DELTAMETHRIN-INDUCED THYMUS ATROPHY IN MALE BALB C MICE/

The action of deltamethrin, a potent type II synthetic pyrethroid inse cticide, on the thymus of the Balb/c mouse was studied in vivo and in vitro. We found that deltamethrin produced atrophy in the thymus in a dose and time dependent fashion. The lowest effective dose was found t o be 6 mg/kg, 24 hr after a single intraperitoneal treatment. Treated animals did not recover during the time course of the experiment (35 d ays after treatment); however, deltamethrin did not affect the body we ight of the treated animals during the course of the study. To determi ne if deltamethrin-induced [Ca2+](i) signaling could lead to thymic at rophy via programmed cell death, mice were treated with 25 mg deltamet hrin/kg for 24 hr or the isolated thymocyte suspension was treated wit h 50 mu M deltamethrin. A significant stimulation of inositol 1,4,5-tr iphosphate (IP3) and inositol 1,4-diphosphate (IP2) production was fou nd after 24 hr of deltamethrin-1R (active isomer) treatment. An inacti ve stereoisomer of deltamethrin (i.e. 1S) did not cause a significant rise in the production of IP3 and IP2. In addition, deltamethrin-1R in duced a transient increase of [Ca2+], mobilization in the thymocyte su spension after 10 min of in vitro treatment, and substantially reduced the rate of calcium-calmodulin (Ca/CaM) dependent protein dephosphory lation in in vivo treated animals (25 mg deltamethrin/kg for 24 hr). T he in vivo effects of deltamethrin treatment demonstrated induction of DNA fragmentation and cell death in thymocytes. Moreover, using a his tochemical approach, it was evident that deltamethrin at 25 mg/kg was able to produce cell death in the thymus of treated animals 72 hr afte r treatment. In the present work, we found that cell death was apoptot ic in nature as noted first by the inhibition of deltamethrin-induced cell death by aurintricarboxylic acid, an inhibitor of apoptosis, and second, by internucleosomal DNA fragmentation, a hallmark of apoptosis , produced by deltamethrin in treated animals as well in thymocyte sus pensions. In addition, the involvement of the Ca/CaM-dependent protein phosphorylation-dephosphorylation cascade in the induction of apoptos is by deltamethrin was supported by the protective role of the calmodu lin inhibitor trifluoperazine against the apoptotic effect of deltamet hrin on thymocyte suspension. Our results suggest that deltamethrin in duced thymus atrophy and altered the Ca/CaM-dependent protein kinase p hosphatase cascade, which might induce programmed cell death.