harboring these changes revealed 51 genes (Phillips and Goodman, 2008a). This is extended by the current study, which employed RNA isolated from the same liver tissue used in the earlier investigations. Genes elucidated from both the methylation and expression analyses are involved in identical processes/pathways (e.g., cell cycle, apoptosis, angiogenesis, epithelial-mesenchymal cell transition (EMT), invasion/metastasis, and mitogen-activated protein kinase (MAPK), transforming growth factor-beta (TGF-β), and Wingless (Wnt) signaling). Therefore, these changes might represent very early events that directly contribute to PB-induced tumorigenesis. It is instructive to consider the possibility that, in a hypothesis-driven fashion, these genes are initial candidates that could be utilized to develop a biomarker "fingerprint" of early exposure to PB and PB-like compounds.
Key Words: B6C3F1; CAR; gene expression; mouse liver; phenobarbital; tumors.
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  J. M. Phillips, L. D. Burgoon, and J. I. Goodman The Constitutive Active/Androstane Receptor Facilitates Unique Phenobarbital-Induced Expression Changes of Genes Involved in Key Pathways in Precancerous Liver and Liver Tumors Toxicol. Sci., August 1, 2009; 110(2): 319 - 333. [Abstract] [Full Text] [PDF]
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