Levels of manganese and iron in the brain of normal and manganese-poisoned rats

Forty rats were poisoned by manganese inhalation and were sacrificed after six and nine months. Tissue concentrations (in mg/g dry weight) were measured in brain, cerebellum and stem-brain of the experimental animals and the twenty control rats, for atomic absorption spectometry. The increase in tissue manganese concentrations were very pronounced in cerebellum, and minor in brain and stem-brain. The tissue iron concentrations undergo a light increase in cerebellum and stem-brain.     

Influence of spontaneous diabetes on tissue status of zinc, copper, and manganese in the BB Wistar rat

The concentrations of zinc, copper, and manganese in liver, kidney, duodenum, pancreas, testes, bone, and serum from control and untreated, spontaneously diabetic BB Wistar rats were compared. Chronic insulin deficiency resulted in significant alterations in the concentrations of one or more of these essential micronutrients in several tissues. The amounts of zinc and copper bound to metallothionein in the liver and kidney of untreated spontaneously diabetic rats were also markedly increased. The tissue trace metal status in diabetic rats was altered similarly in both male and female rats. Daily injections of insulin blocked many of the changes in the tissue concentrations of the metals. The effects of spontaneous diabetes on tissue trace metal status are quite similar to those reported for chemically induced diabetes. Thus, these results demonstrate that chronic endocrine imbalance is responsible for a series of tissue specific changes in the transport and metabolism of zinc, copper, and manganese.     

Altered transition metal homeostasis in mice following manganese injections for manganese-enhanced magnetic resonance imaging

In manganese-enhanced magnetic resonance imaging (MEMRI), the paramagnetic divalent ion of manganese (Mn²⁺) is injected into animals to generate tissue contrast, typically at much higher exposures than have been previously used in studies of Mn toxicity. Here we investigate the effect of these injections on the homeostasis of the transition metals iron and copper in mice to see if there are disruptions which should be considered in MEMRI studies. Manganese shares transport proteins with other transition metals including iron and copper, so it is possible that changes in manganese levels in tissue following injections of the metal may affect other metal levels too. This in turn may affect MRI contrast or the investigation of disease processes in the animal models being imaged. In this study, we measured manganese, iron, and copper concentrations in the blood, kidney, liver and in brain regions in mice treated with four injections of 30 mg/kg MnCl₂ 4H₂O (dry chemical weight/body weight)—a common dose used in MEMRI. In addition to the expected increases in manganese in tissues, we noted a statistically significant reduction in copper in the kidney and liver. Also, we noted a statistically significant decrease in concentration of iron in the thalamus of the brain. These findings suggest that the high doses of manganese injected in MEMRI studies can disrupt the homeostasis of other transition metals in mice.     

Copper, zinc, iron, and manganese accumulation in cattle from Asturias (northern Spain)

Monitoring levels of mineral concentrations in animal tissues is important for assessing the effect of contamination on animal health and safety of animal origin products in human nutrition. This study evaluated the levels of certain trace elements (copper, zinc, iron, and manganese) in cattle from an industrial and mining region in the north of Spain (Asturias). Samples of 312 animals aged 9–12 mo were collected from the whole region and analyzed after acid digestion using atomic absorption spectrophotometry (AAS). The geometric mean concentrations obtained per wet weight for the liver, kidney, muscle, and blood were 34.3 mg/kg, 4.04 mg/kg, 1.65 mg/kg, and 0.651 mg/L for copper, respectively, and 38.5 mg/kg, 23.0 mg/kg, 47.0 mg/kg, and 2.44 mg/L for zinc, respectively. For iron, blood was not analyzed and results were 96.2 mg/kg, 105 mg/kg, and 56.0 mg/kg for the liver, kidney and muscle, respectively. For manganese, only the liver and kidney were analyzed, and the results were 3.11 mg/kg and 1.19 mg/kg, respectively. There was no evidence of an accumulation of toxic levels of trace metals in Asturian cattle. Females accumulated more iron in the liver (p<0.001, F _1,310=18.4) and the kidney (p<0.001, F _1,310=13.5) and more manganese in the liver (p<0.01, F _1,310=9.55) than males.     

Uptake and tissue distribution of manganese in the white sucker (Catostomus commersoni) under conditions of low pH

Concentrations of manganese were determined in the liver, kidney, muscle and bone of white suckers (Catostomus commersoni) from five acid (pH < 5.8), and two circumneutral lakes in south-central Ontario. Manganese tissue concentrations were greater in fish captured from the most acidified lakes with the greatest concentrations of dissolved manganese. These fish had increased concentrations of manganese in the liver, as indicated by a comparison of liver:kidney manganese concentration ratios among the seven fish populations. Tissue concentrations of manganese from all populations either were negatively correlated (P < 0.05) or remained constant with fish size indicating homeostatic regulation of this metal. Manganese concentrations of the benthic fauna were positively correlated to sediment concentrations (R=0.30). Lake sediment manganese concentrations were significantly correlated to maximum lake depth (R=0.80, P < 0.03), with the concentrations in the top 0–1 cm dependent on the redox conditions in the seven lakes. Based on the seven lakes studied, manganese concentrations in the benthic-feeding white sucker correlated better with dissolved manganese, than with either the concentrations in food or surficial sediments.     

Partition of divalent and total manganese in organs and subcellular organelles of MnCl2-treated rats studied by ESR and neutron activation analysis

The possibility that Mn2+ is converted to other valency states in vivo was examined by measuring the ratio of Mn2+, determined by ESR, to total manganese, determined by neutron activation analysis combined with chemical separation, in various organs of control rats and rats treated with MnCl2. In control rats, the total manganese content was high in the thyroid, hypophysis, adrenal, pancreas, liver and kidney, but the Mn2+ contents of these organs were low. In rats treated with Mn2+, the total manganese contents of all organs increased, but the Mn2+ contents still remained low. With regard to subcellular distribution, the total manganese content was high in the nuclear and mitochondrial fractions of the liver and kidney, and in the microsomal and supernatant fractions of the pancreas. The ratio of Mn2+ to total manganese was relatively high in the microsomes of the liver and kidney of control rats, and in the nuclear fraction of the pancreas of Mn2+-treated rats. Thus, the distribution and behavior of manganese in the pancreas were different from those in other organs. Purified liver nuclei and mitochondria were demonstrated to contain manganese, indicating that manganese is tightly bound in each cellular compartment.     

Manganese status,gut endogenous losses of manganese,and antioxidant enzyme activity in rats fed varying levels of manganese and fat

We hypothesized that manganese deficient animals fed high vs moderate levels of polyunsaturated fat would either manifest evidence of increased oxidative stress or would experience compensatory changes in antioxidant enzymes and/or shifts in manganese utilization that result in decreased endogenous gut manganese losses. Rats (females in Study 1, males in Study 2,n = 8/treatment) were fed diets that contained 5 or 20% corn oil by weight and either 0.01 or 1.5 μmol manganese/g diet. In study 2,⁵⁴Mn complexed to albumin was injected into the portal vein to assess gut endogenous losses of manganese. The manganese deficient rats:

The effects of age and sex on seven elements of Sprague-Dawley rat organs

This study reports age-related changes in 7 element (iron, copper, zinc, manganese, mercury, cadmium and lead) concentrations in the liver, kidney and brain of male and female Sprague-Dawley rats from 1 to 364 days of age. Atomic absorption spectrometry was used for the measurements. Copper, mercury and cadmium in the male and female kidneys increased from weaning until 127 days of age, as did iron concentrations in the female liver and kidney. After 127 days, especially, the copper concentration in the female kidney and cadmium concentration in the male and female kidney increased further. Consistent and statistically significant (P less than 0.05) sex differences in element concentrations were found for three elements (iron, copper and zinc). Except for the zinc concentration in the liver from 50 to 72 days, iron (in liver and kidney), zinc (in kidney) and copper (in liver, kidney and brain) concentrations in female rats during the adult stage, were all higher than those of male rats. Isolated differences for other elements (manganese, mercury and cadmium) were also found. The data will be helpful when setting up long-term animal investigations of the biological effect of elements.     

Distribution of amiodarone and its metabolite, desethylamiodarone, in human tissues

The distribution of the antiarrhythmic drug amiodarone and its principal lipophilic metabolite, desethylamiodarone, was determined in postmortem tissues of six patients who received amiodarone therapy (treatment period, 6-189 days; total dose, 4.8-127.0 g). Amiodarone concentration was highest in liver, lung, adipose tissue, and pancreas, followed by kidney, heart (left ventricle), and thyroid gland, and lowest in antemortem plasma. There was no measurable amiodarone in brain (less than 1.0 microgram/g). Desethylamiodarone concentration was highest in liver and lung, followed by pancreas, adipose tissue, kidney, heart, thyroid gland, and brain, and lowest in plasma. For most patients, the desethylamiodarone concentration was higher than the amiodarone concentration in liver, lung, kidney, heart, thyroid gland, and brain, whereas the parent drug concentration was higher than the metabolite concentration in adipose tissue, pancreas, and plasma. Tissue amiodarone and desethylamiodarone concentrations appeared to be related more closely to the total dose of amiodarone than to their respective plasma concentrations. One patient died of apparent amiodarone-induced pulmonary toxicity after an 18-day period of pharmacotherapy. Clinical evidence of pulmonary dysfunction appeared at 15 days after the initiation of amiodarone therapy, and the patient died at 23 days. Histologic assessment of a lung necropsy specimen revealed acute alveolar interstitial damage. This case represents the earliest reported incident of amiodarone-induced pulmonary toxicity.     

Reduction of liver manganese concentration in response to the ingestion of excess zinc: identification using metallomic analyses

To date, minerals of interest have been analyzed individually to understand mineral dynamics and metabolism. Our recent development of metallomic analyses enabled us to evaluate minerals in an unbiased and global manner. Here, we evaluated the effects of ingestion of excess zinc to plasma and tissue concentrations of minerals in growing rats. A total of 26 minerals were simultaneously evaluated by metallomic analyses using inductively coupled plasma-mass spectrometry (ICP-MS) in semi-quantification mode; the concentrations of several minerals exhibited consistent changes in response to the concentrations of dietary zinc. Manganese concentrations in plasma and femur increased, while concentrations in the liver and pancreas decreased with increasing dietary zinc concentrations. Because the interaction between zinc and manganese is not known, we further focused our analysis on liver manganese. Quantitative analyses also indicated that the hepatic concentration of manganese decreased in response to the ingestion of diets containing excess zinc, a result that is partly explained by the decreased expression of hepatic Zip8, a manganese transporter. The present study reveals mineral interaction by using metallomic analyses and proposes a possible mechanism that underlies this novel interaction.     

Mucosal uptake and whole-body retention of dietary manganese are not altered in beta2-microglobulin knockout mice

To further examine the interrelationships between manganese and iron absorption, the mucosal uptake, initial rate of loss, wholebody retention, and tissue distribution of an orally administered ⁵⁴Mn radiotracer were compared between normal and β₂-microglobulin knockout [β₂m(-/-)] mice. These mutant mice are commonly used as a model for the study of human hemochromatosis, a hereditary ironoverload disease. Initial uptake of ⁵⁴Mn by the intestinal mucosa, the liver, and the brain was not different between the two strains. The mutant mice had much higher concentrations of nonheme and total iron in the liver, but hepatic manganese, copper, magnesium, and zinc concentrations were similar between the two strains. In summary, the mucosal uptake and whole-body retention of manganese and tissue manganese concentrations were not altered in β₂m(-/-) mice; this suggests that normal homeostasis of manganese is not affected by the altered HFE protein-β₂m complex in these mice. Mention of a trademark or proprietary product does not constitute a guarantee or warranty of the product by the US Department of Agriculture and does not imply its approval to the exclusion of other products that may also be suitable. The US Department of Agriculture, Agricultural Research Service, Northern Plains Area, is an equal opportunity/affirmative action employer and all agency services are available without discrimination.     

双峰驼不同生态环境条件下组织中微量元素的分布研究

对砾石和沙质两种不同的荒漠区双峰驼组织中６种微量元素的含量及分布规律进行了研究。结果表明,Ｃｕ、Ｍｎ、Ｆｅ、Ｍｏ的丰度在肝脏最高,Ｓｅ和Ｚｎ则分别在肾脏和肌肉组织中最高。由于砾石荒漠区土壤和牧草中Ｆｅ、Ｃｕ、Ｍｏ含量极显著高于沙质荒漠区（Ｐ〈０．０１）,导致两地双峰驼肝脏和肾脏Ｃｕ含量差异极显著（Ｐ〈０．０１）．同时发现,上述两地区双峰驼组织中Ｍｎ含量显著低于其他反刍动物。     

Broad expression of fructose-1,6-bisphosphatase and phosphoenolpyruvate carboxykinase provide evidence for gluconeogenesis in human tissues other than liver and kidney

The importance of renal and hepatic gluconeogenesis in glucose homeostasis is well established, but the cellular localization of the key gluconeogenic enzymes liver fructose-1,6-bisphosphatase (FBPase) and cytosolic phosphoenolpyruvate carboxykinase (PEPCK) in these organs and the potential contribution of other tissues in this process has not been investigated in detail. Therefore, we analyzed the human tissue localization and cellular distribution of FBPase and PEPCK immunohistochemically. The localization analysis demonstrated that FBPase was expressed in many tissues that had not been previously reported to contain FBPase activity (e.g., prostate, ovary, suprarenal cortex, stomach, and heart). In some multicellular tissues, this enzyme was detected in specialized areas such as epithelial cells of the small intestine and prostate or lung pneumocytes II. Interestingly, FBPase was also present in pancreas and cortex cells of the adrenal gland, organs that are involved in the control of carbohydrate and lipid metabolism. Although similar results were obtained for PEPCK localization, different expression of this enzyme was observed in pancreas, adrenal gland, and pneumocytes type I. These results show that co-expression of FBPase and PEPCK occurs not only in kidney and liver, but also in a variety of organs such as the small intestine, stomach, adrenal gland, testis, and prostate which might also contribute to gluconeogenesis. Our results are consistent with published data on the expression of glucose-6-phosphatase in the human small intestine, providing evidence that this organ may play an important role in the human glucose homeostasis.     

The effect of high dose oral manganese exposure on copper,iron and zinc levels in rats

Manganese is an essential dietary nutrient and trace element with important roles in mammalian development, metabolism, and antioxidant defense. In healthy individuals, gastrointestinal absorption and hepatobiliary excretion are tightly regulated to maintain systemic manganese concentrations at physiologic levels. Interactions of manganese with other essential metals following high dose ingestion are incompletely understood. We previously reported that gavage manganese exposure in rats resulted in higher tissue manganese concentrations when compared with equivalent dietary or drinking water manganese exposures. In this study, we performed follow-up evaluations to determine whether oral manganese exposure perturbs iron, copper, or zinc tissue concentrations. Rats were exposed to a control diet with 10 ppm manganese or dietary, drinking water, or gavage exposure to approximately 11.1?mg manganese/kg body weight/day for 7 or 61 exposure days. While manganese exposure affected levels of all metals, particularly in the frontal cortex and liver, copper levels were most prominently affected. This result suggests an under-appreciated effect of manganese exposure on copper homeostasis which may contribute to our understanding of the pathophysiology of manganese toxicity.     

The content of manganese and iron in hip joint tissue

Manganese and iron are elements that constitute components of bone tissue. The aim of this study was to determine presence of manganese and iron in hip joint tissue and interdependencies between these elements. The objects of the research were hip joint elements from people residing in cities on the territory of the Upper Silesian Industrial District. The number of people in the study group was 91 samples, including 66 samples from women and 25 from a man. The examined tissues were obtained intraoperatively during hip replacement procedures. The content of manganese and iron was determined using the atomic absorption spectrophotometry (AAS) method. The lowest content of manganese and iron was found in the cortical bone, and the largest, in the case of manganese, in the articular cartilage, whereas in the case of iron in a fragment of the cancellous bone from the intertrochanteric area. The content of iron in selected elements of the hip joint decreased with age. Higher content of manganese in hip joint tissue of women compared to men was confirmed. What is more, higher content of iron in hip joint tissue of men was confirmed as well.     

Effect of manganese on some bioantioxidants in various organs of protein-deficient rats

The effect of manganese exposure (Mn2+ 4 mg Mn/kg intraperitoneally) on certain bioantioxidants in brain, liver, kidney and testes in growing rats maintained on 21% and 8% casein diet were investigated. Manganese administration for 30 days caused significant reduction in the level of GSH (reduced glutathione) in liver and testes and GR (glutathione reductase) and G-6-PDH (glucose-6-phosphate dehydrogenase) in brain, liver and testes. The magnitude of alteration was greater in 8% casein diet fed animals compared to rats maintained on 21% casein diet. These results indicate that protein deficient animals are more susceptible to the manganese induced biochemical changes in various tissues. The mechanism of such changes is discussed.     

The regional distribution of manganese in the normal human brain

The concentration of manganese per gram dry tissue weight was determined in samples from 39 areas of 8 normal human brains. Manganese was shown to be unevenly distributed with the largest concentrations in the pineal gland and the olfactory bulb. The gray matter yielded a higher content of manganese than the white matter. Significant differences between individuals were found for identical areas of the gray and white matter of the cerebral cortex. Higher levels of manganese were demonstrated in the tail of the caudate nucleus than in the body and the head of the same structure. No significant correlation was shown between the amount of manganese in brain and age.     

The effect of dietary protein source on manganese bioavailability to the rat

Rats were fed diets containing 20% protein from casein, beef, chicken, tuna, or soybean. All diets contained 15% fat and were supplemented with limiting amino acids as necessary to meet National Research Council requirements. In Experiment 1, the manganese content of all diets was the same; manganese content was 5 mg/kg. In Experiment 2, a basal (adequate) level of minerals was provided in each diet but total mineral content varied depending on the contribution of the protein source; manganese was added to achieve a concentration of 5 mg/kg. In both experiments, 54Mn absorption was greatest from tuna (8.54% and 7.71%) and least from beef (4.57% and 4.14%) (P less than 0.0001). In both experiments, biologic half-life of 54Mn was longest in rats fed beef (18.5 and 26.9 days) and shortest in rats fed soy (14.5 and 16.2 days) (P less than 0.0002). Except for beef, biologic half-life was similar for dietary groups between the two experiments. In Experiment 1, only kidney manganese concentration was significantly affected by diet and was highest in soy-fed animals. In Experiment 2, plasma, kidney, and liver manganese were all significantly affected by diet and were highest in soy-fed animals and lowest in beef-fed animals.     

Amino acid metabolizing enzymes in rat submaxillary gland, normal or neoplastic, and in pancreas.

The activities of 12 enzymes, many related to ornithine metabolism, were measured in rat submaxillary gland, submaxillary gland tumors and pancreas. In submaxillary gland, the activities of arginase, ornithine aminotransferase, pyrroline-5-carboxylate reductase and glutamine synthetase were high, but no ornithine transcarbamylase or proline oxidase could be detected. In the fetal submaxillary gland, arginase was at almost adult levels while ornithine aminotransferase reached 50% of its adult value postnatally. Submaxillary tumors deviated from their cognate tissue by lower levels of amino acid metabolizing enzymes and by high concentrations of thymidine kinase. In pancreas, none of the pyrroline-5-carboxylate metabolizing enzymes were as high as in either liver or submaxillary gland. The outstanding activities were those of gamma-glutamyl transpeptidase and glutamate dehydrogenase. Although arginase activities in submaxillary gland and pancreas were quantitatively similar, they differed qualitatively: submaxillary gland contained the same variant as liver while the pancreatic isozymes resembled those of other nonhepatic tissues.     

Ultrastructural observations in the carbonyl iron-fed rat, an animal model for hemochromatosis

Rats fed a carbonyl iron-supplemented diet for 4-15 months were studied for iron content and morphologic changes in the liver, spleen, intestinal mucosa, pancreas and heart. All organs had an increased iron content measured by atomic absorption, with the highest concentrations in the liver and spleen. The periportal distribution of stored iron in the liver was similar to that in human hemochromatosis. In animals treated beyond 6 months Kupffer cells and sinusoidal lining cells also showed cytosiderosis. Electron microscopy provided information on ferritin and hemosiderin content and distribution within parenchymal and sinusoidal cells of the liver but no excessive fibrosis was found. Except for the spleen, the other organs showed less iron deposition. Iron-filled lysosomes (siderosomes) were found in macrophages in the intestinal lamina propria and pancreas, as well as in enterocytes, pancreatic acinar cells and heart muscle cells. Heavily iron-laden siderosomes had increased membrane instability which was demonstrated both morphologically and by measurements of latent lysosomal enzyme activities. Even though cirrhosis was not found, the distribution pattern of accumulated storage iron and lysosomal lability indicated that the carbonyl iron-fed rat is a suitable experimental model for human hemochromatosis.