Dietary Copper Deficiency Research Articles

Leukocyte–endothelial adhesion is impaired in the cremaster muscle microcirculation of the copper-deficient rat

Dietary copper deficiency impairs the function of both the vascular endothelium and circulating leukocytes. In the current study, leukocyte–endothelium adhesion was observed in the in vivo cremaster muscle microcirculation of copper-adequate and copper-deficient rats. Male, weanling Sprague–Dawley rats were fed purified diets that were either adequate (5.6 μg/g) or deficient (0.3 μg/g) in copper. Adhesion was stimulated with the inflammatory mediators tumor necrosis factor-α and bradykinin, and the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine. Intravascular adhesion of leukocytes to the vascular endothelium was significantly attenuated in the copper-deficient group in response to all three agonists. These results occurred without any difference in intravascular wall shear rate between the dietary groups. Based on previous work, we propose that the attenuated response is caused by either decreased expression of adhesion molecules on leukocytes and endothelial cells or by inhibition of the endothelial cell calcium signaling associated with copper deficiency.

Copper Deficiency Induces Hepatic Fatty Acid Synthase Gene Transcription in Rats by Increasing the Nuclear Content of Mature Sterol Regulatory Element Binding Protein 1

Dietary copper (Cu) deficiency results in an accelerated rate of hepatic fatty acid synthase gene transcription and an enhanced rate of hepatic lipid synthesis. Because the nuclear transcription factor sterol regulatory element binding protein-1 (SREBP-1) is a strong enhancer of fatty acid synthase promoter activity, it was hypothesized that Cu deficiency induces fatty acid synthase gene transcription by increasing the nuclear localization of mature SREBP-1. Male weanling rats were pair-fed a Cu-adequate (6.0 mg/kg) or Cu-deficient (0.6 mg/kg) diet (AIN-93) for 28 d. DNase I hypersensitivity site mapping of the hepatic fatty acid synthase gene revealed the presence of four major hypersensitivity sites located at -8700 to -8600, -7300 to -6900, -600 to -400 and -100 to +50. Although Cu deficiency did not change the hypersensitivity site pattern or intensity, in vitro footprinting of the region between -100 and +50 indicated that Cu deficiency enhanced DNA protein interactions within this region. The sequence between -68 and -58 contains the DNA recognition sequence for SREBP-1 and upstream stimulatory element-1 (USF-1). Western blot analysis revealed that the dietary Cu deficiency increased the hepatic nuclear content of mature SREBP-1 by 150% (P: < 0.05), and it concomitantly decreased the membrane content of precursor SREBP-1 by 45% (P: < 0.05). Changes in the hepatic distribution of SREBP-1 associated with Cu deficiency were not accompanied by changes in SREBP-1 mRNA. The nuclear content of USF-1 was unaffected by dietary Cu status. The hepatic increase in mature SREBP-1 of Cu-deficient rats was accompanied by a 400% increase and an 80% decrease in the abundance of fatty acid synthase and cholesterol 7-alpha hydroxylase mRNA, respectively. hepatic These data indicate that a Cu deficiency stimulates hepatic lipogenic gene expression by increasing the hepatic translocation of mature SREBP-1.

Copper deficiency and cardiovascular disease: role of peroxidation, glycation, and nitration

Dietary copper deficiency causes a variety of cardiovascular deficits. Systemic effects include high blood pressure, enhancement of inflammation, anemia, reduced blood clotting, and possibly arteriosclerosis. Effects on specific organs or tissues include weakened structural integrity of the heart and blood vessels, impairment of energy use by the heart, reduced ability of the heart to contract, altered ability of blood vessels to control their diameter and grow, and altered structure and function of circulating blood cells. In some instances, the cause of a defect can be directly attributed to reduced activity of a specific copper-dependent enzyme. However, three nonspecific mechanisms of damage have been implicated in cardiovascular defects of copper deficiency. They are peroxidation, the interaction of oxygen-derived free radicals with lipids and proteins (possibly DNA); glycation, the nonenzymatic glycosylation of proteins; and nitration, the interaction of nitric oxide and its metabolites with peptides and proteins. Though independently these mechanisms present great potential for damage, the possibility that they may interact presents an added reason for concern. Furthermore, the fact that at least two of these mechanisms are associated with diabetes and aging suggests that copper deficiency may exacerbate deficits associated with these two conditions.Key words: copper, heart, circulation, peroxidation, glycation, nitric oxide.

Copper Deficiency Suppresses Effector Activities of Differentiated U937 Cells

Dietary copper (Cu) deficiency impairs both innate and acquired branches of immunity. Specific roles of Cu in the activation and effector activities of host-defense cells remain largely unknown. The effects of Cu status on effector activities of a monocytic cell line were investigated as an initial step in the elucidation of specific functions of Cu in phagocytic cells. Exposure of differentiating U937 human promonocytic cells to 5 micromol/L 2,3, 2-tetraamine (tet), a high affinity Cu chelator, for 4 d decreased cellular Cu by 62% without altering cellular Cu,Zn-superoxide dismutase (SOD) activity, Zn content, mitochondrial activity and protein synthesis. In contrast, Cu deficiency suppressed the respiratory burst activity and markedly compromised the ability of U937 cells to kill Salmonella. Similarly, treatment of RAW264.7 murine macrophages with 5 micromol/L tet decreased cell Cu by 78% and Cu,Zn-SOD activity by 15% and increased bacterial survival by 180%. The tet-induced impairment of respiratory burst and bactericidal activities was blocked in cultures supplemented with Cu, but not Zn or Fe. In addition, lipopolysaccharide (LPS)-induced secretion of the inflammatory mediators, tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6 and prostaglandin E(2) (PGE(2)), was decreased by 30-60% in tet-treated U937 cells. Flow cytometric analysis of the surface antigens CD11b and CD71 showed that the suppressed activities of Cu-deficient cells were not due to an attenuation in the degree of differentiation or secondary iron deficiency. These data demonstrate that U937 cells provide a useful model for examining the biochemical roles of Cu in monocyte activity.

Copper deficiency and cardiovascular disease: role of peroxidation, glycation, and nitration.

Dietary copper deficiency causes a variety of cardiovascular deficits. Systemic effects include high blood pressure, enhancement of inflammation, anemia, reduced blood clotting, and possibly arteriosclerosis. Effects on specific organs or tissues include weakened structural integrity of the heart and blood vessels, impairment of energy use by the heart, reduced ability of the heart to contract, altered ability of blood vessels to control their diameter and grow, and altered structure and function of circulating blood cells. In some instances, the cause of a defect can be directly attributed to reduced activity of a specific copper-dependent enzyme. However, three nonspecific mechanisms of damage have been implicated in cardiovascular defects of copper deficiency. They are peroxidation, the interaction of oxygen-derived free radicals with lipids and proteins (possibly DNA); glycation, the nonenzymatic glycosylation of proteins; and nitration, the interaction of nitric oxide and its metabolites with peptides and proteins. Though independently these mechanisms present great potential for damage, the possibility that they may interact presents an added reason for concern. Furthermore, the fact that at least two of these mechanisms are associated with diabetes and aging suggests that copper deficiency may exacerbate deficits associated with these two conditions.

Endothelial cell calcium mobilization to acetylcholine is attenuated in copper-deficient rats.

Dietary copper deficiency significantly attenuates nitric oxide (NO)-mediated vascular smooth muscle relaxation and vasodilation. There is evidence for both increased inactivation of the NO radical by superoxide anion, and oxidative damage to the endothelium where NO is produced. The current study was designed to examine the NO synthetic pathway in the endothelium during copper deficiency. Male weanling rats were fed a copper-adequate (CuA, 6.4 mg Cu/kg diet) or copper-deficient (CuD, 0.4 mg Cu/kg diet) diet for four weeks. Cremasteric arterioles (approximately 100 microm diameter) were isolated and used for the experiments. Western blot analysis of the arteriole endothelial nitric oxide synthase (eNOS) concentration did not show a difference between dietary groups. Acetylcholine (Ach)-induced vasodilation was significantly reduced in the CuD group both before and after pretreatment with the eNOS substrate L-arginine. Endothelial intracellular calcium ([Ca2+]i) stimulated by 10(-6) M Ach was significantly inhibited in the arterioles from CuD rats. Coincident with the inhibition of [Ca2+]i and vasodilation was a depression of vascular Cu/Zn-SOD activity and an increase in plasma peroxynitrite activity. These data suggest that endothelial Ca2+ signaling and agonist-stimulated NO-mediated vascular dilation are likely reduced by increased oxidative damage in copper-deficient rats.

Elemental composition of anatomically distinct regions of rat liver.

Experiments were conducted to test the commonly held assumption that analysis of a portion of rat liver is representative of the elemental concentration of the whole organ. Male Sprague-Dawley rats (initial body weight approximately 250 g) fed a chow diet or weanling male Long-Evans rats (initial body weight approximately 50 g) fed a semipurified diet with or without copper in the mineral premix were sacrificed after 4 wk on their respective diets and livers were dissected into seven portions representing major anatomical divisions of this organ. Elemental analyses by atomic absorption spectroscopy (calcium, magnesium, iron, zinc, copper, manganese), atomic emission spectroscopy (sodium, potassium), or colorimetric assay (phosphorus) demonstrated no statistically significant differences in composition of these nine elements among anatomical regions of liver. Dietary copper deficiency led to equivalently reduced copper concentration in all portions of rat liver and did not cause any other significant alterations in liver composition of these nine elements within the 4 wk of these studies. These results confirm the validity of the common assumption that analysis of a portion of rat liver can be representative of the elemental composition of the whole organ. This conclusion will allow more analyses to be performed on fewer animals, thereby reducing animal use and reagent costs without sacrificing analytical accuracy.

Level of Dietary Iron, Not Type of Dietary Fat, is Hyperlipidemic in Copper-Deficient Rats

Objective: This study was conducted to determine whether high dietary iron will negate the protective effect of unsaturated fat against hyperlipidemia.Methods: Forty-eight weanling, male Sprague Dawley rats were randomly assigned to eight dietary groups differing in the levels of copper and iron and type of dietary fat (saturated or unsaturated). The diets were either deficient (0.6 μg Cu/g) or adequate (6.8 μg Cu/g) copper and either adequate (53 μg Fe/g) or high (506 μg Fe/g) iron. All diets contained starch as the sole source of dietary carbohydrate.Results: Regardless of the type of dietary fat, three copper-deficient rats fed the high levels of dietary iron died prematurely due to ruptured hearts. Surviving rats belonging to the copper deficiency and high-dietary iron regimen developed severe anemia, enlarged hearts and livers, and exhibited the highest levels of liver iron. These rats also developed hypercholesterolemia. Triglycerides were elevated by the consumption of high iron diets.Conclusion: Data show that levels of dietary iron, not the type of dietary fat, are potential inducers of hypertriglyceridemia. Data also show that the combination of high iron intake and dietary copper deficiency is responsible for elevating blood cholesterol.

Cardiovascular Measurements Relevant to Heart Size in Copper-Deficient Rats

Dietary copper deficiency in animals is often associated with cardiac enlargement and anemia. In this study we examined the hypothesis that anemia leads to a high cardiac output state that results in work-induced (physiological) cardiac hypertrophy. Blood pressure was measured by carotid cannulation and cardiac output was measured by aortic flow probe in anesthetized, open-chested rats that had been subjected to various degrees of dietary copper deficiency for five weeks. Cardiac output was unaffected by dietary copper deficiency. However, the components of cardiac output were found to vary reciprocally, heart rate decreasing and stroke volume increasing with copper deficiency. Further, total peripheral resistance, calculated as the ratio of mean arterial blood pressure and cardiac output, was depressed by dietary copper deficiency. These findings suggest that bradycardia and depression of vascular resistance induced by copper deficiency contribute to increased venous filling and a resultant increase in stroke volume; these factors may lead to cardiac hypertrophy. A significant correlation between stroke volume and heart weight in rats of varying copper status supports this conclusion.

Evaluation of rat white blood cell and plasma peptidylglycine α-amidating monooxygenase activity as indicators of copper status

Activity of the cuproenzyme peptidylglycine α-amidating monooxygenase (PAM) was studied in two-month-old male Holtzman rats following dietary copper (Cu) deficiency. Compared to Cu-adequate controls, Cu-deficient rats exhibited cardiac hypertrophy (94% increase) and lower liver Cu concentrations (87% decrease). White blood cell PAM activity was not altered by dietary Cu deficiency but activity of Cu,Zn-superoxide dismutase, another cuproenzyme, was lower in the same cells from Cu-deficient rats (68% decrease). Plasma PAM activity was lower in samples from Cu-deficient rats (32% decrease) compared to Cu-adequate rats. In additional studies it was found that PAM activity of serum was higher than plasma, that gender and type of anesthesia had little influence on PAM activity of plasma. Plasma but not white blood cell PAM activity is a useful indicator of Cu status.

Early and advanced glycation end-products are increased in dietary copper deficiency

The hypothesis that nonenzymatic glycosylation of proteins (glycation) contributes to damage associated with dietary copper deficiency has depended largely on indirect evidence. Thus far, the observation of an elevated percentage of glycated hemoglobin in copper-deficient rats has provided the only direct evidence of an increase in glycation. We sought further direct evidence of increased glycation in copper deficiency. Male weanling rats were fed a copper-adequate (CuA, 6.4 mg Cu/kg diet) or copper-deficient diet (CuD, 0.4 mg Cu/kg diet) for 5 weeks. Rats fed the CuD diet were copper deficient as judged by depressed organ copper concentrations and a variety of indirect indices. Measurements of hemoglobin A 1 and serum fructosamine (both early glycation end-products) as well as serum pentosidine (an advanced glycation end-product) indicated that all three compounds were elevated in CuD rats relative to CuA rats. This finding further supports the view that glycation is enhanced and thus may contribute to defects associated with dietary copper deficiency.

Relationship between dietary copper concentration and acetylcholine‐induced vasodilation in the microcirculation of rats

Dietary copper deficiency has been shown to significantly reduce acetylcholine (Ach)-induced vascular smooth muscle relaxation. The current study was designed to examine the relative relationship between dietary copper and the vasodilator response to Ach in the microcirculation of the rat. Male weanling rats were fed a purified basal diet supplemented with 6.0, 3.0, 1.5 or 0.0 microg Cu/g diet for 4 weeks to provide an adequate, two marginal, and deficient intakes of dietary copper. Arteriole dilation in response to increasing concentrations of acetylcholine (10(-7) to 10(-4) M) was measured in the in vivo cremaster muscle microcirculation for each dietary group. Liver copper and both aortic and erythrocyte Cu,Zn-SOD activity were used as indices of systemic copper status. Dilation to the increasing concentrations of Ach was only different in the 0 microg Cu supplemented group compared to the copper-adequate control values. However, the combined results showed an exponential increase in 10(-5) M Ach-induced vasodilation as liver copper concentration increases from 0 microg Cu/g dry wt. This relationship suggests that dilation is attenuated at liver Cu concentrations below 5 microg/g dry wt. The results indicate that Ach-induced vasodilation is copper-dependent but that the pathway is not very sensitive to short-term marginal restriction of copper intake.

Cardiovascular effects of dietary copper deficiency.

Dietary copper deficiency may impair cardiovascular health by contributing to high blood pressure, enhancement of inflammation, anemia, reduced blood clotting and arteriosclerosis. The purpose of this review is to compile information on the numerous changes of the heart, blood and blood vessels that may contribute to these cardiovascular defects. These alterations include weakened structural integrity of the heart and blood vessels, impairment of the use of energy by the heart, reduced ability of the heart to contract, altered ability of blood vessels to control their diameter and to grow, and altered structure and function of circulating blood cells. The fundamental causes of these changes rest largely on reduced effectiveness of enzymes that depend on copper for their activity.

Hepatic fatty acid synthase gene transcription is induced by a dietary copper deficiency.

A dietary copper (Cu) deficiency is associated with a twofold increase in hepatic fatty acid biosynthesis. We hypothesized that the induction of hepatic lipogenesis associated with a dietary Cu deficiency reflected an enhanced expression of genes encoding lipogenic enzymes, i.e., fatty acid synthase (FAS). Male weanling rats were pair-meal fed for 42 days a high-sucrose diet that was Cu deficient (CuD; 0.7 microgram Cu/g) or Cu adequate (CuA; 5.0 micrograms Cu/g). The CuD diet increased FAS enzymatic activity twofold (P < 0.05). This rise in enzymatic activity was accompanied by a threefold increase in FAS mRNA and a 2.5-fold increase in FAS gene transcription (P < 0.05). Neither the mRNA abundance nor the rate of gene transcription for phosphoenolpyruvate carboxykinase or beta-actin was affected by the CuD diet. The induction of FAS gene transcription was associated with a 65-85% increase in hepatic reduced glutathione (GSH; P < 0.05). When hepatic GSH synthesis was suppressed by treating CuD rats with L-buthionine sulfoximine, the induction of FAS expression was completely prevented. Similarly, feeding N-acetylcysteine to CuA rats increased hepatic GSH levels 2.5-fold, and this was accompanied by a significant induction in FAS expression. These data indicate that the increase in hepatic lipogenesis associated with a Cu deficiency reflects an induction in hepatic lipogenic gene transcription (i.e., FAS) and that the rate of gene transcription may be dependent on hepatic thiol redox.

Angioarchitecture of the atrophic pancreas.

The pancreas has a complex vasculature which comprises both exocrine and endocrine structures. Copper deficiency induces highly selective acinar cell degeneration and progressive noninflammatory lipomatosis in pancreas while Langerhans islets, ducts, and nerves remain unaffected. Pancreatic vasculature was examined in rats that had dietary copper deficiency to characterize changes in the angioarchitecture of the gland. This model was used to assess the degree to which the vasculature of non-acinar components of the gland are potentially altered under conditions of exocrine atrophy. Ultrastructure of pancreas was examined by histology, enzyme histochemistry and immunohistochemistry, corrosion casting and scanning electron microscopy, in situ vascular staining, microsphere injection, biochemical analysis, and morphometry in copper-deficient rats. Results show that no acute angiopathic changes indicative of vascular disorganization accompany atrophy. Only a reduction in the complexity of the capillary beds, which normally vascularize the dense acinar parenchyma, was found. Microsphere quantitation also showed that blood flow to the lipomatous gland remains intact. Furthermore, analysis of the angioarchitecture of the atrophied pancreas supports a largely autonomous blood supply to islets and ducts. These observations support the hypothesis that while the vasculature of the atrophied gland is modified in vascular regions severely targeted by acinar necrosis, the overall structural features of the angioarchitecture are preserved. The atrophied gland thus provides an experimental model to study the vascular routes supplying islet and ductal blood flow within the complex pancreatic circulation.

Angioarchitecture of the atrophic pancreas

The pancreas has a complex vasculature which comprises both exocrine and endocrine structures. Copper deficiency induces highly selective acinar cell degeneration and progressive noninflammatory lipomatosis in pancreas while Langerhans islets, ducts, and nerves remain unaffected. Pancreatic vasculature was examined in rats that had dietary copper deficiency to characterize changes in the angioarchitecture of the gland. This model was used to assess the degree to which the vasculature of non-acinar components of the gland are potentially altered under conditions of exocrine atrophy. Ultrastructure of pancreas was examined by histology, enzyme histochemistry and immunohistochemistry, corrosion casting and scanning electron microscopy, in situ vascular staining, microsphere injection, biochemical analysis, and morphometry in copper-deficient rats. Results show that no acute angiopathic changes indicative of vascular disorganization accompany atrophy. Only a reduction in the complexity of the capillary beds, which normally vascularize the dense acinar parenchyma, was found. Microsphere quantitation also showed that blood flow to the lipomatous gland remains intact. Furthermore, analysis of the angioarchitecture of the atrophied pancreas supports a largely autonomous blood supply to islets and ducts. These observations support the hypothesis that while the vasculature of the atrophied gland is modified in vascular regions severely targeted by acinar necrosis, the overall structural features of the angioarchitecture are preserved. The atrophied gland thus provides an experimental model to study the vascular routes supplying islet and ductal blood flow within the complex pancreatic circulation. Microsc. Res. Tech. 37:520–542, 1997. © 1997 Wiley-Liss, Inc.

Copper Deficiency Reduces Interleukin-2 (IL-2) Production and IL-2 mRNA in Human T-Lymphocytes , ,

Although dietary copper (Cu) deficiency has been associated with decreased production of interleukin-2 (IL-2) by activated splenic mononuclear cells in rodent models, the basis for this relationship and its relevance for humans remain unknown. To address these matters, we have developed an in vitro model of cellular copper deficiency by treating Jurkat, a human T-lymphocyte cell line, with low concentrations of 2,3,2-tetraamine (2,3,2-tet), a high affinity copper chelator. Exposure to 5–20 μmol/L 2,3,2-tet for 35 h decreased cell copper and the activity of Cu,Zn-superoxide dismutase (Cu,Zn-SOD) by 30–40% and IL-2 production by 60–70% in cultures activated with phytohemagglutinin and phorbol myristate acetate. Similarly, IL-2 mRNA levels were 40–70% lower in chelator-treated cells than in untreated cells at 3–12 h after activation. In contrast, chelator treatment had no significant effect on cell viability, growth, protein synthesis or mitochondrial activity. The presence of a slight molar excess of copper, but not zinc or iron, during exposure to 2,3,2-tet prevented the chelator-induced decrease in Cu,Zn-SOD activity and the reductions in IL-2 mRNA and bioactivity. Moreover, binding of diferric transferrin (Tf) and cellular uptake of Tf-59Fe by Jurkat cells were not increased by 2,3,2-tet, indicating that chelator-treated cells were not iron deficient. Finally, incubation of human peripheral blood mononuclear cells (PBMC) with 2,3,2-tet decreased mitogen-induced IL-2 production by 50% compared with untreated controls. These data indicate that a decline in copper status decreases IL-2 production by activated human T-cells due to reduced synthesis and/or stability of IL-2 mRNA.

In Vivo Oxidative Modification of Erythrocyte Membrane Proteins in Copper Deficiency

Oxidative stress has been postulated to contribute to the pathology associated with dietary copper deficiency. In vivo, erythrocytes are probable targets of oxidative damage because they are exposed to high concentrations of oxygen and contain heme iron that can autoxidize, which results in the formation of superoxide anions. Activity of the important antioxidant enzyme, copper, zinc superoxide dismutase, decreases markedly in erythrocytes during copper deficiency. The effect of dietary copper deficiency on indicators of oxidative stress was examined in erythrocyte membranes of rats maintained on a purified copper-deficient diet for 35 days after weaning. Erythrocytes were separated into young and old populations on a Percoll gradient prior to membrane isolation and quantification of lipid peroxides and protein carbonyls. Protein carbonyls, determined by Western blot immunoassay, were detected predominantly in both the alpha and beta chains of spectrin. Alpha and beta subunits of spectrin in erythrocyte membranes from copper-deficient rats contained higher amounts of carbonyls than controls, regardless of the population of erythrocytes studied. This study suggests that spectrin may be a specific target for oxidative damage when erythrocyte copper, zinc superoxide dismutase activity is reduced by copper deficiency. Copyright © 1997 Elsevier Science Inc.

Suppression of renal γ-glutamylcysteine synthetase expression in dietary copper deficiency

A dietary deficiency of copper (CuD) is associated with a 50–70% and a 2-fold increase in hepatic reduced glutathione (GSH) concentration and synthesis, respectively, which leads to a 50–80% increase in plasma GSH. Moreover, the kidneys of CuD rats remove 40% more GSH from the blood than copper adequate (CuA) rats. These findings have led us to propose that the increase in hepatic synthesis of GSH in CuD rats is accompanied by a comparable increase in the hepatic expression of γ-glytamylcysteine synthetase (γ-GCS), the rate limiting enzyme of glutathione biosynthesis, and that the enhanced uptake of GSH by the kidney would lead to a compensatory decrease in renal γ-GCS expression. In experiment I, male weanling rats (3–4 weeks) were ad libitum fed a CuD (0.5 μg Cu/g) or CuA (5.8 μg/g) diet for 70 days; and in experiment II, male weanling rats were pair-meal fed the CuD or CuA diet for 35 days. In both studies, CuD diet caused a significant increase in hepatic GSH concentration, but hepatic γ-GCS activity and mRNA abundance were unchanged. In contrast, renal GSH concentration was unaffected by the CuD diet. However, renal γ-GCS activity was reduced 40% and this was paralleled by a 50% decrease in γ-GCS mRNA. Moreover, the decrease in renal γ-GCS mRNA was caused by a reduction in renal γ-GCS gene transcription. The results of these studies indicate that the increase in renal uptake of GSH resulting from a dietary Cu deficiency is associated with a compensatory decrease in γ-GCS expression.

Feeding of 1,1,1-trichloro-2,2-bis( p-chlorophenyl)ethane (DDT) reduces some effects of dietary copper deficiency in rats

This study was conducted to examine the influence of dietary addition of 0.5g/Kg 1,1,1-trichloro-2,2-bis( p-chlorophenyl)ethane (DDT) on the effects of dietary copper deficiency in rats. Copper-deficient diet lowered tissue copper concentrations, elevated liver iron concentration, enlarged heart size, caused anemia, reduced plasma ceruloplasmin activity, and elevated levels of thiobarbituric acid reactive substances (TBARS, an indicator of oxidative stress), in liver, heart and intestinal mucosa. Although DDT feeding had no influence on tissue concentrations of copper and iron, it significantly suppressed the cardiac enlargement and elevation of TBARS levels in intestinal mucosa caused by copper-deficient diet, and elevated tissue levels of ascorbic acid. In addition, DDT feeding tended to reduce other variables associated with dietary copper deficiency, including the levels of blood hemoglobin and TBARS in liver and heart. DDT. These results indicate that DDT feeding reduces some effects of copper deficiency.