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TRIBUTYLTIN AND DEXAMETHASONE INDUCE APOPTOSIS IN RAT THYMOCYTES BY MUTUALLY ANTAGONISTIC MECHANISMS
Citation:
Zucker, R., K. Elstein, D. Thomas, AND J. Rogers. TRIBUTYLTIN AND DEXAMETHASONE INDUCE APOPTOSIS IN RAT THYMOCYTES BY MUTUALLY ANTAGONISTIC MECHANISMS. U.S. Environmental Protection Agency, Washington, D.C., EPA/600/J-94/526 (NTIS PB95148888).
Description:
We observed that rat thymocyte cultures exposed to 1.O'- 2. 5 uM tri-n-butyltin methoxide (TBT) exhibiteda rapid time- and concentration-dependent induction of apoptosis, with > 85% of cells exhibiting reduced DNAcontent within 1 hr after ensure to 2.0 - 2,5 uM TBT. Moreover, with continuous exposure to TBT, the DNAcontent of apoptotic nuclei increased with time, suggesting a reduced ability of DNA fragments to leave the nucleus of TBT-exposed cells following detergent-mediated cytolysis, possibly as a consequence of membrane/cytoplasm fixation. n contrast, exposure to 1.0 uM dexamethasons phosphate (DEX) resulted in a gradual time-dependent increase to -45% induction of apoptosis by 6 hr (versus -15% spontaneous induction in controls). owever, simultaneous exposure to TBT and DEX resulted in a decreased response: TBT concentrations between 0.1 and 0.5 uM (which alone did not induce apoptosis) reduced the ability of DEC to induce apoptosis; at TBT concentrations > 1.0 AAM, simultaneous exposure to DEX substantially decreased the extent of both TBT-induced cytotoxicity and apoptosis. urthermore, while treatment with cycloheximide (CHX), a protein synthesis inhibitor, or H-7, a protein kinase C (PKC) inhibitor, completely blocked DEX-induced apoptosis, neither significantly reduced induction of apoptosis by TBT. oth the toxicant-specific differences in the timing and extent of apoptotic induction and the dissimilar responses to CHX and H-7 suggest that TBT and DEX induce apoptosis through different mechanisms. oreover, the ability of each agent to retard the action of the other suggests that these mechanisms are mutually antagonistic.