Cobalt - trace element, nutritional supplement and regulator of hematopoiesis

Cobalt (II) is a wide used metal as erythropoietic agent, nutritional supplement, in cosmetics, medical devices. The aim of the study was to evaluate the regulatory role of chronic treatment with cobalt compounds on mouse hematopoiesis. An in vivo experimental model for chronic exposure to cobalt chloride (CoCl2) and/or cobalt-EDTA (Co-EDTA) was established. Pregnant ICR mice were subjected to daily dose of 75 and/or 125 mg/kg body weight CoCl2x6H2O and/or Co-EDTA 2-3 days prior delivery. The compounds were dissolved in tap water. 25 pn newborn mice were separated into individual cages and treatment continued until day 90 pn. The animals were sacrificed on days 18, 25, 30, 45, 60 and 90. The control group consisted of age-matched mice obtaining tap water. Co(II) accumulation was analyzed in blood plasma and tissues. Whole blood was used for hematological analyses and histological studies were performed to evaluate the morphological changes. Results showed diverse effect of Co(II) compounds on immature and mature mice. Analysis of whole blood samples demostrated that immature mice (days 18 to 30) show signs of anemia determined by reduced RBC and hemoglobin (Hb) content. Hb was significantly increased in mature (day 45 to 90) mice suggesting time- and age-dependent effect of the compounds. More Hb was measured in samples of mice exposed to the higher dose (125 mg/kg), indicating a dose-dependent effect as well. CoCl2 exhibited stronger stimulatory effect compared to Co-EDTA. The results correspond to higher concentrations of Co(II) in the plasma of immature mice, compared to the mature ones.Exposure to cobalt ions affected megakaryocyte formation. In the spleen, CoCl2 stimulated megakaryocyte formation while Co-EDTA inhibited it.Results suggest that the regulatory role of cobalt on hematopoiesis depends on the type of compound, the duration of treatment, as well as on the age of the experimental animals.

The effect of subacute cadmium intoxication and subsequent detoxification with chelating agents on murine spleen

Cadmium (Cd) is an immunotoxic agent and is one of the most toxic environmental pollutants. Our previous results and literature data demonstrated that Cd induced spleenomegaly in rodents, subjected to subacute Cd intoxication. So far there are no effective antidotes for treatment of Cd-poisoning. Herein we compare the effect of DMSA (2,3-dimercaptosuccinic acid) and two polyether ionophorous antibiotics monensin and salinomycin on Cd-induced morphological alterations in spleen of Cd-intoxicated mice. The experimental animals were divided into five groups (n = 9 mice) as follow: group 1 consisted of untreated mice and obtained distilled water for 28 days; group 2 (toxic control group) - obtained orally an average daily dose of 20 mg/kg b.w. Cd(II) acetate for 2 weeks, followed by 2 weeks on distilled water; groups 3, 4 and 5 consisted of mice exposed to Cd(II) acetate treatment for 2 weeks, as described for group 2 and subsequently treated with an average daily dose of 20 mg/kg b.w. DMSA, tetraethylammonium salts of monensic and/or salinomycinic acids respectively for 2 weeks. All compounds were dissolved and obtained in the drinking (distilled) water. During the experimental protocol mice received food ad libitum.Experimental results showed increased spleen weight index (SI) in the toxic control group which restored to normal in the detoxicated groups. Morphological changes in the red and white pulp were also observed. The antibiotics had better effect on the spleen compared to DMSA. The results presented herein demonstrated the potential application of monensin and salinomycin as antidotes for Cd-poisoning.Acknowledgments: The work was supported by grant No 5/2016, financed by the Sofia University `St. Kl. Ohridski` Fund for Scientific Research

Histological and quantitative evaluation of adult mouse spermatogenesis after acute treatment with sodium nitrite

Introduction: Sodium nitrite (NaNO2) is an inorganic salt with various applications. Industrialization and un­controlled use of nitrate/nitrite salts has increased human exposure to high levels of NaNO2, which can act as a pro-oxidant and pro-carcinogen. The adverse health effects of NaNO2 are typically due to the formation of methe­moglobin in the blood and respectively to hypoxia. Most mammals have little tolerance to hypoxia.Materials and Methods: Adult male ICR mice were intraperitoneally injected with a single toxic dose of 120 mg. kg-1 b.w. NaNO2 to evaluate the early effect of acute hemic hypoxia on the testes and sperm count. Treated animals were sacrificed at different time intervals (1h, 5h, 1d, 2d and 5d) following the administration. Testes and epidid­ymides were sampled, weighed and embedded in paraffin using routine histological practice. Spermatozoa were isolated from both vasa deferentia and counted.Results: Apart from the normal morphology of the tubules, histological observations of the testis in all investigat­ed groups demonstrated areas with disorganization of the seminiferous epithelium and collections of undiffer­entiated germ cells in the luminal region. We observed overgrowth and lumen distension of rete testis, a marker for accumulation of seminal fluid in the testis. Data correspond to increased testicular weight/body weight index. The epididymal index in all groups was reduced bu about 40% compared to controls. Regarding sperm count, we established a reduction in almost all of the groups, statistically significant only 48 h after treatment.Conclusion: The quantitative changes of macro-parameters and sperm count were supported by a histopatholog­ical alteration of mice testes even in the early periods after NaNO2-induced hemic hypoxia

Comparative effects of meso-2,3-dimercaptosuccinic acid, monensin and salinomycin on the concentrations of cadmium and some essential elements in skeletal muscles of Cd-exposed mice

Cadmium (Cd) is an environmental pollutant shown to induce multi organ dysfunction. In this study we present novel data about the effects of meso-2,3-dimercaptosuccinic acid (DMSA), monensin and salinomycin on the concentration of Cd in skeletal muscles of mice exposed to Cd (II) acetate treatment for 14 days. The impact of Cd and the chelating agents on the endogenous concentrations of calcium (Ca), copper (Cu), iron (Fe), magnesium (Mg), phosphorous (P), selenium (Se) and zinc (Zn) was also investigated. Subacute exposure of mice to Cd (II) acetate resulted in a significant accumulation of the toxic metal ion in the skeletal muscles compared to the untreated controls. Salinomycin most effectively mobilized Cd from the muscles compared to DMSA and monensin. The Cd exposure and the tested chelating agents did not significantly alter the endogenous concentrations of the selected essential elements in mouse muscles. The presented results confirmed that among the tested chelating agents salinomycin is superior as a potential antidote to Cd poisoning. © 2018 Elsevier Gmb

Comparative effects of meso-2,3-dimercaptosuccinic acid, monensin and salinomycin on the concentrations of cadmium and some essential elements in skeletal muscles of Cd-exposed mice

Cadmium (Cd) is an environmental pollutant shown to induce multi organ dysfunction. In this study we present novel data about the effects of meso-2,3-dimercaptosuccinic acid (DMSA), monensin and salinomycin on the concentration of Cd in skeletal muscles of mice exposed to Cd (II) acetate treatment for 14 days. The impact of Cd and the chelating agents on the endogenous concentrations of calcium (Ca), copper (Cu), iron (Fe), magnesium (Mg), phosphorous (P), selenium (Se) and zinc (Zn) was also investigated. Subacute exposure of mice to Cd (II) acetate resulted in a significant accumulation of the toxic metal ion in the skeletal muscles compared to the untreated controls. Salinomycin most effectively mobilized Cd from the muscles compared to DMSA and monensin. The Cd exposure and the tested chelating agents did not significantly alter the endogenous concentrations of the selected essential elements in mouse muscles. The presented results confirmed that among the tested chelating agents salinomycin is superior as a potential antidote to Cd poisoning. © 2018 Elsevier Gmb

Ameliorative effect of salinomycin on some quantitative parameters of spermatogenesis in cadmium-intoxicated mice

Cadmium (Cd) is a heavy metal of considerable toxicity with destructive impact on most organs. Our previous re­sults and numerous reports demonstrate that Cd induces complete degeneration of the seminiferous tubules with severe depletion of germ cells and spermatogenesis arrest. So far, there are no effective antidotes for treatment of Cd poisoning. In our study, we present the effect of polyether ionophorous antibiotic salinomycin on some quan­titative parameters of spermatogenesis in Cd-intoxicated mice.The experimental animals were divided into four groups as follows: Group 1 consisted of untreated control mice receiving distilled water for 28 days; Group 2 (toxic control group) - received Cd(II) acetate orally at a daily dose of 20 mg/kg b.w. for 2 weeks, followed by 2 weeks of distilled water; Group 3 consisted of mice exposed to Cd(II) acetate for 2 weeks, as described for group 2, and subsequently treated with an average daily dose of 20 mg/kg b.w. of tetraethylammonium salt of salinomycinic acid for 2 weeks; Group 4 consisted of mice who received distilled wa­ter for 2 weeks and were subsequently treated with an average daily dose of 20 mg/kg b.w. of tetraethylammoni­um salt of salinomycinic acid for 2 weeks. All compounds were dissolved and received in the drinking (distilled) water. Animals and testes were weighed to calculate testicular index (testicular weight/body weight ratio). Sper­matozoa were isolated from both vasa deferentia and counted.We found statistically significant increase of the testicular index in Group 4 (salinomycin alone) compared to the Cd-intoxicated group as well as to the control. Sperm count significantly increased (87%) after salinomycin ad­ministration to Cd-intoxicated animals. These positive effects correspond to our data for restoration of morphol­ogy in other organs of Cd-intoxicated mice and demonstrate the potential application of salinomycin as an anti­dote for the treatment of Cd-poisoning

The Impact of Perinatal Cobalt Chloride Exposure on Extramedullary Erythropoiesis, Tissue Iron Levels, and Transferrin Receptor Expression in Mice

The objective of the present study was to elucidate the effect of perinatal cobalt chloride (CoCl2) exposure on extramedullary erythropoiesis in suckling mice in relation to iron (Fe) content and transferrin receptor (TfR) expression. Pregnant ICR mice were subjected to a daily dose of 75 mg CoCl2/kg body weight 2–3 days prior and 18 days after delivery. Co exposure significantly increased erythrocyte count (RBC), and reduced the erythrocytic parameters mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) in the offspring. Total iron-binding capacity (TIBC) was decreased while bilirubin values were ~ 1.2-fold higher in the metal-exposed mice. Perinatal CoCl2 treatment also induced pathohistological changes in target organs (spleen, liver, and kidneys) as altered organ weight indices, leukocyte infiltration, abundant Kupffer cells in the liver, increased mesangial cellularity, and reduced capsular space in the kidney. CoCl2 administration induced significant 68-, 3.8-, 41.3-, and 162-fold increase of Co content in the kidney, spleen, liver, and RBC, respectively. Fe content in the target organs of CoCl2-treated mice was also significantly elevated. Immunohistochemical analysis demonstrated that TfR1 was well expressed in the renal tubules, hepatocytes, the red pulp, and marginal zone of white pulp in the spleen. TfR2 showed similar expression pattern, but its expression was stronger in the spleen and liver samples of Co-treated mice compared with that of the untreated controls. The results demonstrate that exposure to CoCl2 during late pregnancy and early postnatal period affects body and organ weights and alters hematological and biochemical parameters, iron content, and TfR expression in target organs. © 2019, Springer Science+Business Media, LLC, part of Springer Nature

Влияние перинатального воздействия кобальта на обмен железа, меди, марганца и цинка в организме незрелых ICR мышей

The aim of the study was to investigate the effect of perinatal cobalt exposure (75 mg / kg / day CoCl2·6H2O to pregnant and lactating females) on the exchange of copper, iron, manganese, and zinc in early-aged ICR mice (18 days). Cobalt and other metals were determined by mass spectrometry with inductively coupled argon plasma (ICP-DRC-MS) after microwave digestion of the samples. It is established that perinatal cobalt exposure leads to a 68-, 3.8-, 11.3-, 41.3-, and 162-fold increase of metal content in kidneys, spleen, muscle, liver, and erythrocytes, respectively. Cobalt intake was also accompanied by a significant increase of the iron content in the kidney and liver by 27% and 15%, respectively. A significant increase of the copper level in the spleen parenchyma (+ 24%) and red blood cells (2-fold) was also noted. Co-induced manganese accumulation exceeded the corresponding control values by a factor of more than 2 for spleen, liver and erythrocytes, whereas the increase in muscle content was 3-fold. The elevation of zinc content in spleen, skeletal muscles, liver, and erythrocytes was 45%, 11%, 10%, and 16% as compared to the corresponding values in the control group. It is supposed the effect of cobalt on the iron, copper, manganese and selenium metabolism may be mediated by cobalt-induced stimulation of hypoxia-inducible factor 1 (HIF-1) with a subsequent effect on the activity of metal transporters (DMT-1, ferroportin) including a modulation of hepcidin production.Изучено влияние перинатального воздействия кобальта на обмен меди, железа, марганца и цинка у ICR мышей в раннем возрасте с использованием масс-спектрометрии с индуктивно-связанной плазмой. Высказано предположение, что влияние кобальта на обмен железа, меди, марганца и селена может быть опосредовано кобальт-индуцированной стимуляцией гипоксия-индуцибельного фактора 1 (HIF-1) с последующим влиянием на активность транспортеров металлов (DMT-1, ферропортин), в том числе через модуляцию продукции гепсидина