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Constitutive androstane receptor (CAR) mediates dieldrin-induced liver tumorigenesis in mouse
Zemin Wang1, Qiangen Wu1, Xilin Li1
1Laboratory of Investigative Toxicology and Pathology, Department of Environmental Health, Indiana University School of Public Health, 1025 E 7th St, Bloomington, IN, 47405, USA.
Abstract:
Dieldrin has been shown to induce liver tumors selectively in mice. Although the exact mechanism is not fully understood, previous studies from our laboratory and others have shown that dieldrin induced liver tumors in mice through a non-genotoxic mechanism acting on tumor promotion stage. Two studies were performed to examine the role of nuclear receptor activation as a possible mode of action (MOA) for dieldrin-induced mouse liver tumors. In the initial study, male C57BL/6 mice (6- to 8-week old) were treated with dieldrin in diet (10 ppm) for 7, 14, and 28 days. Phenobarbital (PB), beta-naphthoflavone (BNF) and Di (2-ethylhexyl) phthalate (DEHP) were included as positive controls in this study for evaluating the involvement of CAR (constitutive androstane receptor), AhR (aryl hydrocarbon receptor) or PPARα (peroxisome proliferator activated receptor alpha) in the MOA of dieldrin hepatocarcinogenesis. A significant increase in hepatocyte DNA synthesis (BrdU incorporation) was seen in treated mice compared with the untreated controls. Analysis of the expression of the nuclear receptor responsive genes revealed that dieldrin induced a significant increase in the expression of genes specific to CAR activation (Cyp2b10, up to 400- to 2700-fold) and PXR activation (Cyp3a11, up to 5- to 11-fold) over untreated controls. The AhR target genes Cyp1a1 and Cyp1a2 were also slightly induced (2.0- to 3.7-fold and 1.7- to 2.8-fold, respectively). PPARα activation was not seen in the liver following dieldrin treatment. In addition, consistent with previous studies in our lab, treatment with dieldrin produced significant elevation in the hepatic oxidative stress. In a subsequent study using CAR, PXR, and CAR/PXR knockout mice, we confirmed that the dieldrin-induced liver effects in mouse were only mediated by the activation of CAR receptor. Based on these findings, we propose that dieldrin induced liver tumors in mice through a nuclear receptor CAR-mediated mode of action. The previously observed oxidative stress/damage may be an associated or modifying factor in the process of dieldrin-induced liver tumor formation subsequent to the CAR activation.
Insights
Dieldrin induces mouse liver tumors via a non-genotoxic pathway, primarily through the activation of the constitutive androstane receptor (CAR). This nuclear receptor activation is key to the mode of action for dieldrin-induced hepatocarcinogenesis.
Area of Science:
- Toxicology
- Hepatocarcinogenesis
- Nuclear Receptor Signaling
Background:
- Dieldrin is a known liver tumor inducer in mice, acting through a non-genotoxic mechanism.
- The precise mode of action (MOA) for dieldrin-induced hepatocarcinogenesis remains incompletely understood.
- Nuclear receptor activation is a potential pathway for dieldrin's tumor-promoting effects.
Purpose of the Study:
- To investigate the role of nuclear receptor activation in dieldrin-induced mouse liver tumors.
- To elucidate the specific nuclear receptors involved in dieldrin's mode of action.
- To confirm the involvement of CAR, AhR, and PPARα in dieldrin's hepatocarcinogenic effects.
Main Methods:
- Mice were treated with dieldrin, and liver tissues were analyzed for DNA synthesis and gene expression.
- Positive controls (PB, BNF, DEHP) were used to assess CAR, AhR, and PPARα activation.
- CAR, PXR, and CAR/PXR knockout mice were utilized to confirm the mediating receptor.
Main Results:
- Dieldrin significantly increased hepatocyte DNA synthesis and induced genes specific to CAR and PXR activation.
- CAR activation was confirmed as the primary mediator of dieldrin's effects in knockout mouse studies.
- PPARα activation was not observed; AhR target genes showed minor induction.
Conclusions:
- Dieldrin induces liver tumors in mice via a mode of action mediated by constitutive androstane receptor (CAR) activation.
- CAR activation is the principal pathway for dieldrin-induced hepatocarcinogenesis.
- Hepatic oxidative stress may be a secondary or modifying factor in this process.
