Organotin-induced apoptosis occurs in small CD4(+)CD8(+) thymocytes and is accompanied by an increase in RNA synthesis.
The organotin compounds di-n-butyltin dichloride (DBTC) and tri-n-butyltin chloride (TBTC) induce thymus atrophy in rats. At low doses they inhibit immature thymocyte proliferation, whereas at higher doses in particular TBTC induces apoptotic cell death. In vitro, a similar concentration-effect relationship was observed, i.e. low concentrations inhibit DNA and protein synthesis and higher concentrations induce apoptosis. The mechanism of apoptosis by organotins has been partly investigated, but their capacity to inhibit protein synthesis seems to contradict with the idea that macromolecular synthesis is required for organotin-induced apoptosis. Therefore, we aimed to evaluate the relation between apoptosis and the synthesis of RNA and proteins, with a focus on the apoptosis-sensitive thymocyte subset. Results showed that DBTC increases RNA synthesis in particular in the subset of small CD4(+)CD8(+) thymocytes, which normally shows a high incidence of DNA fragmentation. Moreover, the RNA synthesis inhibitor actinomycin D or the protein synthesis inhibitor cycloheximide protected cells from apoptosis by DBTC or TBTC. Although organotin compounds increase synthesis of the heat shock protein HSC73/HSP72, heat shock treatment did not initiate apoptosis in thymocytes, neither antagonized organotin-induced apoptosis. This indicates that synthesis of heat shock proteins is not related to organotin-induced increase of RNA synthesis, and that other RNA-molecules are probably involved.
Gennari
Alessandra
A
Immunotoxicology Section, Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands. alessandra.gennari@jrc.it
Bol
Marianne
M
Seinen
Willem
W
Penninks
André
A
Pieters
Raymond
R
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis; D003609:Dactinomycin / Q000494:pharmacology; D005434:Flow Cytometry; D050884:HSP72 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D008297:Male; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D009947:Organotin Compounds / Q000633:toxicity*; D014176:Protein Biosynthesis; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012313:RNA / Q000096:biosynthesis*; D051381:Rats; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014220:Trialkyltin Compounds / Q000633:toxicity*
D050884:HSP72 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D009947:Organotin Compounds; D011500:Protein Synthesis Inhibitors; D014220:Trialkyltin Compounds; C056189:di-n-butyltin; D003609:Dactinomycin; C011559:tributyltin; D012313:RNA; D004247:DNA; D003513:Cycloheximide