Deltamethrin-induced thymus atrophy in male Balb/c mice.
The action of deltamethrin, a potent type II synthetic pyrethroid insecticide, 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 to be 6 mg/kg, 24 hr after a single intraperitoneal treatment. Treated animals did not recover during the time-course of the experiment (365 days after treatment); however, deltamethrin did not affect the body weight of the treated animals during the course of the study. To determine if deltamethrin-induced [Ca2+]i signaling could lead to thymic atrophy via programmed cell death, mice were treated with 25 mg deltamethrin/kg for 24 hr or the isolated thymocyte suspension was treated with 50 microM deltamethrin. A significant stimulation of inositol 1,4,5-triphosphate (IP3) and inositol 1,4-diphosphate (IP2) production was found after 24 hr of deltamethrin-1R (active isomer) treatment. An inactive stereoisomer of deltamethrin (i.e. 1S) did not cause a significant rise in the production of 1P3 and 1P2. In addition, deltamethrin-1R induced a transient increase of [Ca2+]i mobilization in the thymocyte suspension after 10 min of in vitro treatment, and substantially reduced the rate of calcium-calmodulin (Ca/CaM)-dependent protein dephosphorylation in in vivo treated animals (25 mg deltamethrin/kg for 24 hr). The in vivo effects of deltamethrin treatment demonstrated induction of DNA fragmentation and cell death in thymocytes. Moreover, using a histochemical approach, it was evident that deltamethrin at 25 mg/kg was able to produce cell death in the thymus of treated animals 72 hr after treatment. In the present work, we found that cell death was apoptotic 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 suspensions. In addition, the involvement of the Ca/CaM-dependent protein phosphorylation-dephosphorylation cascade in the induction of apoptosis by deltamethrin was supported by the protective role of the calmodulin inhibitor trifluoperazine against the apoptotic effect of deltamethrin on thymocyte suspension. Our results suggest that deltamethrin induced thymus atrophy and altered the Ca/CaM-dependent protein kinase-phosphatase cascade, which might induce programmed cell death.
Enan
E
E
Department of Environmental Toxicology, University of California, Davis, CA 95616, USA.
Pinkerton
K E
KE
Peake
J
J
Matsumura
F
F
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001284:Atrophy; D001835:Body Weight / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003208:Concanavalin A; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism; D007306:Insecticides / Q000008:administration & dosage / Q000633:toxicity*; D007700:Kinetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009570:Nitriles; D011722:Pyrethrins / Q000008:administration & dosage / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects; D013237:Stereoisomerism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013950:Thymus Gland / Q000187:drug effects* / Q000473:pathology / Q000502:physiology
D007295:Inositol Phosphates; D007306:Insecticides; D009570:Nitriles; D011722:Pyrethrins; D003208:Concanavalin A; C017180:decamethrin; C044259:inositol 1,4-bis(phosphate); D015544:Inositol 1,4,5-Trisphosphate