1. Sponsor Organization: NIH/NCI

2. Project Title: 53887-05 MECHANISM OF DIOXIN ACTION

3. Project Focus:

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

4. Description:

The long-term goal of this project is to understand the molecular mechanism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) action. TCDD is a widespread, persistent environmental contaminant that, in animals, produces morphological, immunologic, biochemical, teratogenic, and neoplastic effects. The risk that TCDD and related halogenated aromatic hydrocarbons pose to humans is unknown, with potential reproductive and carcinogenic effects being of most concern. The induction of CYP1A1 gene transcription in mouse hepatoma cells is a useful response for analyzing the mechanism of dioxin action. Increased gene expression requires the binding of TCDD to an intracellular protein (the Ah receptor), followed by the interaction of the liganded receptor with a specific DNA recognition sequence, which is present in multiple copies within a transcriptional enhancer located upstream of the CYP1A1I gene. The studies described in this application are designed to analyze the mechanism of dioxin action in greater depth. The experiments involve the use of molecular genetic techniques to analyze (a) the structure and function of the dioxin-responsive enhancer and CYP1A1I transcriptional promoter, (b) the TCDD inducible, Ah receptor-dependent protein-DNA interactions at the enhancer/promoter region within the intact cell, (c) the chromatin structure of the CYP1A1 gene and the changes that occur in response to TCDD, (d) the mechanism by which inhibition of protein synthesis superinduces CYP1A1 transcription, (e) the structure and function of the Ah receptor, and (f) TCDD-inducible, Ah receptor-dependent transcription in vitro.

5. References:

6. Inventory Category:

• Primary: Models
• Secondary:

7. Inventory Subcategory:

• Primary: Basic Research
• Secondary:

8. Keywords for Experimental System/Species:

• Species:
• Study Type:
  • In Vitro
  • Laboratory Study
• Fate and Transport:

9. Keywords for Experimental Endpoints:

• Health Effect:
• Hormonal Measures:
  • Ah Receptor
• Level Of Study:
  • Gene Expression
  • Molecular
• Chemistry Metabolism:
• Life Stage:
• Risk Assessment:

10. Chemical Agents:

• Dioxins

11. Performing Institution:

• STANFORD UNIVERSITY

12. Contact:

Edit (password needed)