Calmodulin inhibitors protect against cadmium-induced testicular damage in mice

Recent reports showing that cadmium can interact with calmodulin and activate calmodulin-sensitive enzymes have lead us to examine the effects of calmodulin inhibitors on cadmium-induced testicular toxicity in mice. Male CF-1 mice were pretreated with the various calmodulin inhibitors or inactive analogs and then, one hour later, given CdCl2 X 2 1/2 H2O (32 mumoles/kg). After 24 hours, the mice were killed and the testes were removed and weighed. The extent of hemorrhaging was quantified by determining the absorbance of hemoglobin at 414 nm in the soluble fraction of testicular homogenates. Exposure to Cd2+ increased the mean testicular weight from 118 +/- 5 mg to 146 +/- 4 mg and the hemoglobin absorbance from 0.096 +/- 0.006 to 0.767 +/- 0.138. Pretreatment with the calmodulin inhibitors, trifluoperazine (40 mumoles/kg), chlorpromazine (40 mumoles/kg) or W-7 (140 mumoles/kg) greatly attenuated the CD2+-induced increase in both parameters, whereas pretreatment with chlorpromazine sulfoxide (140 mumoles/kg), pentobarbital (140 mumoles/kg), verapamil (80 mumoles/kg) or ethylenediaminetetraacetate (140 mumoles/kg) did not. These results indicate that calmodulin inhibitors can protect against certain toxic effects of cadmium and are consistent with the hypothesis that some of the effects of cadmium may result from the improper activation of calmodulin-dependent enzymes.