1. Sponsor Organization: NIH/NIEHS

2. Project Title: 06811-03 AH RECEPTOR--TRANSGENIC MICE FOR RISK ASSESSMENT

3. Project Focus:

• Project Primary Focus: Human Health Effects
• Project Secondary Focus:

4. Description:

Toxicity and cancer caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin) and benzo[a]pyrene (BaP) appear to be mediated by way of the aromatic hydrocarbon receptor (AHR). Tthere exist inbred mouse strains having genes for high- and low-affinity AHRs. Mice with the high-affinity-AHR phenotype metabolize numerous environmental chemicals, to form reactive intermediates, 15-20 times faster than mice with the low-affinity-AHR phenotype. DNA adduct formation, mutagenesis, oncogene activation, and certain types of cancer occur more frequently in mice with the fast-metabolism phenotype. Approximately one-tenth of the human population has a fast-metabolism phenotype, and in this group the risk of certain types of cancer among smokers appears to be several-fold greater than that in the slow-metabolism group. The laboratory animal data for high vs low-affinity-AHR differences in toxicity and cancer are very convincing, whereas the human AHR-related differences in toxicity and cancer remain equivocal, largely due to the ethical difficulties in carrying out definitive experiments in humans. Here we propose to: (1) determine the nucleotide difference(s) in the human AHR gene responsible for human high and low-affinity-AHR phenotype among members in one 3- generation family; (2) make heterozygous and homozygous disruptions of the Ahr gene in murine embryonic stem (ES) cells; (3) replace the murine disrupted gene with the human low-affinity (AHR) gene in one cell line, and in another cell line with the human high-affinity (AHRA) gene; and (4) generate the two human transgenic mouse lines. These animals will be helpful in examining the role of the human high vs low-affinity AHR in toxicity and cancer-- on a common mouse background where every other gene is identical.

5. References:

6. Inventory Category:

• Primary: Models
• Secondary:

7. Inventory Subcategory:

• Primary: Basic Research
• Secondary:

8. Keywords for Experimental System/Species:

• Species:
  • Mammal
  • Human
  • Mouse
• Study Type:
  • Laboratory Study
• Fate and Transport:

9. Keywords for Experimental Endpoints:

• Health Effect:
• Hormonal Measures:
  • Transgenic Model, Ah Receptor
• Level Of Study:
• Chemistry Metabolism:
• Life Stage:
• Risk Assessment:

10. Chemical Agents:

• Dioxins

11. Performing Institution:

• UNIVERSITY OF CINCINNATI

12. Contact:

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