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Mechanistic Investigation of Toxaphene Induced Mouse Liver Tumors
Zemin Wang1, Barbara H Neal2, James C Lamb2
1*Department of Environmental Health, Indiana University Bloomington, Indiana 47405; and.
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.
Insights
Toxaphene causes liver tumors in mice through a non-genotoxic pathway. This involves the constitutive androstane receptor (CAR), leading to increased cell proliferation and tumor formation.
Area of Science:
- Toxicology
- Hepatocarcinogenesis
- Molecular Biology
Background:
- Chronic toxaphene exposure is linked to increased liver tumors in B6C3F1 mice.
- Understanding the precise mechanism of toxaphene-induced hepatocarcinogenesis is crucial for risk assessment.
Purpose of the Study:
- To investigate the mode of action underlying toxaphene-induced mouse liver tumors.
- To elucidate the role of specific molecular pathways, including CAR and AhR, in toxaphene's effects.
Main Methods:
- A dose-range finding study followed by a mechanistic study in male mice exposed to varying dietary concentrations of toxaphene (0-320 ppm) for up to 28 days.
- Gene expression analysis of CAR, AhR, and peroxisome proliferator-activated receptor alpha (PPARα) target genes.
- Assessment of lipid peroxidation and hepatic DNA synthesis.
- Confirmation using CAR knockout mice to validate the role of CAR.
Main Results:
- Toxaphene significantly upregulated CAR target genes (Cyp2b10, Cyp3a11) at 32 and 320 ppm.
- A slight increase in AhR target genes was observed at the highest dose (320 ppm).
- No significant PPARα activation was detected; however, lipid peroxidation and increased hepatic DNA synthesis occurred at 320 ppm.
- CAR knockout mice showed no induction of CAR-responsive genes upon toxaphene treatment, confirming CAR's essential role.
Conclusions:
- Toxaphene-induced liver tumors in mice operate via a non-genotoxic mechanism.
- The primary pathway involves constitutive androstane receptor (CAR) activation, leading to increased liver cell proliferation.
- This CAR-mediated process promotes the expansion of preneoplastic lesions, ultimately resulting in adenoma formation.
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