APPLICATION OF GENE MANIPULATION TECHNOLOGY TO GENERATION OF MODEL ANIMALS FOR ENVIRONMENTAL ASSESSMENT

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1. Generation of AhR-overexpressing mouse. Mice carrying AhR cDNA driven by keratin14 promoter displayed inflammation and hyperkeratinization of the skin. These mice are now under examination whether they are more vulnerable to chemical carcinogens.2. Generation of human AhR (hAhR)-knock-in mice. The mouse AhR gene was replaced with human AhR cDNA by homologous recombination in ES cells. By injecting the ES cells into blastcysts, we generated hAhR-knock-in mouse expressing human AhR molecule instead of mouse AhR. When exposed to 3-methylcholanthrene, hAhR-knock-in mice displayed the comparable induction of the phase I enzyme genes with the control animals. When TCDD was used, hAhR-knock in mice showed much weaker response than the control mice. We suspect that the response observed in hAhR-knock in mouse mimics that of the humans. This mouse will serve as an animal model for the assessment of the toxicity of environmental chemicals.3. Analysis on the responses to environmental chemicals of Nrf2-deficient mice. Nrf2-deficient mice were challenged by several environmental chemicals to examine the significance of Nrf2 contribution in vivo. Nrf2-deficient mice were more sensitive to acetaminophen hepatotoxicity due to the increased level of active metabolic intermediates. Increased levels of DNA adducts was observed in Nrf2-null mutant mice after the exposure to diesel exhaust. Oral administration of benzo[a]pyrene caused severer gastric cancer in Nrf2-deficient mice than the control animals. These results indicate that Nrt2 is a key regulator of the protective responses against the toxicity of environmental chemicals.