Modeling of some biochemical mechanisms of development of manganese hypermicroelementosis
Authors: O. V. Goncharenko, O. O. Konovalova
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The aim of this work was to study the mechanisms of action of sub-toxic dose (LD50) of the manganese chloride on cell metabolism in rats’ organs and tissues under model conditions. A model of assessment of integral response of an organism to exogenous manganese at exposure levels close to the threshold that was realized as the repeated impact of sub-toxic doses. White Wistar rats aged 3 months were injected intramuscularly with MnCl2 with the metal concentration of 50 mg/kg for 8 days. Effect of exogenous manganese load on the content of macro- and microelements, such as Ca, Mg, Mn, Cu, Zn, and Pb, was studied in liver, heart, spleen, kidneys, muscles and bones of experimental animals the use of C-115-M1 atomic absorption spectrophotometer. Study of enzymes activity and lipid peroxidation products in serum and liver homogenates of experimental animals was conducted on a spectrophotometer Spekord UV/VIS. Hemolysis of red blood cells was determined by the Yacher method. Sorption capacity of the erythrocytes glycocalyx to alcian blue was determined by the Artsishevsky method. A study of the influence of Mn-load on the functional activity of energy metabolism was performed on a model system of rat liver mitochondria by the polarography. Intake of MnCl2 in a dose of LD50 generates weight loss of the rats by 44%, hemoglobin level decrease by 25%, and reduction of the transaminases activity by 40%. That indicates serious disorders in ions homeostasis and metabolic processes. MnCl2 load leads to a significant increase in the content of manganese in all tissues tested: the largest amount was found in the spleen (600% increase), liver (300%) and muscles (240%) as compared with the initial state. Apparently, these organs are depots of manganese. It was established that the introduction of MnCl2 in a dose of LD50 causes a redistribution of elements in the body, resulting in a significant reduction in the concentration of magnesium ions in heart, bones, muscles, liver and spleen. It was accompanied by increasing calcium content in liver, heart, muscle, kidneys and bones as well as by disorders of Ca/Mg ratios. MnCl2causes significant redistribution of the microelements in the rats’ organs. It is characterized by a decrease of copper, zinc and nickel contents in almost all studied tissues. The most antagonistic effect of manganese manifested in relation to nickel and copper in heart and spleen. A reduction of zinc content was most pronounced in spleen, while its contents in bones and kidneys almost don’t change. The study of the impact of manganese on biochemical parameters of membranes proved for the first time the malfunction of erythrocytes’ membranes. It results in increasing sorption capacity of the red blood cells glycocalyx to alcian blue. Using the erythrocyte model we established that manganese cations cause a significant increase in sorption capacity of the red blood cells (53.4 ± 1.8%) and their osmotic fragility, as evidenced by an increase of spontaneous hemolysis to 42%. The other evidence is the change of surface properties (glycocalyx), which indicated by an increase in the sialic acid content by 60% as compared with the control. The obtained data of the model study of the dynamics of the sorption capacity of erythrocytes glycocalyx to alcian blue, osmotic resistance of erythrocytes, activation of lipid peroxidation and increased level of sialic acid may be a signal that the primary mechanism of manganese intoxication is a damage of cell (plasma) membranes. The data obtained on a mitochondrial model suggests that MnCl2, acting as an antagonist of magnesium, has the ability to disturb respiration and oxidative phosphorylation that inhibits the energy metabolism of a cell. Mitochondrial oxidation of malate+glutamate was affected by MnCl2 in narrow range concentrations 3–4.5 mM that cause disengagement (3 mM) and complete inhibition (4.5 mM). The effectiveness of manganese intoxicated rats treatment with the poly-elemental phyto-complex “Valeoton” and zinc-pectin (drug-antagonist of manganese) was experimentally proved. Thus, the overall effect of manganese is its accumulation in organs and antagonistic relations to all divalent metals. Experimental results with manganese chloride loading point not only to changes in the concentrations of elements and their redistribution, but also to serious disturbances in regulation of ions homeostasis.