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Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor
P Fernandez-Salguero1, T Pineau, D M Hilbert
1Laboratory of Molecular Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract:
The aryl hydrocarbon (Ah) receptor (AHR) mediates many carcinogenic and teratogenic effects of environmentally toxic chemicals such as dioxin. An AHR-deficient (Ahr-/-) mouse line was constructed by homologous recombination in embryonic stem cells. Almost half of the mice died shortly after birth, whereas survivors reached maturity and were fertile. The Ahr-/- mice showed decreased accumulation of lymphocytes in the spleen and lymph nodes, but not in the thymus. The livers of Ahr-/- mice were reduced in size by 50 percent and showed bile duct fibrosis Ahr-/- mice were also nonresponsive with regard to dioxin-mediated induction of genes encoding enzymes that catalyze the metabolism of foreign compounds. Thus, the AHR plays an important role in the development of the liver and the immune system.
Insights
Mice lacking the aryl hydrocarbon receptor (AHR) showed developmental issues, including liver fibrosis and immune system alterations. These AHR-deficient mice were also unresponsive to dioxin, highlighting the receptor's crucial role.
Area of Science:
- Toxicology
- Immunology
- Developmental Biology
Background:
- The aryl hydrocarbon receptor (AHR) mediates toxic effects of environmental pollutants like dioxin.
- AHR signaling is implicated in various physiological and pathological processes.
Purpose of the Study:
- To investigate the role of AHR in mammalian development and response to toxins.
- To characterize the phenotype of AHR-deficient mice.
Main Methods:
- Generation of AHR-deficient (Ahr-/-) mice using homologous recombination in embryonic stem cells.
- Phenotypic analysis of Ahr-/- mice, including survival, fertility, immune cell distribution, liver morphology, and gene expression.
Main Results:
- Ahr-/- mice exhibited reduced survival rates shortly after birth, with survivors being fertile.
- Significant decrease in lymphocyte accumulation in spleen and lymph nodes, but not thymus.
- Ahr-/- mice displayed 50% smaller livers with bile duct fibrosis and non-responsiveness to dioxin-induced gene expression.
Conclusions:
- AHR is essential for normal liver development and immune system homeostasis.
- AHR plays a critical role in mediating the biological effects of dioxin and related compounds.