Influence of iron and the sex of rats on hematological, biochemical and immunological changes during copper deficiency

The influence of dietary iron and the sex of rats on suppressed lymphocyte functions caused by copper deficiency was examined. Male and female weanling Lewis rats were fed two concentrations of copper (0.6 or 5.6 micrograms Cu/g diet) and iron (50 or 300 micrograms Fe/g diet) for 42 d. Regardless of dietary iron concentrations, male and female rats consuming low copper diets had lower serum ceruloplasmin activity and serum and liver copper concentrations than those fed the high copper diet. However, hemoglobin and hematocrit levels were higher in copper-deficient females than in copper-deficient males and were unaffected by copper deficiency in females fed the high iron diet. Copper-deficient females also had higher serum and liver iron concentrations than copper-deficient males. Proliferation of concanavalin A (Con A)-stimulated spleen lymphoid cells (SLC) was suppressed in copper-deficient males and females, but the suppression was less in the females. Thus, the primary cause of suppressed SLC proliferation in copper-deficient rats is poor copper status; poor iron status induced by copper deficiency had little influence on proliferation.     

铜缺乏对大鼠铁代谢影响的研究

目的研究铜缺乏对大鼠铁营养状况和肝脏转铁蛋白受体mRNA及铁调素mRNA的影响。方法 48只雄性SD大鼠按体重随机分为4组,每组12只,正常对照组(Ⅰ组),铁正常铜完全缺乏组(Ⅱ组),铁正常铜轻度缺乏组(Ⅲ组),铁/铜轻度缺乏组(IV组)。喂饲8周后处死,取大鼠肝脏、脾脏和血清,测定血红蛋白,血清铜、血清铁、血清转铁蛋白受体、血清铁蛋白、肝脏铁和铜含量、脾脏铁和铜含量,并用逆转录-聚合酶链反应(RT-PCR)法检测各组大鼠肝脏转铁蛋白受体(TfR)和铁调素mRNA的表达水平。结果与正常对照组相比,铜缺乏使血清铁、血清铁蛋白含量显著降低(P0.05),血清转铁蛋白受体水平、肝脾脏铁含量显著升高(P0.05),铜缺乏时肝脏TfRmRNA表达增强,而肝脏铁调素mRNA表达下降。结论铜缺乏可能通过影响铁吸收、储存、转运来影响体内铁的营养状况。铜缺乏对大鼠铁调素mRNA的表达与IRE-IRP途径调节的转铁蛋白受体mRNA的表达均产生影响。     

Influence of dietary lipids on iron and copper levels of rats administered oral contraceptives.

Interrelationships between oral contraceptives and dietary lipids on iron and copper levels in plasma and tissues were investigated in rats. Diets containing either 20% (by weight) safflower oil or hydrogenated coconut oil with and without cholesterol (0.5%) were fed to weanling, female, Wistar-strain rats for a period of 19 weeks. Three types of oral contraceptive agents differing in estrogen/progesterone ratios were administered during weeks 16 through 19 of the experiment. Control rats received the dietary treatment without oral contraceptives. Hemoglobin concentration, hematocrit, red blood cell counts, mean cell hemoglobin and hemoglobin concentration, and mean cell volume values were similar among the various dietary and drug-treatment groups. Elevated levels of copper were found in livers of drug-treated animals fed diets containing cholesterol and safflower oil, whereas levels of copper or iron in spleen and kidney were not influenced by oral contraceptives. Dietary safflower or coconut oil had no influence on levels of iron or copper in plasma. However, iron levels were higher in liver, spleen, and kidneys of rats fed coconut oil compared with those fed safflower oil. Cholesterol-fed rats had reduced levels of iron in plasma and tissues and increased levels of copper in plasma and liver. Iron deficiency in cholesterol-fed rats was indicated by low levels of iron in plasma, liver, spleen, and kidney. In experiment 2, animals were fed the 20% safflower oil diet, with and without sodium glycocholate or cholesterol, to determine whether the apparent malabsorption of iron resulted from sodium glycocholate or cholesterol. Sodium glycocholate resulted in a marked increase in the absorption of iron, whereas cholesterol depressed absorption.     

氟硒联合作用对大鼠体内铜,锌,铁影响的研究

采用原子吸收光谱法对饮用含氟、硒及氟和硒的去离子水溶液达八周的大鼠血清、心、肝、脾、肾组织中的铜、锌、铁含量进行了测定，以观察氟及氟硒联合作用 鼠体内这些微量元素的影响。本研究结果表明，氟化物可引起大鼠血清铜、铁含量增高、心、肝、脾、肾组织中锌、铁含量增高，而使肾组织铜含量降低，氟硒联合作用可使大鼠血清铜明显降低，锌、铁含量明显增高，心、肝、脾、肾组织中铜、锌、铁含量增高。硒对氟致血清铜升高、肾铜     

Vitamin B-12 deficiency and hyperhomocysteinemia are partly ameliorated by cobalt and nickel supplementation in pigs

Vitamin B-12 deficiency and hyperhomocysteinemia alter the metabolism of trace elements. This study tested the hypothesis that there is a reverse relationship in which diets high in iron, copper, nickel and cobalt would influence vitamin B-12 deficiency outcomes including hyperhomocysteinemia. Piglets (German Landrace x Pietrain) were assigned to six groups of 8 and fed one of the following diets for 166 d: a vitamin B-12-adequate and folate-fortified diet (30 microg/kg vitamin B-12 and 0.5 mg/kg folate) with normal trace element concentrations or one of five vitamin B-12-free, folate nonsupplemented diets (0.36 mg/kg), with either normal trace element concentrations or high concentrations of iron (300 mg/kg), copper (30 mg/kg), cobalt (1 mg/kg) or nickel (6 mg/kg). Feed intake and weight gain did not differ significantly among the groups. Vitamin B-12-deficient pigs developed diminished serum and liver concentrations of vitamin B-12 and folate, an accumulation of iron in the liver and hyperhomocysteinemia. The magnitude of changes differed among vitamin B-12-deficient groups. Vitamin B-12-deficient pigs fed 6 mg/kg nickel had distinctly higher vitamin B-12 concentrations in liver and serum and 45% lower serum concentration of homocysteine than the corresponding deficiency group fed 1 mg/kg nickel; iron concentration in liver was completely normalized. Vitamin B-12-deficient pigs fed 1 mg/kg cobalt had 47% lower homocysteine concentrations in serum than the vitamin B-12-deficient group fed 0.13 mg/kg cobalt, but the vitamin B-12 status was unaffected. Supplementation of iron and copper did not affect these variables. The dietary manipulations had no detrimental effects on variables symptomatic of oxidative stress. The findings indicate a collaborative relationship between vitamin B-12 metabolism and the trace elements nickel and cobalt.     

Vitamin A deficiency increases hepcidin expression and oxidative stress in rat

ObjectiveThe interaction between vitamin A and iron status has been widely reported; however, the exact mechanism involved in this interaction has not been well characterized. The present study investigated the mechanism involved in tissue iron accumulation and changes in the oxidative status in vitamin A–deficient rats.MethodsRats were treated with a control diet, a vitamin A–deficient diet, or a vitamin A/iron-deficient diet for 57 d. The animals were sacrificed; the blood, liver, and spleen were collected for biochemical analysis. Analysis of variance or Mann-Whitney tests were used to compare groups and Pearson's or Spearman's tests to investigate the bivariate correlation.ResultsVitamin A deficiency increased liver hepcidin mRNA and iron spleen concentrations; however, iron deficiency in vitamin A–deficient rats deeply inhibits liver hepcidin mRNA expression and significantly increases divalent metal transporter-1 mRNA levels. Liver ferroportin and hereditary hemochromatosis gene mRNA levels did not change in either treatment. In the vitamin A–deficient groups, liver carbonyl protein increased, whereas catalase and glutathione S-transferase activities decreased, suggesting that vitamin A protects the liver against protein oxidation. A significant positive correlation was found between lipid oxidative damage and iron concentration in the liver and spleen (r = 0.611, P = 0.007; r = 0.558, P = 0.025, respectively).ConclusionThese results suggest that vitamin A maintains iron homeostasis by the modulation of liver hepcidin expression. The increase of lipid peroxidation in vitamin A deficiency seems to be iron dependent, whereas protein oxidation is not.     

Variable effects of iron status on the concentration of ferritin in rat plasma, liver, and spleen

The present studies were conducted to determine the relationships between iron status and ferritin levels in plasma, liver, and spleen of rats. Rats were fed either iron-adequate or iron-deficient purified diets, and measurements of hemoglobin and plasma and tissue ferritin levels were made at various times during iron depletion and iron repletion. Although mean plasma ferritin concentrations of iron-deficient rats were directionally less than those of iron-adequate rats, these differences were not statistically significant due to high variability among similarly treated animals. During iron repletion plasma ferritin concentrations again were so variable that no significant effect of iron repletion on plasma ferritin concentrations was observed. On the other hand, liver and spleen ferritin concentrations of similarly treated rats were much less variable. Ferritin liver and spleen stores decreased more rapidly than hemoglobin during iron deficiency and were restored more slowly than hemoglobin during iron repletion. There was no evidence of correlation between liver and plasma ferritin concentration. Because of the variable responses of plasma ferritin concentration to iron depletion and repletion and the lack of relationship between plasma and liver ferritin concentrations, it is concluded that plasma ferritin concentration is not a good indicator of iron status in rats.     

Effects of dietary nickel and protein on growth, nitrogen metabolism and tissue concentrations of nickel, iron, zinc, manganese and copper in calves

Thirty male calves were used in a 2 X 3 factorial arrangement of treatments to determine the effects of dietary nickel and protein on performance, urease activity and tissue concentrations of nickel, iron, zinc, copper and manganese. Protein levels evaluated were 10.0, 12.25 and 14.5%, and nickel was supplemented at a level of 0 or 5 mg/kg of diet. Nickel did not affect growth during the 140-d study but tended to increase efficiency of gain in calves fed 14.5% protein. Rumen fluid urease activity was increased by nickel only in animals receiving the low protein diet. Urease activity in rumen fluid was higher in calves fed 10.0% than in animals fed 12.25% or 14.5% protein. Neither nickel nor protein affected urease activity in rumen epithelium. Increasing dietary protein resulted in increased urease in cecal digesta. Lung, liver, kidney and serum nickel concentrations were increased by supplemental nickel. A nickel X protein interaction was noted for kidney nickel. Nickel supplementation increased kidney nickel to a greater degree in calves fed 10.0% protein than in calves fed higher protein levels. Nickel supplementation reduced iron concentrations in lung, liver and muscle and manganese concentrations in muscle. Increased dietary protein decreased iron in liver and spleen but increased manganese concentrations in heart. These findings indicate that dietary protein influences responses of ruminants to nickel supplementation and relatively small increases in dietary nickel and protein can influence metabolism of other trace elements.     

Interaction of dietary carbohydrate, ascorbic acid and copper with the development of copper deficiency in rats

The effects of dietary carbohydrate and ascorbic acid on the development of copper deficiency were investigated. Male Sprague-Dawley rats (n = 48) were fed one of eight diets in a 2 X 2 X 2 factorial design for 21 d. These diets varied in copper (1.11 or 8.96 micrograms Cu/g diet), carbohydrate (sucrose or cornstarch, 62.3%) and ascorbic acid (0 or 1%). Compared to controls, copper-deficient rats had lower hematocrit and ceruloplasmin levels, lower levels of copper and iron in several tissues, higher heart weights and lower spleen weights. During copper deficiency, liver iron levels were higher than control levels when cornstarch, but not sucrose, was the carbohydrate source, while liver and gastrointestinal tract weights were higher with sucrose compared to cornstarch. Copper-deficient rats fed ascorbic acid had significantly (P less than 0.05) lower hematocrits when fed sucrose compared to starch [29.6 +/- 1.2 vs. 36.8 +/- 1.2 g/dl (mean +/- SEM), respectively]. In copper-deficient rats, sucrose tended to lower the apparent absorption of copper compared to cornstarch, while ascorbic acid reduced the apparent absorption of iron. Thus, sucrose and ascorbic acid appeared to reduce hematocrit levels through effects on mineral absorption.     

Effect of cellulose on iron, zinc and copper metabolism in growing rats

The purpose of the study was determination of the effect of cellulose on the apparent absorption and tissue concentrations of iron, zinc and copper in growing rats. Male Wistar rats with initial body weight 108 +/- 2 g were fed during 6 weeks isocaloric diets containing 1%, 5% or 10% of dietary fibre. The diets contained about 18% protein (casein and wheat gluten 1:1) and iron 28 mg, zinc 17 mg and copper 4.5 mg per kg of diet. In the 2nd, 4th and 6th weeks of the experiment feaces were collected during 2 days. Mineral components of the diets, cases liver, spleen, kidneys and femur were determined by atomic absorption spectrophotometry. No significant differences were noted in diet intake or in body weight gain between these groups. Increased cellulose content in diet, that is 5% or 10%, reduced significantly the absolute and per cent apparent absorption of copper and its concentration in liver, which indirectly led to disturbances of iron metabolism. As a result, the concentration of haemoglobin was reduced and the hepatic iron reserve was raised. No adverse effect of cellulose was found on the apparent absorption of iron and zinc and on zinc concentration in the studied tissues. The per cent coefficients of apparent absorption of iron decreased during the experiment, while those of zinc and copper increased.     

Tucum-Do-Cerrado (Bactris setosa Mart.) Consumption Modulates Iron Homeostasis and Prevents Iron-Induced Oxidative Stress in the Rat Liver

This study investigated the effect of tucum-do-cerrado consumption in the oxidative status of iron-supplemented rats. Four groups of rats were treated: Control (AIN-93G), Tuc (AIN-93G added of tucum-do-cerrado), Fe (AIN-93G iron-enriched), or TucFe (AIN-93G with tucum-do-cerrado and iron-enriched) diet, for 30 days. Iron-enriched diet increased serum, liver, spleen, and intestine iron levels; transferrin saturation; liver lipid oxidation; mRNA levels of hepatic Hamp and Bmp6, and Nrf2 in the intestine. Tucum-do-cerrado consumption reduced spleen lipid and protein oxidation; mRNA levels of hepatic Hamp and Ftl, and increased serum antioxidant capacity and hepatic mRNA levels of Bmp6, Hmox1, Nqo1, and Nrf2. TucFe diet consumption abrogated the liver Hamp iron-induced up-regulation, prevented intestinal iron accumulation; hepatic lipid peroxidation; splenic protein damage, and the increase of catalase, glutathione reductase, and glutathione peroxidase activity in some tissues. These results suggest that tucum-do-cerrado protects tissues against oxidative damage, by reducing iron availability in liver and consequently inhibiting liver Hamp expression.     

不同锌营养状况对大鼠铁代谢的影响

目的研究不同锌营养状况对大鼠铁代谢和肝脏铁调节蛋白(IRP)mRNA、铁蛋白(Fn)mRNA及转铁蛋白受体(TfR)mRNA的影响。方法 40只雄性SD大鼠按体重随机分为4组,每组10只,铁和锌正常对照组(ZA组),铁正常锌缺乏组(ZD组),铁和锌正常配饲组(PF组),铁正常锌过量组(ZE组)。喂饲8周后麻醉处死,取大鼠肝脏、脾脏和血清,测定血红蛋白,血清锌、血清铁、血清转铁蛋白受体、血清铁蛋白、肝脏铁和锌含量、脾脏铁和锌含量,并用逆转录-聚合酶链反应(RT-PCR)法检测各组大鼠IRP2 mRNA和肝脏TfR mRNA以及Fn mRNA的表达水平。结果与对照组相比,锌过量使肝脏和脾脏铁含量、血清铁水平显著降低(P<0.05);锌缺乏使肝脏铁含量、血清转铁蛋白受体水平显著增高(P<0.05),同时,血清铁水平显著降低(P<0.05);锌缺乏时肝脏IRP mRNA及TfR mRNA表达显著增强。结论锌缺乏可能通过影响铁吸收、储存、转运来影响体内铁的营养状况。锌缺乏通过改变IRP2表达、IRP-RNA结合活性,在转录后水平改变TfR mRNA和FnmRNA表达,影响铁稳态。     

The effects of an oral contraceptive,ascorbic acid and iron on glucose and copper metabolism in the rat

The effects of norethynodrel-mestranol, administered alone or by gavage in a diet high in ascorbic acid and/or iron, on glucose and copper metabolism were studied in the rat. After oral administration of glucose, serum glucose levels were significantly lower in animals receiving the high ascorbic acid diet (p less than .05) and in rats receiving norethynodrel-mestranol (p less than .01) than in controls. None of the dietary regimens had any effect on pancreatic histology. Norethynodrel-mestranol significantly increased serum levels of copper (p less than .05) and ceruloplasmin (p less than .01), and significantly reduced liver copper storage (p less than .01). 250 mg/kg diet of iron significantly increased copper and ceruloplasmin levels over those induced by 25 mg/kg diet of iron (p less than .05). The combination of norethynodrel-mestranol with high dietary iron and ascorbic acid intake did not adversely affect glucose tolerance and pancreatic histology.     

铁和复合微量营养素改善缺铁性贫血的实验研究

目的 :探讨铁和多种微量营养素改善缺铁性贫血的效果。方法 :用小鼠建立缺铁性贫血动物模型 ,设铁、多种微量营养素 3个补充剂量组和对照组。结果 :铁和复合微量营养素显著提高小鼠的血红蛋白、红细胞压积和血清铁水平 ,并显著降低高剂量组小鼠红细胞内游离原卟啉水平。结论 :在补铁的同时加用铜、锌等多种微量营养素能明显改善缺铁性贫血的症状     

Effect of zinc and copper deficiency on microsomal NADPH-dependent active oxygen generation in rat lung and liver

Both dietary zinc and copper deficiencies can cause lipid peroxidation in microsomes in rats. The cytochrome P-450 enzyme system can generate active oxygens by uncoupling of the P-450-oxy complex in the catalytic cycle and/or the electron transfer mediated by the NADPH-cytochrome P-450 reductase. The effects of dietary zinc and copper deficiencies on NADPH-dependent H2O2 generation, the catalytic activity of the cytochrome P-450 enzyme with aminopyrine as the substrate and the activity of NADPH-cytochrome P-450 reductase were determined. Zinc deficiency caused increased H2O2 production, increased NADPH-cytochrome P-450 reductase activity, decreased aminopyrine demethylation and two- and fivefold increases in iron concentration in lung and liver microsomes, respectively, compared to Zn-adequate, ad libitum--fed controls. Active oxygen generation by uncoupling of the cytochrome P-450 enzyme system and accumulation of iron are thus possible mechanisms by which zinc deficiency causes microsomal lipid peroxidation. Copper deficiency did not affect H2O2 production; however, it caused two- and fourfold increases in iron concentration in lung and liver microsomes, respectively, compared to Cu-adequate, ad libitum--fed controls. The mechanism by which cooper deficiency causes microsomal lipid peroxidation is still unknown but could be related to the observed accumulation of iron.     

A postweaning iron-adequate diet following neonatal iron deficiency affects iron homeostasis and growth in young rats

Iron deficiency is among the most prevalent of nutrient-related diseases worldwide, but the long-term consequences of maternal and neonatal iron deficiency on offspring are not well characterized. We investigated the effects of a postweaning iron-adequate diet following neonatal iron deficiency on the expression of genes involved in iron acquisition and homeostasis. Pregnant rats were fed an iron-adequate diet (0.08 g iron/kg diet) until gestational d 15, at which time they were divided into 2 groups: 1) a control group fed an iron-adequate diet, and 2) an iron-deficient group fed an iron-deficient diet (0.005 g iron/kg diet) through postnatal d (P) 23 (weaning). After weaning, pups from both dietary treatment groups were fed an iron-adequate diet until adulthood (P75). Rat pups that were iron deficient during the neonatal period (IDIA) had reduced weight gain and hemoglobin concentrations and decreased levels of serum, liver, and spleen iron on P75 compared with rats that were iron sufficient throughout early life (IA). IDIA rats developed erythrocytosis during postweaning development. Further, hepatic expression of hepcidin in IDIA rats was 1.4-fold greater than in IA rats, which paralleled an upregulation of IL-1 expression in the serum. Our data suggest that an iron-adequate diet following neonatal iron deficiency induced an inflammatory milieu that affected iron homeostasis and early growth and development.     

Serum and secretory proteins in iron-deficient rat pups and dams

The effects of iron status during reproduction on serum and secretory proteins in rat dams and pups were studied. Pregnant rats were fed ad libitum diets containing 10 or 250 ppm iron throughout gestation and lactation. Litters were adjusted on day 1 to contain 7 pups, and on day 17, dams and pups were sacrificed. Iron status was determined, and concentrations of various serum and secretory proteins were measured. Iron-deficient pups had lower hemoglobin, serum iron, and liver iron compared to controls. Serum albumin and globulin concentrations were significantly increased in iron-deficient pups. Pup serum lysozyme and myeloperoxidase levels were unchanged by iron deficiency. The serum protein profile of dams was relatively unaltered by dietary iron deficiency. Milk iron concentration was significantly decreased in iron-deficient dams; however, milk from all dams was similar in concentration of three immunoproteins measured: lysozyme, peroxidase, secretory IgA. Salivary total protein, lysozyme, and secretory IgA concentrations were similar between groups of dams. It is concluded that dietary iron deficiency during reproduction which does not retard growth of pups but does deplete iron stores has a minimal effect on the secretory immunoproteins measured.     

Zinc-vitamin A interaction in pregnant and fetal rats: supplemental vitamin A does not prevent zinc-deficiency-induced teratogenesis

The influence of a higher-than-normal intake of vitamin A on the detrimental effects of zinc deficiency on vitamin A metabolism was investigated in pregnant Sprague-Dawley rats. At mating, rats were fed diets containing 100 (control), 4.5, or 0.5 micrograms/g zinc combined with 4 (control) or 8 micrograms retinyl acetate/g. Low intake of zinc, but not of vitamin A, caused food intake, total body weight change, fetal weight and placental weight to be low. Incidence of teratogenic effects was more pronounced in low zinc groups than in controls. Concentrations of vitamin A in maternal plasma and liver were affected by the amount of zinc in the diet. Dietary vitamin A, however, did not affect either of these parameters. Maternal plasma zinc concentration was affected only by low dietary zinc, whereas plasma copper and iron were unaffected by the dietary treatments. Maternal liver iron was higher in zinc-deficient rats than in controls; however, maternal liver zinc and copper concentrations were not altered by dietary treatments. No significant differences in vitamin A concentration of fetal liver, fetal plasma, or placenta were seen among the groups. Fetuses from zinc-deficient dams had significantly lower levels of liver vitamin A and liver zinc than did controls. Fetal liver iron was higher in zinc-deficient fetuses than in controls, whereas fetal liver copper was not affected by dietary treatment. These data suggest that supplemental dietary vitamin A does not ameliorate the effect of zinc deficiency on vitamin A metabolism during pregnancy.     

Oxidation, excretion, and tissue distribution of [26-14C] cholesterol in copper-deficient rats

The effect of copper deficiency on in vivo catabolism and excretion of [26-14C] cholesterol was studied in male rats. The study involved four treatments, namely, control, copper-deficient, control plus cholesterol, and copper-deficient plus cholesterol supplement. Significant elevations of serum ester and total cholesterol concentrations and reductions of serum free, ester, and total cholesterol specific activities were observed in rats fed the copper-deficient diets. In addition, a significant reduction of liver free cholesterol concentration was observed in rats fed the copper-deficient diets. Cholesterol supplementation significantly increased the concentrations of, and reduced the specific activities of, the different serum and liver cholesterol fractions. The only exception was that the liver free cholesterol concentration was not altered by cholesterol supplementation. The serum free cholesterol concentration was significantly increased and the specific activities of liver ester cholesterol were significantly reduced in rats fed the copper-deficient diet with no added cholesterol. The rates of oxidation and excretion of [26-14C] cholesterol were not influenced by dietary copper but were significantly increased by cholesterol supplementation. A shift of cholesterol from the liver to the serum pool appeared to be responsible for the hypercholesterolemia observed in copper deficiency.