Exposure of rat hippocampal astrocytes to Ziram increases oxidative stress

Abstract

Pesticides have been shown in several studies to be the leading candidates of environmental toxins and may contribute to the pathogenesis of several neurodegenerative diseases. Ziram (zinc-bis(dimethyldithiocarbamate)) is an agricultural dithiocarbamate fungicide that is used to treat a variety of plant diseases. In spite of their generally acknowledged low toxicity, dithiocarbamates are known to cause a wide range of neurobehavioral effects as well as neuropathological changes in the brain. Astrocytes play a key role in normal brain physiology and in the pathology of the nervous system. This investigation studied the effects of 1.0 µM Ziram on rat hippocampal astrocytes. The thiobarbituric acid reactive substance assay performed showed a significant increase in malondialdehyde, a product of lipid peroxidation, in the Ziram-treated cells. Biochemical analysis also revealed a significant increase in the induction of 70 kDa heat shock and heme oxygenase 1 stress proteins. In addition, an increase of glutathione peroxidase (GPx) and a significant increase in oxidized glutathione (GSSG) were observed in the Ziram-treated cells. The ratio GSH to GSSG calculated from the treated cells was also decreased. Light and transmission electron microscopy supported the biochemical findings in Ziram-treated astrocytes. This data suggest that the cytotoxic effects observed with Ziram treatments may be related to the increase of oxidative stress.

Developmental toxicity of the fungicide ziram in zebrafish (Danio rerio)

“…Oxidative damage is proposed to be another reason for the developmental defects induced by ziram exposure, as teratogenic toxicity of many chemicals to fish early life stages are highly correlated with oxidative stress (Jin et al, 2013;Mu et al, 2015;Zhu et al, 2015). Ziram has been reported to induce oxidative stress in rat hippocampal astrocytes when the cells are treated with 1.0 mM for 1 h (Matei and Trombetta, 2016) and in rat thymocytes treated with 0.1 and 0.3 mM for 2 h (Kanemoto-Kataoka et al, 2018). Based on this knowledge, we assessed the expression levels of sod1 and sod2 in zebrafish larvae as one endpoint to determine if ziram induced oxidative stress responses at the molecular level.…”

“…Gene-specific primers were obtained from published sequences of zebrafish (Table S1). The mRNA levels of genes encoding superoxide dismutase 1 (sod1 and sod2) in the oxidative stress pathway due to evidence for ziram caused oxidative stress in rat cells by Matei and Trombetta (2016) and Kanemoto-Kataoka et al (2018), as well as dopamine synthesis (tyrosine hydroxylase 1, th1), dopamine transport (dat) and dopamine receptors (drd1, drd2a, drd3 and drd4b) in the dopamine system as ziram was toxic to dopaminergic neurons of zebrafish embryos in the study of Lulla et al (2016). Ribosomal subunit 18 (rps18) and ribosomal protein L13a (rpl13a) were selected as housekeeping genes, which were used to normalize all target gene expression.…”

Delayed Puberty by Ziram Is Associated with Down Regulation of Testicular Phosphorylated AKT1 and SIRT1/PGC-1α Signaling

“…38 In vivo ziram treatment to mice by nasal administration also increased ROS production in the brain. 39 Indeed, in vitro ziram treatment significantly increased ROS levels (Figure 5) and apoptosis rates (Figure 6) as well as decreased ΔΨm levels (Figure 6). A nutrient and energy sensor, AMPK and its phosphorylation, 25 were also investigated.…”

Dithiocarbamate fungicides increase intracellular Zn2+ levels by increasing influx of Zn2+ in rat thymic lymphocytes

“…Several papers have evaluated the cellular toxicity of dithiocarbamate fungicides. For example, these fungicides can induce oxidative stress [5,13,19,34]. The cellular thiol content was also reduced in preparations treated with these fungicides [6,18].…”