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. The kinetics of atrophy induction and reductions in lymphocyte stem cell targets associated with this atrophy are remarkably similar between these agents at pharmacologically or environmentally relevant doses. Unlike corticosteroid, single doses of 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) or 17beta-estradiol valerate (E2) in mice cause an atrophy that takes several days to manifest itself but persists for several weeks, and appears to be related to nonthymic stem cell reductions. Both of these agents mediate their affects through their specific receptors, the aryl hydrocarbon receptor (AhR) or estrogen receptor (ER) which are transcription factors involved in modulation of gene expression in most cell types. Both 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. The long range objectives are to determine how activation of these receptors can lead to thymic atrophy and the appearance of T-cells that could promote autoimmune disease. Will inhibitors of these receptors (partial or complete antagonists) delay or reverse normal age related thymic atrophy? Will such inhibitors prevent or delay 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 determine 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, i 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 phenotype, including determining, by use of the stem cell markers for the recombination activating genes (RAG-1 and 2) and terminal transferase (TdT) whether they arise de novo in the liver from stem cells, or whether they are migrants. 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.
| Feng, F; Silvin, C J; Fiore, N C et al. (2012) 17ýý-Estradiol (E-2) administration to male (NZB ýý SWR)Fýýý mice results in increased Id(LN)Fýýý-reactive memory T-lymphocytes and accelerated glomerulonephritis. Lupus 21:288-301 |
