1. Sponsor Organization: NIH/NIEHS

2. Project Title: 02515-16 MOLECULAR TOXICITY OF TCDD

3. Project Focus:

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

4. Description:

The studies proposed here will focus on those factors that control the functional activity of the Ah receptor (AhR). Certain compounds inhibit theformation of an active AhR. Further studies will characterize the mechanisms by which these and certain other antagonists act, define the chemical characteristics determining antagonist activity, examine the structure-activity relationships for these actions, and design and synthesize chemicals that may be more potent antagonists. Previous data suggests that for the AhR to bind to DNA, it must interact with an additional protein. This interaction generates a heterodimer complex that specifically recognizes DNA elements responsible for enhancing the expression of certain genes. However, additional recent data indicate that more complex relationships exist. Using a purified AhR DNA-binding complex and a protein biocheMical techniques, experiments will examine the nature of the DNA-binding AhR forms in different species and tissues, characterize their interactions with DNA, and determine if the AhR interacts with other proteins in a ligand-dependent manner. Indirect evidence suggests changes in the phosphorylation state of the AhR may determine its activity. Utilizing responsive cells in culture and methodology developed to characterize different AhR forms, studies will determine if phosphorylation of the AhR and/or associated proteins occurs during transformation to a DNA-binding state, at what step this occurs, and if this phosphorylation regulates AhR activity. Initial data indicates that certain cytokines regulate the activity and/or expression of the AhR in isolated cells. Experiments are designed to determine the cytokine specificity of these effects, the mechanisms by which this regulation occurs, and the tissue and cell specificity of thesemechanisms.

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
• Chemistry Metabolism:
  • Toxicokinetics
  • Tissue Residue
  • Xenobiotic Metabolism
• Life Stage:
• Risk Assessment:

10. Chemical Agents:

• Dioxins

11. Performing Institution:

• UNIVERSITY OF ROCHESTER

12. Contact:

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