Signaling Mechanisms and Disrupted Cytoskeleton in the Diphenyl Ditelluride Neurotoxicity

Abstract

Evidence from our group supports that diphenyl ditelluride (PhTe)2 neurotoxicity depends on modulation of signaling pathways initiated at the plasma membrane. The (PhTe)2-evoked signal is transduced downstream of voltage-dependent Ca2+ channels (VDCC), N-methyl-D-aspartate receptors (NMDA), or metabotropic glutamate receptors activation via different kinase pathways (protein kinase A, phospholipase C/protein kinase C, mitogen-activated protein kinases (MAPKs), and Akt signaling pathway). Among the most relevant cues of misregulated signaling mechanisms evoked by (PhTe)2 is the cytoskeleton of neural cells. The in vivo and in vitro exposure to (PhTe)2 induce hyperphosphorylation/hypophosphorylation of neuronal and glial intermediate filament (IF) proteins (neurofilaments and glial fibrillary acidic protein, resp.) in different brain structures of young rats. Phosphorylation of IFs at specific sites modulates their association/disassociation and interferes with important physiological roles, such as axonal transport. Disrupted cytoskeleton is a crucial marker of neurodegeneration and is associated with reactive astrogliosis and apoptotic cell death. This review focuses the current knowledge and important results on the mechanisms of (PhTe)2 neurotoxicity with special emphasis on the cytoskeletal proteins and their differential regulation by kinases/phosphatases and Ca2+-mediated mechanisms in developmental rat brain. We propose that the disrupted cytoskeletal homeostasis could support brain damage provoked by this neurotoxicant.

Resuspendable Powders of Lyophilized Chalcogen Particles with Activity against Microorganisms

“…Many organotellurium compounds, as well as simple tellurium salts, often show considerable activity against pathogenic organisms, in some instances even re-sensitizing drug resistant strains against common antibiotics [ 34 ]. Yet tellurium is also a fairly toxic element per se, and any application, even a topical one, clearly requires further investigations to exclude any unwanted side effects [ 35 , 36 ]. The particular particulate structure may actually be a benefit rather than drawback in this context, as it almost rules out the kind of systemic uptake and distribution characteristic of soluble, toxic organotellurium compounds and, at the same time, may provide a slowly releasing system for certain reactive tellurium species (RTeS).…”

Diphenyl Ditelluride Intoxication Triggers Histological Changes in Liver, Kidney, and Lung of Mice

“…Currently, the toxicological properties of (PhTe) 2 have been investigated in in vivo and in vitro experimental models. Especially in liver, acute and/or chronic intoxication have been reported to increase the organ-to-body weight ratio, inhibit δ -ALA-D enzyme, increase thiobarbituric acid reactive substances, decrease nonprotein SH levels, and modify antioxidant enzymes activities in rodents [ 17 , 19 , 29 , 37 ]. In morphological terms, herein we observed that the liver of animals exposed to (PhTe) 2 (10 and 50 μ mol/kg), for few days, contained hepatocytes with extensive cytoplasmic vacuolization, hydropic degeneration (edema), and hyperchromatic nuclei.…”

“…With regard to mechanisms, it has been postulated that the toxic action of Te forms (organic and inorganic) involves their prooxidant potential towards thiol groups from biologically active molecules [ 10 , 14 – 19 ]. In a similar way, accumulating evidence has showed that the compound diphenyl ditelluride ((PhTe) 2 ), an organotellurium used commonly as intermediate in organic synthesis [ 9 ], is toxic to different tissues [ 20 – 29 ] and inhibits sulfhydryl containing enzymes in vitro and in vivo [ 9 , 16 , 19 ]. Moreover, (PhTe) 2 exposure has been associated with teratogenic, mutagenic, and genotoxic events [ 28 – 30 ].…”

Intermediate Filaments as a Target of Signaling Mechanisms in Neurotoxicity

“…Indeed, developmental exposure to (PhTe) 2 is teratogenic and is associated with long-term behavioral and neurochemical changes in rats. Until recently, the general toxicity of (PhTe) 2 was considered to be exclusively related to the oxidation of thiol-containing proteins (for review, see [16]). However, compelling evidence from our laboratory points to an important role played by signaling mechanisms involved in regulating IF phosphorylation/dephosphorylation as target of (PhTe) 2 neurotoxicity.…”