1. Sponsor Organization: NIH/NIEHS

2. Project Title: 07216-03 CONSEQUENCS OF THYMIC ATROPHY INDUCED BY TCDD AND E2

3. Project Focus:

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

4. Description:

Both estrogens and dioxins have potent immunomodulatory properties. They both induce immunosuppression and thymic atrophy. Estrogens have also been clearly associated with certain autoimmune diseases in humans and rodents, while dioxin exposure has been shown to induce certain markers of hyperimmunity. Both 17beta-estradiol valerate (E2), and TCDD not only cause thymic atrophy, but also, unlike corticosteroid or radiation, induced increased numbers of liver lymphocytes, many expressing T-cell receptors normally deleted in the periphery of selected mouse strains. This project aims to determine how activation of these receptors can lead to thymic atrophy and the appearance of T-cells that could promote autoimmune disease. Specifically, studies will be carried out on the mechanism of thymic atrophy induction by these agents by determining the cell types expressing these receptors in the thymus and thymic stem cell compartments. At time points determined to be critical to atrophy induction or recovery, the activation status of the receptors will be determined by their ability to bind to their specific DNA response elements, in the cell types believed to be candidates for proximal targets. The dosimetry at which specific anti-estrogens (such as ICI 164,384), and partial TCDD antagonists (e.g., a-napthoflavone) can prevent atrophy induction by these agents will be determined. The activity of the receptors during normal physiological aging, and whether the inhibitors can delay or reverse normal age related atrophy will also be determined. The increased populations of liver lymphocytes induced by these two agents will be phenotyped. Whether the inhibitors described above, as doses that can prevent thymic atrophy, can prevent the appearance of these liver lymphocytes will be examined. Studies will be extended on the potential for autoimmune disease production or acceleration by both E2 and TCDD in an adult autoimmune model (SWR x NZB, SLE model). A perinatal exposure model in B6 x AJ mice which develop organ specific autoimmune disease after 3 days old neonatal thymectomy will also be examined.

5. References:

6. Inventory Category:

• Primary: Models
• Secondary:

7. Inventory Subcategory:

• Primary: Basic Research
• Secondary:

8. Keywords for Experimental System/Species:

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

9. Keywords for Experimental Endpoints:

• Health Effect:
  • Immunology
• Hormonal Measures:
• Level Of Study:
• Chemistry Metabolism:
• Life Stage:
• Risk Assessment:

10. Chemical Agents:

• Dioxins
• Alpha-Napthoflavone

11. Performing Institution:

• HEALTH SCIEE CENTER AT SYRACUSE

12. Contact:

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