Effects of the dithiocarbamate fungicide propineb in primary neuronal cell cultures and skeletal muscle cells of the rat.
After repeated-dose toxicity studies with the fungicide propineb, reversible effects on muscle functions were found. Therefore, mechanistic investigations should contribute to clarification of its mode of action in relation to disulfiram and diethyldithiocarbamate neurotoxicity or direct effects on muscle cells. In principle, besides the dithiocarbamate effects, two different mechanisms have been discussed for this fungicide. One mechanism is the degradation to carbon disulfide (CS(2)) and propylenthiourea (PTU) and the other are direct effects of zinc. Primary neuronal cell cultures of the rat are a well established model to identify neurotoxic compounds like n-hexane or acrylamide. In this cell culture model, endpoints such as viability, energy supply, glucose consumption and cytoskeleton elements were determined. Additionally, skeletal muscle cells were used for comparison. Propineb and its metabolite PTU were investigated in comparison to CS(2), disulfiram and diethyldithiocarbamate. The toxicity of zinc was tested using zinc chloride (ZnCl(2)). It was clearly shown that propineb exerted strong effects on the cytoskeleton of neuronal and non-neuronal cell cultures (astrocytes, muscle cells). This was similar to ZnCl(2,) but not to CS(2). With CS(2) and disulfiram effects on the energy supply were more prominent. In conclusion, the toxicity of propineb is not comparable to disulfiram, diethyldithiocarbamate or CS(2) neurotoxicity. In regard to these findings, a direct reversible effect of propineb on skeletal muscle cells seems to be more likely.
Schmuck
Gabriele
G
Bayer AG, Pharma Research Centre, Aprather Weg, 42096 Wuppertal, Germany. GABRIELE.SCHMUCK.GS@bayer-ag.de
Ahr
Hans-Jürgen
HJ
Mihail
Florin
F
Stahl
Bernhard
B
Kayser
Martin
M
D000818:Animals; D002246:Carbon Disulfide / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002712:Chlorides / Q000633:toxicity; D003599:Cytoskeleton / Q000187:drug effects; D004221:Disulfiram / Q000633:toxicity; D004050:Ditiocarb / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005659:Fungicides, Industrial / Q000378:metabolism / Q000633:toxicity*; D005947:Glucose / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects*; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D013890:Thiourea / Q000031:analogs & derivatives* / Q000633:toxicity; D017967:Zinc Compounds / Q000633:toxicity; D015038:Zineb / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity*
D002712:Chlorides; D005659:Fungicides, Industrial; D017967:Zinc Compounds; C012509:propineb; C035039:propylenethiourea; C016837:zinc chloride; D004050:Ditiocarb; D013890:Thiourea; D005947:Glucose; D002246:Carbon Disulfide; D004221:Disulfiram; D015038:Zineb