Organotin-induced apoptosis as observed in vitro is not relevant for induction of thymus atrophy at antiproliferative doses.
The organotin compounds di-n-butyltin dichloride (DBTC) and tri-n-butyltin chloride (TBTC) selectively cause thymus atrophy. Previously, DBTC and TBTC were shown to inhibit proliferation of immature thymocytes, but other studies demonstrated that TBTC but not DBTC increased apoptosis in vitro and also in vivo. In this study, we examined whether apoptosis is increased in vitro by DBTC and TBTC at various concentrations and periods of incubation and whether apoptosis is involved in the induction of thymus atrophy at selective antiproliferative doses. In vitro, DBTC or TBTC at a concentration of 3 microM significantly increased DNA fragmentation in freshly isolated rat thymocytes after preincubation for 10 min followed by a 22-hr culture period. After continuous exposure for 22 hr, apoptosis was observed to be optimum at 1 microM TBTC and 0.3 microM DBTC and lower or absent at higher concentrations. Apparently, apoptosis induced by organotins in vitro depends on both duration and concentration of exposure. Selective antiproliferative doses of DBTC nor TBTC increased apoptosis on day 1 or 2 after single oral exposure. In contrast, the corticosteroid dexamethasone caused a depletion of both small and large thymocytes and a marked increase of apoptosis on both days 1 and 2 after dosing. Thus, although apoptosis is involved in the in vitro cytotoxic effects of both organotin compounds, it seems not involved in thymus atrophy at a dose that selectively inhibits immature thymocyte proliferation.
Gennari
A
A
Research Institute of Toxicology, Utrecht University, The Netherlands.
Potters
M
M
Seinen
W
W
Pieters
R
R
D000818:Animals; D017209:Apoptosis; D001284:Atrophy; D002452:Cell Count; D002478:Cells, Cultured; D053938:DNA Fragmentation; D003907:Dexamethasone; D004305:Dose-Response Relationship, Drug; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000633:toxicity*; D008297:Male; D009947:Organotin Compounds / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000187:drug effects / Q000502:physiology; D013950:Thymus Gland / Q000187:drug effects* / Q000473:pathology; D014220:Trialkyltin Compounds / Q000633:toxicity*
D007166:Immunosuppressive Agents; D009947:Organotin Compounds; D014220:Trialkyltin Compounds; C011559:tributyltin; D003907:Dexamethasone; C020735:dibutyldichlorotin