Effects of the dithiocarbamate fungicide propineb in primary neuronal cell cultures and skeletal muscle cells of the rat

Abstract

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.

Effects of the carbamates fenoxycarb, propamocarb and propoxur on energy supply, glucose utilization and SH-groups in neurons

“…Well-known neurotoxicants like n-hexane, acrylamide and 3-nitropropionic acid have shown that the glycolysis plays a central role in aggravating neuropathies (Sabri et al 1979a(Sabri et al , 1979bSchmuck et al 2000). The same effects on the energy supply were seen with disulfiram, a thiocarbamate, and carbon disulfide (Schmuck et al 2002b).…”

“…The amelioration of carbamate-induced effects on ATP production and glucose consumption by acetylcysteine may be related to a comparable mechanism. However, a reaction with SH-groups should be a slow process and may include metabolic degradation of the test compounds because GSH itself is not degraded within 1 h. This is the case with compounds inducing oxidative stress like paraquat and hydrogen peroxide, and therefore this alternative mechanism can also be excluded for carbamates (Ro¨hrdanz et al 2001;Schmuck et al 2002b).…”

Potential developmental neurotoxicity of pesticides used in Europe

“…Dithiocarbamates form lipophilic complexes with di- and trivalent metallic cations, bonding through the sulfur atoms [ 102 ]. They are non-specific in action, and it is difficult to identify a single mechanism for their neurotoxic effects.…”

Exposure to mixtures of endosulfan and zineb induces apoptotic and necrotic cell death in SH‐SY5Y neuroblastoma cells, in vitro

“…Mixtures of these pesticides also showed significantly increased levels of alpha-synuclein, a major component of Lewy bodies that is a hallmark of neurodegenerative diseases such as PD and Alzheimer's disease (Jia, 2006). Although adverse effects of exposure to both endosulfan and zineb have been reported (Gupta, 1976;Zaidi et al, 1985;Seth et al, 1986;Guven et al, 1999;Vaccari et al, 1999;Schmuck et al, 2002), the biochemical mechanisms by which endosulfan and zineb cause neurotoxicity are still largely unknown. The current studies were designed to assess the cytotoxicity of endosulfan and zineb, alone and in combination, as well as to investigate the mechanism of pesticide-induced cell death (apoptosis and necrosis) in the SH-SY5Y cell line.…”