Thymocyte apoptosis as a mechanism for tributyltin-induced thymic atrophy in vivo.
Tributyltin (TBT) immunotoxicity in rodent species is primarily characterised by T-lymphocyte deficiency resulting from a depletion of cortical thymocytes. In this study, bis(tri-n-butyltin) oxide (TBTO) was administered to male rats as a single oral dose of 30 or 60 mg/kg, and assessments were made of thymic cytopathology and the integrity of cellular DNA. TBTO treatment did not cause severe toxicity or overt clinical signs; however, by 48 h post-dosing relative thymus weights at 30 and 60 mg/kg were reduced to 66 and 43%, respectively, of control values. Increased DNA fragmentation was evident in thymic cell isolates (principally thymocytes) obtained from treated animals during the period of thymic involution. When DNA purified from these cells was visualised by agarose gel electrophoresis a multimeric internucleosomal fragmentation pattern, indicative of supra-physiological levels of apoptosis, was detected. Although unassociated apoptotic or necrotic thymocytes were essentially absent in cell preparations from TBTO-treated rats, significantly increased numbers of mononuclear phagocytic cells were observed. Many of these cells contained either apoptotic thymocytes, with nuclear morphologies exhibiting chromatin condensation, or cell remnants which were characterised as apoptotic bodies. Dibutyltin, which is a major metabolic dealkylation product of tributyltin, failed to significantly stimulate apoptosis when added to isolated thymocytes in vitro. Collectively, these findings suggest that activation of apoptosis contributes to TBT-induced thymocyte depletion in vivo, and indicate that it is unlikely that the metabolite dibutyltin is responsible for this effect.
Toxicology Department, School of Pharmacy, University of London, UK.
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M
Raffray
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GM
Cohen
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001284:Atrophy; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013601:T-Lymphocytes / Q000187:drug effects* / Q000502:physiology; D013950:Thymus Gland / Q000187:drug effects* / Q000473:pathology; D014220:Trialkyltin Compounds / Q000633:toxicity*
D014220:Trialkyltin Compounds; C005961:bis(tri-n-butyltin)oxide; D004247:DNA