Studies Using the AHR-Null Mice
Abstract
The aryl hydrocarbon receptor (AHR) is believed to mediate the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polychlorinated biphenyls, and polycyclic aromatic hydrocarbons. AHR is a member of the Per, ARNT, Sim/basic-helix-loop-helix superfamily of ligand-activated transcription factors that also harbors the transcription factors involved in the hypoxia response, development of the central nervous system, and day-night adaptations. To investigate the role of AHR in chemical toxicity and carcinogenesis and to determine any possible function in mammalian development and physiological homeostasis, AHR-null mice were developed. The AHR-null mice were resistant to the acute toxicity of TCDD and had an altered teratogenic response to this compound. These mice were found to have a number of abnormal phenotypes, thus confirming that AHR plays an important developmental and physiological role. Among the most consistent phenotypes was an altered liver pathology that was associated with accelerated rates of apoptosis. Evidence suggests that this may be related to an abnormal accumulation of levels of hepatic retinoic acid that cause an activation of transforming growth factor β, resulting in stimulation of apoptosis. AHR may directly or indirectly control levels of a cytochrome P450 that is responsible for catabolizing retinoic acid.
Footnotes
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Send reprint requests to: Dr. Frank J. Gonzalez, Building 37, Room 3E-24, National Cancer Institute, Bethesda, MD 20892. e-mail: fjgonz{at}helix.nih.gov
- Abbreviations used are::
- TCDD
- 2,3,7,8-tetrachlorodibenzo-p-dioxin
- AHR
- aryl hydrocarbon receptor
- ARNT
- AH receptor nuclear translocator
- bHLH
- basic-helix-loop-helix
- PAS
- Per AHRSim
- HSP90
- heat shock protein 90
- Ig
- immunoglobulin
- TGF
- transforming growth factor
- RA
- retinoic acid
- P450
- cytochrome P450
- EGF
- epidermal growth factor
- TGase-2
- type II transglutaminase
- The American Society for Pharmacology and Experimental Therapeutics
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