Type of Document Dissertation Author Kamath, Arati B URN etd-102298-214410 Title Apoptosis as a Mechanism of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-Induced Immunotoxicity Degree PhD Department Biomedical Sciences and Pathobiology Advisory Committee
Advisor Name Title Nagarkatti, Mitzi Committee Chair Blodgett, Dennis J. Committee Member Holladay, Steven D. Committee Member Lee, John C. Committee Member Nagarkatti, Prakash S. Committee Member Keywords
- 8-Tetrachlorodibenzo-p-dioxin (TCDD)
Date of Defense 1998-11-10 Availability restricted AbstractAPOPTOSIS AS A MECHANISM OF 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD)-INDUCED IMMUNOTOXICITY
Arati B. Kamath
Mitzi Nagarkatti, Chairperson
Department of Biomedical Sciences and Pathobiology
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly toxic environmental pollutant and is well known for its immunotoxic effects, particularly on the thymus. The exact mechanism by which TCDD induces thymic atrophy is not known. In the current study, we investigated whether TCDD triggers apoptosis in the thymocytes and whether Fas and Fas ligand play a role in TCDD-mediated immunotoxicity. Administration of a single dose of TCDD at 0.1, 1, 5 or 50 mg/kg body weight intraperitoneally into C57BL/6 +/+ mice caused a significant dose-dependent decrease in the thymic cellularity; whereas, in the C57BL/6 lpr/lpr (lpr) (Fas-deficient) and C57BL/6 gld/gld (gld) (Fas ligand-defective) mice, TCDD failed to induce a decrease in thymic cellularity at doses of 0.1-5 mg/kg body weight. In the lpr and gld mice, thymic atrophy was seen only at 50 mg/kg body weight of TCDD. Significant apoptosis was detected within 8-12 hours after injection in the wild type mice, whereas, in the lpr and gld mice apoptosis could not be detected. Upon culturing the thymocytes from TCDD-treated mice for 24 hours in vitro, the wild-type cells showed increased apoptosis when compared to the control; whereas, similar cells from lpr and gld mice did not show apoptosis. Furthermore, TCDD-treatment caused significant alterations in the expression of surface molecules on the thymocytes in the wild-type mice and minimal changes in the lpr or gld mice. Sera from TCDD-treated wild-type mice also exhibited increased levels of soluble Fas ligand. Also, TCDD-induced apoptosis was inhibited both in vitro and in vivo by caspase inhibitors and other inhibitors of apoptosis. Together, the current study demonstrates that TCDD-induced apoptosis plays an important role in thymic atrophy caused by TCDD in vivo. Furthermore, phenotypic changes in the density of thymocyte surface molecules may serve as a useful biomarker for chemical toxicity involving apoptosis. The current study also demonstrates that Fas-Fas ligand interactions play an important role in the induction of apoptosis and immunotoxicity by TCDD.
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