Mechanistic Investigation of Toxaphene Induced Mouse Liver Tumors.

Abstract

Chronic exposure to toxaphene resulted in an increase in liver tumors in B6C3F1 mice. This study was performed to investigate the mode of action of toxaphene induced mouse liver tumors. Following an initial 14 day dietary dose range-finding study in male mice, a mechanistic study (0, 3, 32, and 320 ppm toxaphene in diet for 7, 14, and 28 days of treatment) was performed to examine the potential mechanisms of toxaphene induced mouse liver tumors. Toxaphene induced a significant increase in expression of constitutive androstane receptor (CAR) target genes (Cyp2b10, Cyp3a11) at 32 and 320 ppm toxaphene. aryl hydrocarbon receptor (AhR) target genes (Cyp1a1 and Cyp1a2) were slightly increased in expression at the highest toxaphene dose (320 ppm). No increase in peroxisome proliferator-activated receptor alpha activity or related genes was seen following toxaphene treatment. Lipid peroxidation was seen following treatment with 320 ppm toxaphene. These changes correlated with increases in hepatic DNA synthesis. To confirm the role of CAR in this mode of action, CAR knockout mice (CAR(-/-)) treated with toxaphene confirmed that the induction of CAR responsive genes seen in wild-type mice was abolished following treatment with toxaphene for 14 days. These findings, taken together with previously reported studies, support the mode of action of toxaphene induced mouse liver tumors is through a nongenotoxic mechanism involving primarily a CAR-mediated processes that results in an increase in cell proliferation in the liver, promotes the clonal expansion of preneoplastic lesions leading to adenoma formation.

• Authors: Zemin Wang, Barbara H Neal, James C Lamb, James E Klaunig
• Journal: Toxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 147 Issue 2 Pg. 549-61 (Oct 2015) ISSN: 1096-0929 [Electronic] United States
• PMID: 26187448 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: [email protected].

Chemical References

• Carcinogens
• Constitutive Androstane Receptor
• Receptors, Aryl Hydrocarbon
• Receptors, Cytoplasmic and Nuclear
• Toxaphene

Topics

• Animals
• Carcinogens (administration & dosage, toxicity)
• Constitutive Androstane Receptor
• Dose-Response Relationship, Drug
• Gene Expression Regulation (drug effects)
• Lipid Peroxidation (drug effects)
• Liver (drug effects)
• Liver Neoplasms, Experimental (chemically induced)
• Male
• Mice
• Mice, Inbred Strains
• Receptors, Aryl Hydrocarbon (drug effects, metabolism)
• Receptors, Cytoplasmic and Nuclear (drug effects, metabolism)
• Toxaphene (administration & dosage, toxicity)