In human osteosarcoma MG63 cells, effect of triethyltin, an environmental toxicant, on intracellular Ca 2 + concentration ([Ca 2 + ] i ) was measured by using fura-2. Triethyltin (1-50 μM) caused a rapid and sustained plateau rise of [Ca 2 + ] i in a concentration-dependent manner (EC 5 0 =10 μM). Triethyltin-induced [Ca 2 + ] i rise was prevented by 50% by removal of extracellular Ca 2 + but was not altered by voltage-gated Ca 2 + channel blockers. In Ca 2 + -free medium, thapsigargin, an inhibitor of the endoplasmic reticulum (ER) Ca 2 + -ATPase, caused a monophasic [Ca 2 + ] i rise, after which the increasing effect of triethyltin on [Ca 2 + ] i was attenuated by 60%; also, pretreatment with triethyltin abolished thapsigargin-induced [Ca 2 + ] i increase. Depletion of mitochondrial Ca 2 + with carbonylcyanide m-chlorophenylhydrazone (CCCP; 2 μM) did not affect triethyltin-induced Ca 2 + release. U73122, an inhibitor of phoispholipase C, abolished ATP (but not triethyltin)-induced [Ca 2 + ] i rise. A low concentration (1 μM) of triethyltin failed to alter ATP and bradykinin-induced [Ca 2 + ] i rises. These findings suggest that triethyltin rapidly increases [Ca 2 + ] i in osteoblasts by stimulating both extracellular Ca 2 + influx and intracellular Ca 2 + release via as yet unidentified mechanism(s).