2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a highly toxic environmental contaminant posing major human health concerns. TCDD is toxic to the immune system and causes marked atrophy of the thymus and bone marrow and suppresses the antigen-specific functions of T and B cells in the periphery. The exact mechanism by which TCDD mediates its immunotoxic effects is not clear. Recent studies from the investigator's laboratory demonstrated that TCDD triggers apoptosis in thymocytes in vivo and furthermore, mice deficient/defective in Fas (CD95) or Fas ligand (FasL), important molecules involved in apoptosis, were more resistant to TCDD- mediated thymic atrophy and peripheral T cell dysfunction. Furthermore, TCDD exposed antigen-activated but not naive T cells underwent increased apoptosis in vitro. Based on these studies, the investigators wish to test the hypothesis that TCDD alters the expression of genes involved in apoptosis, thereby favoring programmed cell death and that this may constitute the key mechanism by which TCDD mediates immunotoxicity. In the current study, the investigators will test whether TCDD upregulates Fas and/or FasL gene expression in lymphoid and non-lymphoid organs. Secondly, the role of proteasomes, caspases, p53 and bcl-2 genes in TCDD-induced apoptosis will be studied. They will also test whether caspase inhibitors can prevent TCDD-induced toxicity. Thirdly, we will test the hypothesis that antigen-activated T cells are more susceptible to TCDD-mediated toxicity because they upregulate Fas expression and undergo apoptosis following interaction with FasL induced by TCDD in an autocrine or paracrine fashion. Lastly, perinatal exposure to TCDD has been shown to be the most sensitive indicator of dioxin-induced immunotoxicity. Using mice deficient/defective in Fas (lpr) and FasL (gld), the investigators will test the role of Fas and FasL in perinatal toxicity. Together, these studies should provide novel information on the mechanism by which TCDD induces apoptosis and immunotoxicity following perinatal and postnatal exposure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES009098-04
Application #
6405915
Study Section
Special Emphasis Panel (ZRG1-ALTX-4 (01))
Program Officer
Mastin, Patrick
Project Start
1999-05-01
Project End
2003-04-30
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
4
Fiscal Year
2001
Total Cost
$242,796
Indirect Cost
Name
Virginia Commonwealth University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
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Singh, Narendra P; Singh, Ugra S; Nagarkatti, Mitzi et al. (2011) Resveratrol (3,5,4'-trihydroxystilbene) protects pregnant mother and fetus from the immunotoxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Mol Nutr Food Res 55:209-19
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