Effect of molybdenum on other trace elementscopper

Interaction of molybdate with copper(II) especially with reference to thiomolybdates and molybdenosis in ruminaant animals. Copper-molybdenum interaction in non ruminants. Copper-molybdenum compounds.

Insights into the molybdenum/copper heterometallic cluster assembly in the orange protein: probing intermolecular interactions with an artificial metal-binding ATCUN tag

Orange protein (ORP) is a small bacterial protein, of unknown function, that contains a unique molybdenum/copper heterometallic cluster, [(S2MoS2CuS2MoS2)-S-vI-S-I-S-vl](3-) (Mo/Cu), non-covalently bound. The native cluster can be reconstituted in a protein-assisted mode by the addition of Cull plus tetrathiomolybdate to apo-ORP under controlled conditions. In the work described herein, we artificially inserted the ATCUN ("amino terminus Cu and Ni") motif in the Desulfovibrio gigas ORP (Ala(1)Ser(2)His(3) followed by the native amino acid residues; modified protein abbreviated as ORP*) to increase our understanding of the Mo/Cu cluster assembly in ORP. The apo-ORP* binds Cull in a 1:1 ratio to yield Cu-II-ORP*, as clearly demonstrated by EPR (g(parallel to,perpendicular to) = 2.183, 2.042 and A(parallel to,perpendicular to)(Cu) = 207 x 10(-4) cm(-1), 19 x 10(-4) cm(-1)) and UV-visible spectroscopies (typical d-d transition bands at 520 nm, epsilon = 90 M-1 cm(-1)). The H-1 NMR spectrum shows that His, and Hiss, are significantly affected upon the addition of the Cu-II. The X-ray structure shows that these two residues are very far apart (C-alpha-C-alpha approximate to 27.9 angstrom), leading us to suggest that the metal-induced NMR perturbations are due to the interaction of two protein molecules with a single metal ion. Docking analysis supports the metal-mediated dimer formation. The subsequent tetrathiomolybdate binding, to yield the native Mo/Cu cluster, occurs only upon addition of dithiothreitol, as shown by UV-visible and NMR spectroscopies. Additionally, H-1 NMR of Ag-I-ORP* (Ag-I used as a surrogate of Cu-I) showed that Ag-I strongly binds to a native methionine sulfur atom rather than to the ATCUN site, suggesting that Cu-II and Cu-I have two different binding sites in ORP*. A detailed mechanism for the formation of the Mo/Cu cluster is discussed, suggesting that Cu-II is reduced to Cu-I and transferred from the ATCUN motif to the methionine site; finally, Cu-I is transferred to the cluster-binding region, upon the interaction of two protein molecules. This result may suggest that copper trafficking is triggered by redox-dependent coordination properties of copper in a trafficking pathway.

Maiti, B. K., Almeida, R. M., Maia, L. B., Moura, I., and Moura, J. J. G., Insights into the Molybdenum/Copper Heterometallic Cluster Assembly in the Orange Protein: Probing Intermolecular Interactions with an Artificial Metal-Binding ATCUN Tag, Inorganic chemistry, 2017, 56, 8900-8911.

Copper and molybdenum

Effects of organic and inorganic copper and sulphur supplementation on blood biochemical parameters in sheep

Minerals are essential components in the diet, exercising various functions in the animal. There are many studies to find better results for the organic sources of minerals, and one of the reasons for that is to avoid the negative interactions. The metabolic profile helps in assessment of production indices, therefore analyzes blood biochemical components.

The objective of this study was to investigate the effects of organic and inorganic copper and sulphur supplementation on blood biochemical parameters in sheep.

The experiment was conducted at the FZEA/USP.

Total 40 weaned sheep were divided in a completely randomized design with 10 treatments:

1) basal diet;

2) basal diet plus Mo;

3) basal diet + inorganic Cu + inorganic S;

4) basal diet + inorganic Cu + organic S;

5) basal diet + organic Cu + inorganic S;

6) basal diet + organic Cu + organic S;

7) diet plus Mo + inorganic Cu + inorganic S;

8) diet plus Mo + inorganic Cu + organic S;

9) diet plus Mo + organic Cu + inorganic S;

10) diet plus organic Cu + organic S.

According each treatment was added 10mg kg-1 MS inorganic or organic Cu or 10mg kg-1 MS Mo or 0.2% S inorganic or organic.

The animals were fed twice a day, a total of 3% of body weight.

The experiment lasted 84 days, blood was sampled every 28 days to study glucose, urea, albumin, cholesterol and triglycerides. The parameters were analyzed with factorial structure 2 x 2 x 2 (with and without Mo, organic and inorganic Cu and organic and inorganic S) and a basal diet and a basal diet plus Mo, with 5% significance.

Serum levels of glucose, urea, albumin and cholesterol showed no significant difference between treatment and time (p> 0.05). It observed means of 64.8mg dL-1; 30.0mg dl-1; 2.78mg L-1; 72.2mg dL-1 respectively for glucose, urea, albumin and cholesterol.

Serum levels of triglycerides in the treatments (28.8; 34.8; 30.8; 36.9; 34.3; 27.0; 31.6; 32.1; 34.6; 31.1mg dL-1) were influenced by interaction Cu x S, triglycerides decreased with Cu and S organic.

Conti, R. M. C., Zanetti, M. A., Netto, A. S., Rodrigues, P. H. M., Pacheco, J. C. G., Garrine, C., and Yoshikawa, C. Y. C., Effects of organic and inorganic copper and sulphur supplementation on blood biochemical parameters in sheep, Pesquisa Veterinaria Brasileira, 2015, 35, 875-881.

Combining -omics to unravel the impact of copper nutrition on Alfalfa (Medicago sativa) stem metabolism

Copper can be found in the environment at concentrations ranging from a shortage up to the threshold of toxicity for plants, with optimal growth conditions situated in between. The plant stem plays a central role in transferring and distributing minerals, water and other solutes throughout the plant.

In this study, alfalfa is exposed to different levels of copper availability, from deficiency to slight excess, and the impact on the metabolism of the stem is assessed by a non-targeted proteomics study and by the expression analysis of key genes controlling plant stem development.

Under copper deficiency, the plant stem accumulates specific copper chaperones, the expression of genes involved in stem development is decreased and the concentrations of zinc and molybdenum are increased in comparison with the optimum copper level. At the optimal copper level, the expression of cell wall-related genes increases and proteins playing a role in cell wall deposition and in methionine metabolism accumulate, whereas copper excess imposes a reduction in the concentration of iron in the stem and a reduced abundance of ferritins. Secondary ion mass spectrometry (SIMS) analysis suggests a role for the apoplasm as a copper storage site in the case of copper toxicity.

Determination of copper and other minerals in goats and sheep of the San Francisco river valley in Pernambuco, Brazil

For the determination of copper concentration and its antagonists, 160 serum and liver samples were used, from goat and sheep sent to the municipal slaughterhouse of Petrolina. The samples were correlated with the same animal, in order to prevent errors in data collection. Serum ceruloplasmin activity was determined by colorimetric method. For determination of minerals, the samples were diluted six to twenty times with Milli-Q water. For determining concentrations of mineral elements in the liver, the samples were digested until achieving a solution that maintained the initial sample and minerals totally liquid, without the presence of solid particles which could clog the capillary suction of the spectrometer and prevent reading of samples. The concentrations of copper, molybdenum, iron and zinc were determined by optical emission spectrometry (ICP). Thus, the experiment was conducted to determine the occurrence and distribution of copper deficiency in the San Francisco valley of Pernambuco. No copper deficiency was revealed in this region of the state of Pernambuco, when the mean levels of hepatic copper were evaluated. Zinc levels were within a normal range, whereas iron levels were higher in sheep, and lower levels of molybdenum in goats.

It was also found that the activity of ceruloplasmin was an indicator of serum copper.

Silva, S. S., Antonelli, A. C., Soares, G. W. N., Gomes, I. M. M., and Rocha, J. F.,Determination of copper and other minerals in goats and sheep of the San Francisco river valley in Pernambuco, Brazil, Pesquisa Veterinaria Brasileira, 2015, 35, 767-774.

Serum and hepatic levels of copper, zinc, iron and molybdenum in sheep and goats raised in the semiarid of Bahia state

The aim of this research was to know the copper, zinc, iron and molybdenum content in serum and liver of small ruminants raised in the cities of Casa Nova and Juazeiro, state of Bahia, and verify the occurrence of primary or secondary copper deficiency.

A total of 160 samples of sheep and goats of both sexes collected in the dry and rainy season were evaluated.

The values for serum copper in goats was 13.8+/-0.3 mu mol/L and in sheep it was 12.2+/-0.4 mu mol/L, while the mean liver concentration was 220 ppm for goats and 238 ppm for sheep.

The serum zinc value for goats was 28.3+/-1.0 mu mol/L and for sheep it was 28.7+/-0.8 mu mol/L, while the mean liver concentration was 99 ppm for goats and 92 ppm for sheep.

Serum iron value for goats was 61+/-3 mu mol/L and for sheep it was 64+/-2 mu mol/L, while liver levels were 172 ppm for goats and 221 ppm for sheep.

Copper mean values do not indicate the occurrence of copper deficiency in small ruminants raised in the cities studied. Zinc levels were within the normal values and do not require extra supplementation of this mineral. The serum iron levels were elevated, however it did not interfere in copper metabolism in order to result in a cupric deficiency.

Silva, W. R., Gomes, I. M. M., Rocha, J. F., Mori, C. S., Michima, L. E. S., Ortolani, E. L., and Antonelli, A. C.,Serum and hepatic levels of copper, zinc, iron and molybdenum in sheep and goats raised in the semiarid of Bahia state, Arquivo Brasileiro De Medicina Veterinaria E Zootecnia, 2016, 68, 155-163.

The content of copper and molybdenum in the liver, kidneys, and skeletal muscles of elk (Alces alces) from north-eastern Poland

The aim of the study was to evaluate the content of Cu and Mo in the liver, kidneys, and skeletal muscles of elks from north-eastern Poland.

The investigation material comprised samples obtained in 2010 from 35 animals. Animals were grouped according to age (elks up to 2 years and over than 3 years). The metal concentrations were determined using coupled plasma-mass spectrometry (ICP-MS) method.

The mean Cu concentrations in the liver, kidneys, and skeletal muscles were 23.08, 5.03, and 2.36 mgkg-1 wet weight, respectively.

The mean Mo content in the examined samples was as follows: 0.92, 0.42, and 0.05 mgkg-1 wet weight (w.w.) in the liver, kidneys, and muscles.

In the analysis of correlation between the Cu and Mo levels in particular organs, the presence of significant dependence (p

The mean Cu content in the liver of animals studied is lower compared with data reported from Sweden, Russia, and North America. Concentrations of Cu and Mo in the kidneys and skeletal muscles of Polish elks are similar to data noted in healthy animals from Scandinavian region. The results suggest that elks from north-eastern Poland may be threatened by primary Cu deficiency.

Skibniewski, M., Skibniewska, E. M., Kosla, T., and Olbrych, K., The Content of Copper and Molybdenum in the Liver, Kidneys, and Skeletal Muscles of Elk (Alces alces) from North-Eastern Poland, Biological trace element research, 2016, 169, 204-10.

Superoxide dismutase activity, hydrogen peroxide steady-state concentration, and bactericidal and phagocytic activities against Moraxella bovis, in neutrophils isolated from copper-deficient bovines 

Copper (Cu) deficiency increases occurrence of certain infectious diseases in animals, including infectious keratoconjunctivitis in bovines, a bacterial ocular inflammation caused by Moraxella bovis. Neutrophil leukocytes constitute the first phagocytic cells to arrive at infection sites for bacterial neutralization. The objective of this work was to evaluate whether the functionality of neutrophils against M. bovis is impaired in experimentally induced Cu deficiency in bovines using high molybdenum and sulfur levels in the diet. The Cu tissue values and the periocular achromotrichia observed in +Mo animals showed that the clinic phase of Cu deficiency was reached in this group. Instead, +Cu animals have not evidenced clinical signs or biochemical parameters of hypocuprosis. On the basis of our observations, we concluded that Cu deficiency has no effect on phagocytic and bactericidal activities of neutrophils against M. bovis. However, superoxide dismutase activity and peroxide hydrogen generation were significantly different between groups. Therefore, additional research to explain these results is merited to fully characterize the consequences of Cu status on the risk for infections under field conditions.

Cintia, P. G., Leonardo, M., Israel, O. R., Andrea, S., Beatriz, V. L., and Elena, D. M., Superoxide Dismutase Activity, Hydrogen Peroxide Steady-State Concentration, and Bactericidal and Phagocytic Activities Against Moraxella bovis, in Neutrophils Isolated from Copper-Deficient Bovines, Biological trace element research, 2015.

Tetrathiomolybdate molybdenum copper interaction dog

To evaluate pharmacokinetics of ammonium tetrathiomolybdate (TTM) after IV and oral administration to dogs and effects of TTM administration on trace mineral concentrations.

8 adult Beagles and Beagle crossbreds (4 sexually intact males and 4 sexually intact females).

Dogs received TTM (1 mg/kg) IV and orally in a randomized crossover study. Serum molybdenum and copper concentrations were measured via inductively coupled plasma mass spectrometry in samples obtained 0 to 72 hours after administration. Pharmacokinetics was determined via noncompartmental analysis.

For IV administration: mean +/- SD terminal elimination rate constant 0.03 +/- 0.01 hours(-1), maximum concentration4.9 +/- 0.6 mu g/mL, area under the curve30.7 +/- 5.4 mu g/mL . h, and half-life 27.7 +/- 6.8 hours.

For oral administration: mean +/- SD terminal elimination rate constant0.03 +/- 0.01 hours(-1), time to maximum concentration3.0 +/- 3.5 hours, maximum concentration0.2 +/- 0.4 mu g/mL, area under the curve6.5 +/- 8.0 mu g/mL . h, and half-life 26.8 +/- 8.0 hours.

Oral bioavailability was 21 +/- 22%.

Serum copper concentrations increased significantly after IV and oral administration.

Emesis [the act of vomiting, the technical name for vomiting] occurred after IV (2 dogs) and oral administration (3 dogs).

Conclusions and clinical relevance:

Pharmacokinetics for TTM after a single IV and oral administration was determined for clinically normal dogs.

Absorption of TTM after oral administration was variable.

Increased serum copper concentrations suggested that TTM mobilized tissue copper.

Further studies will be needed to evaluate the potential therapeutic use of TTM in copper-associated chronic hepatitis of dogs.

Chan, C. M., Langlois, D. K., Buchweitz, J. P., Lehner, A. F., Olivier, N. B., Herdt, T. H., Bailie, M. B., and Schall, W. D., Pharmacologic evaluation of ammonium tetrathiomolybdate after intravenous and oral administration to healthy dogs, American Journal of Veterinary Research, 2015, 76, 445.

Sheep pasture Norway

To obtain a better knowledge basis for the correct supply of Cu to sheep in Norway, a systematic, countrywide investigation of element composition of pasture plants was conducted, with emphasis on natural pastures. Samples of pasture grass, herbs, willow shrub leaves and bilberry (N = 575) from 142 locations were analysed for Cu, Mo, S and Fe. A large geographical variation was observed for Mo concentration and Cu:Mo ratio, a somewhat smaller variation for Fe, while Cu and S concentrations showed limited geographical variation. The Mo variation led to a Cu:Mo ratio 20 in 62% of samples, confirming that the trace element composition of Norwegian sheep pastures may represent a risk of Cu deficiency as well as Cu overload, depending on location. A considerable botanical variation was also observed, in particular for Cu and Mo.

Sivertsen, T., Garmo, T. H., Lierhagen, S., Bernhoft, A., and Steinnes, E., Geographical and botanical variation in concentrations of copper, molybdenum, sulphur and iron in sheep pasture plants in Norway, Acta Agriculturae Scandinavica Section A-Animal Science, 2014, 64, 178-187.

Copper molybdenum interaction plants

During the last 40 years, crop breeding has strongly increased yields but has had adverse effects on the content of micronutrients, such as Fe, Mg, Zn and Cu, in edible products despite their sufficient supply in most soils. This suggests that micronutrient remobilization to edible tissues has been negatively selected. As a consequence, the aim of this work was to quantify the remobilization of Cu in leaves of Brassica napus L. during Cu deficiency and to identify the main metabolic processes that were affected so that improvements can be achieved in the future.

While Cu deficiency reduced oilseed rape growth by less than 19% compared to control plants, Cu content in old leaves decreased by 61.4%, thus demonstrating a remobilization process between leaves. Cu deficiency also triggered an increase in Cu transporter expression in roots (COPT2) and leaves (HMA1), and more surprisingly, the induction of the MOT1 gene encoding a molybdenum transporter associated with a strong increase in molybdenum (Mo) uptake.

Proteomic analysis of leaves revealed 33 proteins differentially regulated by Cu deficiency, among which more than half were located in chloroplasts. Eleven differentially expressed proteins are known to require Cu for their synthesis and/or activity. Enzymes that were located directly upstream or downstream of Cu-dependent enzymes were also differentially expressed.

The overall results are then discussed in relation to remobilization of Cu, the interaction between Mo and Cu that occurs through the synthesis pathway of Mo cofactor, and finally their putative regulation within the Calvin cycle and the chloroplastic electron transport chain.

Billard, V., Ourry, A., Maillard, A., Garnica, M., Coquet, L., Jouenne, T., Cruz, F., Garcia-Mina, J. M., Yvin, J. C., and Etienne, P., Copper-Deficiency in Brassica napus Induces Copper Remobilization, Molybdenum Accumulation and Modification of the Expression of Chloroplastic Proteins, Plos One, 2014, 9.

Copper imbalances in ruminants and humans: unexpected common ground

Ruminants are more vulnerable to copper deficiency than humans because rumen sulfide generation lowers copper availability from forage, increasing the risk of conditions such as swayback in lambs. Molybdenum-rich pastures promote thiomolybdate synthesis and formation of unabsorbable copper-thiomolybdate complexes, turning risk to clinical reality (hypocuprosis).

Selection pressures created ruminant species with tolerance of deficiency but vulnerability to copper toxicity in alien environments, such as specific pathogen-free units. By contrast, cases of copper imbalance in humans seemed confined to rare genetic aberrations of copper metabolism. Recent descriptions of human swayback and the exploratory use of thiomolybdate for the treatment of Wilson's disease, tumor growth, inflammatory diseases, and Alzheimer's disease have created unexpected common ground.

The incidence of pre-hemolytic copper poisoning in specific pathogen-free lambs was reduced by an infection with Mycobacterium avium that left them more responsive to treatment with thiomolybdate but vulnerable to long-term copper depletion.

Copper requirements in ruminants and humans may need an extra allowance for the "copper cost" of immunity to infection.

Residual cuproenzyme inhibition in thiomolybdate -treated lambs and anomalies in plasma copper composition that appeared to depend on liver copper status raise this question "can chelating capacity be harnessed without inducing copper-deficiency in ruminants or humans?"

A model of equilibria between exogenous (thiomolybdate ) and endogenous chelators (e.g., albumin, metallothionein) is used to predict risk of exposure and hypocuprosis; although risk of natural exposure in humans is remote, vulnerability to thiomolybdate-induced copper deficiency may be high. Biomarkers of thiomolybdate impact are needed, and copper chaperones for inhibited cuproenzymes are prime candidates.

Suttle, N. F., Copper Imbalances in Ruminants and Humans: Unexpected Common Ground, Advances in Nutrition, 2012, 3, 666-674.

[Hemolysis: breakdown or destruction of red blood cells so that the contained hemoglobin is freed into the surrounding medium.]

Cupromolybdite, Cu3O(MoO4)2, a new fumarolic mineral from the Tolbachik volcano, Kamchatka Peninsula, Russia

Cupromolybdite is a new fumarolic mineral from the New Tolbachik scoria cones of Tolbachik volcano, Kamchatka Peninsula, Russia. Cupromolybdite forms prismatic crystals up to 150 mu m in length or acicular crystals with a thickness and length of 1-5 mu m and 100 mu m, respectively. The acicular crystals of cupromolybdite are typically combined in radiating aggregates.

The mineral is associated with piypite, fedotovite, vergasovaite, hematite, magnetite, aphthitalite, langbeinite, palmierite, As-bearing orthoclase, lammerite, klyuchevskite, alumoklyuchevskite, euchlorine, lyonsite, pseudolyonsite, averievite, rutile and native gold.

Cupromolybdite is honey-yellow or brown, and its acicular crystals are bright yellow. The mineral has yellow or light brown streak and an adamantine lustre.

Cupromolybdite is brittle, and its fracture ranges from uneven to splintery.

The calculated density is 4.512 g/cm3.

The reflectance values (R-1 and R-2, %) in air for the four COM wavelengths are 14.95, 16.3 (470 nm), 13.4, 14.85 (546 nm), 12.73, 14.16 (589 nm), and 12.15, 13.5 (650 nm).

The chemical composition (the mean of 7 electron microprobe analyses) of cupromolybdite is: CuO 43.03, FeO 0.08, ZnO 0.53, MoO3 54.48, SO3 0.71, V2O5 0.28, SiO2 0.04, total 99.15 wt%, corresponding, on the basis of 9 0 atoms, to (Cu2.83Zn0.03Fe0.01)(Sigma 2.87)(Mo1.98S0.05V0.02)(Sigma 2.05)O9. The simplified formula of cupromolybdite is Cu3O(MoO4)2 = Cu3Mo2O9.

Cupromolybdite is orthorhombic, space group Pnma, a = 7.6638(1), h = 6.8670(1), c = 14.5554(2) angstrom, V = 766.01(2) angstrom(3) and Z = 4. The strongest powder-diffraction lines [d in A (I) (hkl)] are: 7.312 (67) (002); 3.518 (55) (113); 3.436 (100) (020); 3.301 (99) (210, 104); 3.065 (79) (121); 2.556 (62) (220); 2.506 (66) (301, 024). The crystal structure was solved from single-crystal data and refined to R = 0.0314. Cupromolybdite is a natural analogue of the synthetic compound Cu3Mo2O9 and the Sfree analogue of vergasovaite, Cu3O[(Mo,S)O4][SO4]. The crystal structure of cupromolybdite contains strings of corner-shared Cu(1)O6 octahedra elongated in the [010] direction. In cupromolybdite, the Cu(2)O5 square pyramids and the Cu(3)O6 distorted octahedra are linked to the Cu(1)O6 octahedra of the strings by edges and to the MoO4 and (Mo,S)O4 tetrahedra by vertices. A minor admixture of S is concentrated in one of two independent tetrahedral positions. Cupromolybdite is named for its chemical composition.

Zelenski, M. E., Zubkova, N. V., Pekov, I. V., Polekhovsky, Y. S., and Pushcharovsky, D. Y., Cupromolybdite, Cu3O(MoO4)(2), a new fumarolic mineral from the Tolbachik volcano, Kamchatka Peninsula, Russia, European Journal of Mineralogy, 2012, 24, 749-757.

Variations in copper concentration and ceruloplasmin activity of dairy cows in relation to lactation stages with regard to ceruloplasmin to copper ratios

Variations of copper (Cu) concentration and ceruloplasmin (Cp) activity in serum and plasma of dairy cows at different stages of lactation were assessed in 240 Holstein dairy cows. Ceruloplasmin to copper ratios were also investigated.

The cows were classified according to their lactation stages into four different groups as close-up stage (3-1 week(s) antepartum), fresh lactation stage (0-1 week postpartum), early lactation stage (3-5 weeks postpartum), and mid-lactation stage (15-18 weeks postpartum). Each group consisted of 60 multiparous cows. Serum and heparinised plasma samples were obtained from each cow.

Concentrations of serum copper (sCu) and plasma copper (pCu) and activities of plasma Cp (pCp) were higher in the group of fresh lactation stage than other groups (P < 0.05).

Serum Cp (sCp) exhibited no significant difference between fresh lactation and early lactation groups (P > 0.05). Low correlations were obtained between sCp and pCu, sCp and sCu, and sCu and pCu.

Plasma copper concentration and plasma ceruloplasmin activity were higher than serum copper concentration and serum ceruloplasmin activity, respectively (P < 0.001). The ratios of Cp activity to Cu concentration (Cp/Cu) were not significantly changed in the different lactation stages of dairy cows (P > 0.05). Use of sCp/pCu and sCp/sCu rather than pCp/pCu will reduce the calculated value of Cp/Cu. Furthermore, for evaluation of copper status, use of sCp/sCu or sCp/pCu identified more animals as 'low' and 'marginal' than using pCp/pCu (P < 0.001).

It can be concluded that ceruloplasmin and copper undergo a physiological increase just after calving; thus, their values should be interpreted with caution during assessment of copper status. Plasma measurements should be used for calculation of Cp/Cu, and further research is required to refine diagnosis criteria for use of such ratio in determining copper status in dairy cows.

Hussein, H. A. and Staufenbiel, R., Variations in Copper Concentration and Ceruloplasmin Activity of Dairy Cows in Relation to Lactation Stages with Regard to Ceruloplasmin to Copper Ratios, Biological Trace Element Research, 2012, 146, 47-52.

The influence of molybdenum on the copper metabolism of the rat at different copper levels of the diet

1. Male WAG/Cpb inbred rats fed on rations with approximately 1-5 rng copper/kg (deficient), 6.0 mg copper/kg (adequate) and 25.0 mg copper/kg (excess) were supplemented with varying amounts of molybdenum (0, 50, 150 and 500 mg/kg diet) (as ammonium heptamolybdate) and the effect on the copper concentration of blood, plasma, liver and kidney, the caeruloplasmin activity of plasma and the molybdenum concentration of liver and kidney were studied. Copper was supplied as copper(II) nitrate.

2. Molybdenum increased the copper concentration of blood, plasma, liver and kidney and the molybdenum concentration of liver and kidney.

3. In the plasma of molybdenum-supplemented rats the presence of a copper-containing fraction was demonstrated, the copper of which did not react with dithiocarbamate and was not related to caeruloplasmin. The copper in this fraction was not able to increase the caeruloplasmin activity in the plasma of copper-deficient molybdenum-supplemented rats. The copper concentration of the erythrocytes did not seem to have been increased by the molybdenum treatment.

4. When compared to copper-adequate rats the effect of molybdenum on the copper distribution was reduced both by copper deficiency and copper excess. This decreased effect of molybdenum was explained by reduced uptake or retention of molybdenum in the body as observed in the liver and kidney.

Nederbragt, H.,Br. J. Nutr., 1980, 43, 329. The influence of molybdenum on the copper metabolism of the rat at different Cu levels of the diet.

Using plasma copper levels alone to diagnose a molybdenum toxic condition is flawed. Thiomolybdates are absorbed into the ruminant body and have toxic effects (molybdenum toxicity) on critical copper metallo-enzymes. The effects are impaired fertility and production. Prevention of molybdenum toxicity is achieved by reducing the iron intake of the animal and by supplementation with copper that is sacrificial in the rumen and not primarily supplied for absorption. A correct diagnosis will allow appropriate supplementation to be undertaken.

Telfer, S.B., Kendall, N. R., Illingworth, D. V., and Mackenzie, A. M., Molybdenum toxicity in cattle: an underestimated problem, Cattle Practice, 2004, 12, 259-263.
Suttle, N. F., Relationships between the concentrations of trichloroacetic acid-soluble copper and caeruloplasmin in the serum of cattle from areas with different soil concentrations of molybdenum, Veterinary Record, 2008, 162, 237-240.

Physiological and genotoxic effects of molybdenum-induced copper deficiency in cattle

Molybdenosis is a disease caused by the depressing effect of molybdenum (Mo) on the physiological availability of Copper (Cu). The present study was carried out in order to analyze the ability of Mo to cause damage on the DNA integrity and changes in membrane fatty acids by oxidative damage.

Holstein male calves were fed a Mo-supplemented diet for 9 months. Variables evaluated were plasma Cu concentration, erythrocyte Cu content and SOD [superoxide dismutase] activity, comet assay and analysis of the fatty acid composition of erythrocyte membranes.

The statistical design was a completely randomized with one single factor and two replications.

Copper plasma concentration, erythrocyte copper concentration and Cu/Zn SOD activity were analyzed using the t test. Chi-square test was used to compare the number of cells with DNA damage, and one-way analysis of variance and Tukey test (p <= 0.05) for fatty acid composition and lipid peroxidation.

Results showed that Mo in the diet induced

  • depletion of hepatic Cu storage,
  • decrease of Cu plasma and erythrocyte levels,
  • fall in Cu/Zn-SOD activity,
  • changes in membrane fatty acids composition
  • DNA damage.

These results are in agreement with the three phases model of Cu deficiency and validate the occurrence of molybdenosis or secondary hypocuprosis. Further studies will be necessary to explore the mechanisms involved in the DNA damage and to distinguish primary molybdenum toxicosis from the molybdenum-induced copper deficiency

Picco, S., Ponzzinibio, M. V., Mattioli, G., Rosa, D., Minatel, L., Fazzio, L., and Seoane, A., PHYSIOLOGICAL AND GENOTOXIC EFFECTS OF MOLYBDENUM-INDUCED COPPER DEFICIENCY IN CATTLE, Agrociencia, 2012, 46, 107-117.

Molybdenum affects the concentrations of other trace elements in the blood and tissues but, except for copper, the interrelationships have not been studied in detail. The interest in the molybdenum-copper relationship arises in connection with the teart condition of sheep and cattle. In the sheep feeding 3 mg Mo/kg live weight as sodium molybdate decreased iron in the blood (by 15%) and increased zinc (by 24%) [Kholod, 1969]. An excess of either copper or molybdenum forms an undissociated Cu-Mo-S complex thereby creating a deficiency of the metal in marginal supply. In the United States dietary excess of copper is common and molybdenum intake may not be optimal. The consequence is a conditioned deficiency of molybdenum which may contribute to abnormalities of iron metabolism and utilisation. Certain forms of anaemia which do not respond to iron therapy, respond to molybdate [Seelig, 1972, 1973].

Kholod, V. M., Uch. Zap. Vitebsk. Vet. Inst., 1969, 21, 64.
Seelig, H. S., Amer. J. Clin. Nutr., 1972, 25, 1022; 1973, 26, 657.

Because of the copper-molybdenum interrelationship and the relationship to sulfate intake, any evaluation of the possible hazard from elevated molybdenum intake in the diet must be related to the concurrent intake of sulfate and copper. In non-ruminants excessive intakes of sulfate will be a key factor in causing copper antagonism [Arthur, 1965]. An evaluation of the quantitative aspects of the copper-molybdenum-sulfate interrelationships required for the assessment of molybdenum dietary risk has been considered [Clarke and Clarke, 1975].

Clarke, E. G. C. and Clarke M. L., Molybdenum in: Veterinary Toxicology, Wilkins & Wilkins, Baltimore, Maryland, 1975, 86.

Molybdenum (and copper) influence the internal transport and release of iron [Seelig, 1972, 1973]. Molybdenum in xanthine oxidase participates in reduction of cellular iron(III) to iron(II).

Seelig, H. S., Amer. J. Clin. Nutr., 1972, 25, 1022; 1973, 26, 657.

High dietary levels of molybdenum produce a conditioned copper deficiency by depleting copper storage in the liver. The antagonism between molybdenum and copper is most pronounced in ruminant animals and gives rise to molybdenosis. For example, liver copper decreased and milk copper concentrations increased in dairy cows on feed containing sodium molybdate (53-300 ppm).

Huber, J. T., Price, N. O. and Engel, R. W., J. Animal Sci., 1971, 32, 364.

Sulfate limits molybdenum retention both by reducing its gastrointestinal absorption and by increasing its urinary and faecal excretion. The transport of molybdenum across tissue membrane is prevented by excess of sulfate ions [Venugopal and Luckey, 1978]. Sulfate may also displace molybdate in the body. So copper, sulfate, and copper sulfate have been used to treat conditions due to excessive molybdenum [Arrington and Davis, 1953].

Venugopal, B. and Luckey, T. D., Metal Toxicity in Mammals, 1978, Vol. 2, Chemical Toxicity of Metals and Metalloids, Plenum Press, New York.
Arrington, L. R. and Davis, G. K., J. Nutr., 1953, 99, 295.

Molybdenum toxicity occurs in cattle and, to a less extent, in sheep on pastures with relatively high molybdenum contents (20-100 ppm compared with 3-5 ppm on "normal" pastures) [Underwood, 1962; Kolomiitseva et al., 1968; Schroeder et al., 1970; Lukashev, 1973; Huisingh et al., 1973; Dick, 1969; Grace, 1969; Clawson et al., 1972; Mareilese et al., 1970].100 ppm Mo in feed is definitely toxic to cattle. Levels of 25 to 50 ppm in feeds have shown mixed results and sometimes no effects. Effects atributed to feeds containing less than 25 ppm Mo have often been associated with very low Cu levels and poorly avilable Cu [Ward, 1994].

Underwood, E. J., in Trace Elements in Human and Animal Nutrition, Academic Press, London, 2nd Ed., 1962, pp. 100-122.
Schroeder, H. A., Balassa, J. J.and Tipton, I. H., J. Chronic Diseases, 1970, 23, 481.
Ward, G.M., Molybdenum requirements, toxicity and nutritional limits for man and animals, Studies in Inorganic Chemistry, 1994, 19, 452 - 476.
Lukashev, A. A., Grig. Tr. Prof. Zabol., 1973, 12, 13.
Kolomiitseva, M. G., Polonskaya, M. N.and Osipov, G. K., Mikroelem. Sel. Khoz. Med., 1968, 4, 183.
Huisingh, J., Gomez, G. G. and Matrone, G., Fed. Proc., Fed. Amer. Soc. Exp. Biol., 1973, 32, 1 921.
Dick, A. T., Australian Vet. J., 1952, 28, 30; 1953, 29, 18, 233; 1954, 30, 196.
Dick, A. T., in Inorganic Nitrogen Metabolism, ed. McElroy, W. D. and Glass, B., John Hopkins Press, Baltimore, 1956, p. 445.
Dick, A. T., Outlook Agr., 1969, 6, 14.
Grace, N. D., Proc. N. Z. Grassl. Ass., 1969, 31, 65.
Clawson, W. J., Lesperance, A. L., Bohman, V. R. and Layhee, D. C., J. Anim. Sci., 1972, 34, 516.
Mareilese, N. A., Ammerman, C. B., Valsecchi, R. M., Dunavant, B. G. and Davis, G. K., J. Nutr. , 1969, 99, 177.

The excess of molybdenum causes a condition known as "teart" which is characterised by scouring (diarrhoea), rapid loss of weight and condition, the development of harsh, discoloured coats, and ultimately death. That a similar condition occurred in cattle on copper-deficient pastures led to the realisation that molybdenum is a copper antagonist, i.e. interferes with the uptake or utilisation of copper. Hence, molybdenum poisoning also known as, "Molybdenosis", "Teart Syndrome" or "Peatscours", is a secondary copper deficiency manifested by diarrhoea, anorexia, depigmentation of the hair or wool, neurological disturbances and premature death [Wennig and Kirsch, 1988; Friberg and Lener, 1986]. The condition can be treated by giving affected animals extra copper in their feed or by injecting copper glycinate.

Webb, J. S., Geol. Soc. Amer., Mem., 1971, 123, 31.
Wennig, R., and Kirsch, N., in: Handbook on Toxicity of Inorganic Compounds, Seiler, H. G., Sigel, H., and Sigel, E. (eds.),1988, 437. Marcel Dekker, New York.

Because of its importance in agriculture and relevance to understanding the metabolism of molybdenum and copper, the mechanism of the molybdenum-copper antagonism has been extensively studied in cattle, sheep, and experimental animals. In the causation of teart molybdenum and sulfate are both required: neither is effective alone. The effect of molybdenum plus sulfate is to increase accumulation of copper in the kidney and increase excretion of copper by way of urine [Dick, 1969; Mareilese et al., 1970]. Various mechanisms have been proposed. The antagonism of molybdenum and copper is considered to be due to the formation of copper sulfide [Kazakov, 1970]. An important finding is that molybdenum plus sulfate reduce formation of ceruloplasmin (a copper binding protein in the blood) and increase the inorganic plasma copper or copper loosely bound to albumin. Molybdenum causes an impairment of copper uptake by liver cells, and thus disturbs the synthesis of copper-containing proteins, including ceruloplasmin [Mareilese et al., 1969]. Molybdenum depresses liver sulfide oxidase activity [Halverson et al., 1960]. The resulting sulfide accumulation leads to the formation of highly insoluble cupric sulfide and the subsequent appearance of symptoms of copper deficiency. However, copper prevents the accumulation of molybdenum in the liver by antagonising the absorption of molybdenum. The point of general interest which emerges from these investigations is the close relationship between the metabolism of molybdenum, copper, and sulfate [Miller and Engel, 1960]. The effect of molybdenum on copper metabolism is greatest in species with a relatively high copper requirement. So cattle and sheep are more susceptible than rabbits, horses, and human beings to molybdenosis.

Dick, A. T., Outlook Agr., 1969, 6, 14.
Mareilese, N. A., Ammerman, C. B., Valsecchi, R. M.and Dunavant, B. G., J. Nutr., 1970, 100, 1399.
Kazakov A. M., Gig. Sanit., 1970, 35, 19.
Mareilese, N. A., Ammerman, C. B., Valsecchi, R. M., Dunavant, B. G. and Davis, G. K., J. Nutr., 1969, 99, 177.
Halverson, A. W., Phifer, J. H. and Monty, K. J., J. Nutr., 1960, 71, 95.
Miller, R. F., Price, N. O. and Engel, R. W., J. Nutr., 1956, 60, 539.

Copper deficiency, or molybdenosis in cattle, sheep and horses, occurred after heavy pollution of a pasture with fly ash. Molybdenum intoxication, seldom seen in non-ruminants, was blamed on the high bioavailability of molybdenum in fly ash. The fly ash was used in road construction. It blew over and contaminated pasture and water. Cows, sheep and horses exhibited Mo intoxication leading to death. The fly ash pH was ca 10 giving high bioavailability of Mo. Copper was low in exposed animals (ca 4 mg/kg wet cf control ca 18) but Mo was normal (ca 1.4) possibly because of the ‘short’ biological half life of Mo (24 h).

Ladefoged, O., Sturup, S., Copper Deficiency In Cattle, Sheep And Horses Caused By Excess Molybdenum From Fly-Ash - A Case-Report, Veterinary And Human Toxicology, 1995, 37, 63-65.

The effects of increased dietary concentrations of molybdenum and sulfur on the accumulation and tissue concentrations of cadmium in sheep were determined and compared with effects on copper. A basal diet containing (per kg dry weight) 0.016 mg Cd, 0.45 mg Mo, 3.4 mg Cu, and 1.9 g S was fed to four dietary treatment groups: control (basal diet plus 4 mg Cd/kg), +Mo (control diet plus 15 mg Mo/kg), +S (control diet plus 4 g S/kg), +Mo+S (control diet+15 mg Mo+4 gS/kg).The treatment period lasted 80 days, Sulfur alone reduced the accumulation of Cd in liver, kidney, and muscle by 60% Molybdenum alone reduced Cd accumulation by 40% in liver and muscle and 30% in kidney. When provided together (+Mo+S), the effect was equivalent to feeding with Mo alone, showing that Mo blocked the effect of S. For Cu in blood and tissues, the effects of Mo and S treatment were consistent with the thiomolybdate hypothesis, and were quite different from those seen for Cd. The results show that increased dietary levels of Mo and S reduce the accumulation of Cd in tissues, and the mechanisms of action differ from those involving Cu.

Smith, G.M., White, C.L., Molybdenum-sulfur-cadmium interaction in sheep, Australian Journal Of Agricultural Research, 1997, 48, 147-154.

Molybdenosis has been reported in Swedish moose.

Frank, A., 'Mysterious' moose disease in Sweden. Similarities to copper deficiency and/or molybdenosis in cattle and sheep, Biochemical background of clinical signs and organ lesions, Science Of The Total Environment, 1998, 20, 17-26.

Molybdenosis risk to cattle consuming corn stover (winter food for cattle) produced on biosolids-amended land is small. Stover Mo concentrations were always low and stover Cu to Mo ratios exceeded 2:1, which avoids molybdenosis problems even at very high biosolids loads and soil Mo loads estimated to be near 18 kg Mo/ha. Data from long-term (continuous corn) plots in Fulton County, IL confirm expected low Mo accumulation by corn stover. Data from plots in Minnesota also suggested essentially no correlations between stover Mo and soil Mo loads for continuous corn, However, greater Mo accumulation in corn grown following soybean [Glycine mar (L.) Merr.] suggests the possibility of enhanced Mo bioavailability to corn in corn-soybean rotations.

O'Connor, G. A., Granato, T. C., and Dowdy, R. H., Bioavailability of biosolids molybdenum to corn, Journal of Environmental Quality, 2001, 30, 140-146.

Thiomolybdates formed in the rumen are known to be involved in copper deficiency in ruminants. However, which particular thiomolybdates are formed has been an issue of contention. The relative proportions of the different thiomolybdates, formed under conditions simulating those within the rumen fluid of ruminants prone to copper deficiency, were measured using UV/visible spectroscopy. Pure synthesized thiomolybdates have also been used to study spectrophotometrically the interactions between the thiomolybdates and copper(II) in the presence and absence of some inorganic ligands, low molecular mass complexing agents and bovine serum albumin in aqueous solutions.

Quagraine, E.K. and Reid, R. S., UV/visible spectrophotometric studies of the interactions of thiomolybdates, copper(II) and other ligands, Journal of Inorganic Biochemistry, 2001, 85, 53-60

In human beings the absorption, tissue distribution, and excretion patterns of molybdenum are similar to those in other species described above. High dietary levels of molybdenum produces a conditioned copper deficiency in humans. Increased copper excretion and elevated levels of plasma copper were found in volunteers ingesting 1.54 mg of molybdenum daily [Deosthale and Gopalan, 1974]. Tungsten is antagonistic to molybdenum. It interferes with absorption and increases urinary excretion of molybdenum. The activities of molybdenum-dependent enzymes are inhibited in neonates when pregnant animals are fed tungsten. Tungsten is believed to replace molybdate in the molybdate-dependent enzymes [De Renzo, 1962]. As a result, sulfite oxidase and xanthine oxidase activities are reduced.

Deosthale, Y. G. and Gopalan, C., Br. J. Nutr., 1974, 31, 351.
De Renzo, E. C., Molybdenum in Mineral metabolism: An Advanced Treatise, (eds) Comar, C. L. and Bronner, F., 1962, U Part B, 483. Academic Press, New York.

In parenteral micronutrition a Mo uptake of >0.5 mg/day can cause significant urinary copper losses.

Leung, F.Y., Trace-Elements In Parenteral Micronutrition, Clinical Biochemistry, 1995, 28, 561-566.

Molybdenosis: copper deficiency caused by high sulfur in forage

An ailment of Przewalski's gazelles in the Hudong area of the Qinghai Lake area in China was caused by secondary copper deficiency, mainly due to high sulfur content in forage. The ailment was characterized by pica, emaciation, dyskinesia, loss of appetite, and anemia. Concentrations of copper in soil and forage from affected and unaffected areas were similar and within the normal range, but concentrations of sulfur in soil and forage were higher (P < 0.01) in affected than in unaffected areas. Concentrations of copper in blood, hair, and liver from the affected Przewalski's gazelles were lower (P < 0.01) than those in healthy animals. Affected Przewalski's gazelles showed a hypochromic microcytic anemia and a low level of ceruloplasmin. Oral administration of copper sulphate (CuSO­4) prevented and cured the disease.

Zhou, L. Y., Long, R. J., Pu, X. Y., Qi, J., and Zhang, W. W., Studies of a naturally occurring sulfur-induced copper deficiency in Przewalski's gazelles, Canadian Veterinary Journal-Revue Veterinaire Canadienne, 2009, 50, 1269-1272.

Copper deficiency induced by molybdenum and iron metabolism in beef cattle

The impact of a severe, long-term Cu deficiency on Fe metabolism in beef cattle was studied over 493 days. Twenty-one Angus calves were born to cows receiving one of the following treatments

(1) adequate Cu (+Cu),

(2) Cu deficiency (-Cu) induced by the addition of 2 mg of Mo/kg of DM

(3) Cu deficient plus high Mn (-Cu+Mn).

After weaning, calves remained on the same treatment as their dam through growing (basal diet analyzed 7 mg of Cu/kg of DM) and finishing (analyzed 4 mg of Cu/kg of DM) phases.

Plasma Fe concentrations were positively correlated (P < 0.01; r = 0.49) with plasma Cu concentrations.

Liver Fe concentrations were greater (P = 0.05) in -Cu vs +Cu calves and further increased (P = 0.07) in -Cu+Mn vs -Cu calves.

There was a negative relationship (P < 0.01; r = -0.31) between liver Cu and Fe concentrations. This relationship may be explained by less (P < 0.01) plasma ceruloplasmin activity in -Cu than +Cu calves.

Relative expression of hepatic hepcidin, as determined by real-time reverse transcription-PCR, was significantly downregulated (> 1.5 fold) in -Cu compared with +Cu calves (P = 0.03), and expression of hepatic ferroportin tended (P = 0.09) to be downregulated in -Cu vs +Cu.

In the duodenum, ferritin tended to be upregulated in -Cu vs +Cu calves (P < 0.06).

No significant change (P > 0.2) due to Cu-deficiency was detected at the transcriptional level for either isoform of divalent metal transporter 1 (DMT1 mRNA with or without an iron responsive element; dmt1IRE and dmt1-nonIRE in liver or intestine.

Duodenal expression of hephaestin and ferroportin protein was not affected by dietary treatment (P > 0.20).

Duodenal expression of DMT1 protein was less (P = 0.04) in -Cu+Mn steers vs -Cu steers.

In summary, Cu deficiency alone did affect hepatic gene expression of hepcidin and ferroportin, but did not affect duodenal expression of proteins important in Fe metabolism. However, the addition of 500 mg of Mn/kg of DM to a diet low in Cu reduced duodenal expression of the Fe import protein DMT1.

Hansen, S. L., Trakooljul, N., Liu, H. C. S., Hicks, J. A., Ashwell, M. S., and Spears, J. W., Proteins involved in iron metabolism in beef cattle are affected by copper deficiency in combination with high dietary manganese, but not by copper deficiency alone, Journal of Animal Science, 2010, 88, 275-283.

Molybdenum + sulfur effective in reducing retention and liver accumulation of dietary copper in sheep

Twelve male 8-month-old lambs were used in a 6-month feeding experiment to determine how dietary molybdenum, molybdenum + sulfur and zinc supplements affected the body retention and tissue accumulation of dietary copper, zinc and iron.

In comparison with the control, each dietary supplement decreased the copper concentration in the liver, but only the molybdenum + sulfur supplement decreased it to a safe range of below 350 mu g/g dry matter.

This was accompanied by the body retention of dietary copper for the control and dietary treatments:

control 24.6%,
Molybdenum 6.7%,
Molybdenum + Sulfur 2.5% and
Zinc 6.5%.

The blood plasma concentration of copper was decreased by the zinc supplement, but was not affected by other supplements.

Only molybdenum + sulfur appeared to be effective in reducing the retention and liver accumulation of the dietary copper to prevent chronic copper toxicity in sheep fed PKC-based diets.

Al Kirshi, R. A., Alimon, A. R., and Ivan, M., Effects of dietary molybdenum, sulfur and zinc on the excretion and tissue accumulation of trace elements in sheep fed palm kernel cake-based diets, Animal, 2011, 5, 1539-1545.

Copper and molybdenum had no effect on reproductive performance in beef cows

Serum concentrations of copper and molybdenum were measured at the end of the summer grazing season in an observational field study of 783 breeding females from 66 cow-calf herds located in western Canada.
The mean copper concentration was 0.82 ppm (sulfur, 0.30 ppm) and the mean molybdenum concentration was 0.056 ppm (sulfur, 0.055 ppm).
Serum copper concentration differed across ecoregions. Serum molybdenum concentrations varied by ecoregion, soil type, soil color, and total precipitation during the growing season.
Copper and molybdenum serum concentrations at the end of the grazing season were not associated with reproductive outcomes.

Van de Weyer, Leanne M. and Waldner, Cheryl L., Geographic determinants of copper and molybdenum concentrations in serum at the end of the grazing season and associations with reproductive performance in beef cows from western Canada, Canadian Journal of Animal Science, 2011, 91, 423-431.

Urinary copper and zinc excretion in cattle require both sulfur and molybdenum

The effects of low and high levels of dietary copper, molybdenum (1.10 mg/kg DM) and sulfur on urinary copper and zinc excretion in cattle (four Simmental and four Angus heifers) were studied.
Urinary copper excretion was greatest with the high copper + high molybdenum + high sulfur diet.
Urinary zinc excretion increased with high sulfur but not with high sulfur in combination with high molybdenum and/or high copper.

Urinary copper excretion in sheep increased only when sulfur (1.1 g/day) was added to the basal diet (5.5 mg copper, 0.7 mg molybdenum) and not with increasing levels of molybdenum alone (5 to 25 mg/day).

The findings that dietary molybdenum and sulfur significantly increase copper excretion through the biliary and urinary routes are in agreement with the reported beneficial effects of molybdenum and sulfur in the treatment of copper-toxicity in sheep.

Observations for the combined effects of molybdenum and sulfur, but not either on its own, are supported by other studies. For example, biliary copper excretion in sheep was much greater with intravenous thiomolybdate than with intravenous molybdenum.

It is the thiomolybdate formation that occurs when cattle are fed on high molybdenum and sulfur diets and the copper chelation by thiomolybdate that is responsible for the increased concentration and excretion of urinary copper (and increased kidney copper concentration), with some of the excess plasma copper filtered by the glomerulus reabsorbed by the kidney tubules.

In cattle fed a high copper + high molybdenum + high sulfur diet, it was the combined effect of high molybdenum and high sulfur that increased copper excretion through both routes, whereby significantly more copper was excreted through bile (0.81 mg/6 h) than through urine (0.29 mg).

Zinc excretion in bile (1.50 mg/6 h) and in urine (0.26 mg) was less influenced by the combination of high copper + high molybdenum + high sulfur in the diet. High sulfur alone contributed to significantly higher urinary zinc excretion than any other combination of dietary copper, molybdenum or sulfur.

[References in full text.]

Gooneratne, S. R., Laarveld, B., Pathirana, K. K., and Christensen, D. A., Effects of dietary Copper, Molybdenum and SULFUR on urinary Copper and Zinc excretion in Simmental and Angus cattle, Research in veterinary science, 2011, 91, e116-e120.

Copper deficiency in baboons due to zinc not molybdenum

In immature wild savannah baboons (Papio cynocephalus) symptoms of copper deficiency and a disorder referred to as white monkey syndrome (WMS) in laboratory primates were observed. Visible symptoms exhibited by WMS infants included whitening of the animal's fur and/or impaired mobility characterized by an apparent "stiffening'' of the hindlimbs.

Three hypotheses were tested: that (1) copper deficiency may have been induced by zinc toxicity, (2) it may have been induced by molybdenum toxicity, and (3) cumulative rainfall during the perinatal period and particularly during gestation is an ecological factor distinguishing infants afflicted with WMS from non-WMS infants.

WMS males had a significantly lower survivorship probability than non-WMS males.

Zinc/copper ratios assessed from hair samples of adult female baboons were higher in females who had produced at least one WMS offspring relative to females who had not had a WMS offspring: low copper levels induced by elevated zinc intake in some individuals.

No significant differences of molybdenum/copper ratios were observed.

Markham, A. Catherine, Gesquiere, Laurence R., Bellenger, Jean Philippe, Alberts, Susan C., and Altmann, Jeanne, White Monkey Syndrome and Presumptive Copper Deficiency in Wild Savannah Baboons, American Journal of Primatology, 2011, 73, 1160-1168.

Copper chelation by tetrathiomolybdate inhibits lipopolysaccharide-induced inflammatory responses

Redox-active transition metal ions, such as iron and copper, may play an important role in vascular inflammation, which is an etiologic factor in atherosclerotic vascular diseases.
Tetrathiomolybdate (TTM), a highly specific copper chelator, can act as an anti-inflammatory agent, preventing lipopolysaccharide (LPS)-induced inflammatory responses in vivo.
Female C57BL/6N mice were daily gavaged with TTM (30 mg/kg body wt) or vehicle control. After 3 wk, animals were injected intraperitoneally with 50 µg LPS or saline buffer and killed 3 h later.
Treatment with TTM reduced serum ceruloplasmin activity by 43%, a surrogate marker of bioavailable copper, in the absence of detectable hepatotoxicity.
The concentrations of both copper and molybdenum increased in various tissues, whereas the copper-to-molybdenum ratio decreased, consistent with reduced copper bioavailability.
TTM treatment did not have a significant effect on superoxide dismutase activity in heart and liver.
TTM significantly inhibited LPS-induced inflammatory gene transcription in aorta and heart, and significantly inhibited LPS-induced increases of serum levels.
Similar inhibitory effects of TTM were observed on activation of nuclear factor-kappa B (NF-kappa B) and activator protein-1 (AP-1) in heart and lungs.
Copper chelation with TTM inhibits LPS-induced inflammatory responses in aorta and other tissues of mice, most likely by inhibiting activation of the redox-sensitive transcription factors, NF-kappa B and AP-1.
Therefore, copper appears to play an important role in vascular inflammation, and TTM may have value as an anti-inflammatory or anti-atherogenic agent.

Wei, Hao, Frei, Balz, Beckman, Joseph SULFUR., and Zhang, Wei Jian, Copper chelation by tetrathiomolybdate inhibits lipopolysaccharide-induced inflammatory responses in vivo, American Journal of Physiology-Heart and Circulatory Physiology, 2011, 301, H712-H720.

Copper deficiency in sheep due to high forage molybdenum and sulfur

The Guizhou semi-fine sheep in the Weining County, Guizhou province, south west China karst mountain area were affected by an ailment characterized by pica [an eating disorder typically defined as the persistent ingestion of nonnutritive substances], emaciation, dyskinesia [abnormal movement - rapid, randomly irregular jerky movements], depressed appetites, unsteady gait and anemia.

Concentrations of copper in soil and forage from affected and unaffected areas were within the normal ranges, but concentrations of sulfur and molybdenum in soil and forage were significantly higher (P<0.01) in affected areas than in unaffected areas.

Concentrations of copper in blood, wool and liver from the affected Guizhou semi-fine sheep were lower (P<0.01) than those in healthy animals. Affected Guizhou semi-fine sheep showed a hypochromic microcytic anemia and a low level of ceruloplasmin. Oral administration of copper(II) sulfate prevented and cured the disease. The disorder of Guizhou semi-fine sheep is caused by secondary copper deficiency, mainly due to high sulfur and molybdenum content in forage.

[Hypochromic microcytic anemia a blood disorder characterized by small red blood cells (erythrocytes) which have insufficient haemoglobin and hence have a reduced ability to carry oxygen through the body. The red blood cells are small due to a failure of haemoglobin synthesis or insufficient quantities of haemoglobin available. The blood disorder is usually caused by conditions such as iron deficiency.]

[Ceruloplasminis a copper-dependent ferroxidase enzyme synthesized in the liver. It is the major copper-carrying protein in the blood carrying about 70% of the total copper in human plasma. Albumin carries about 15% copper; the rest is accounted for by macroglobulins. Albumin binds copper less tightly than ceruloplasmin. Ceruloplasmin has a role in iron metabolism oxidation of Fe2+ to Fe3+ thereby assisting in iron transport in the plasma in association with transferrin which can carry iron only in the iron(III) state.]

Yuan-Rong; Li li-Juan; Wang Qi-Wen; Du Guo-Zhen, Copper deficiency in Guizhou semi-fine wool sheep on pasture in south west China karst mountain area, African Journal of Biotechnology, 2011, 10, 74, 17043-17048.

Molybdenum copper interaction in cashmere goats
Effect of different levels of copper and molybdenum supplements on serum lipid profiles and antioxidant status in cashmere goats

An experiment was conducted to investigate on the effects of different levels of copper (Cu: 0, 19, and 38mg/kg) and molybdenum (Mo: 0 and 5mg/kg) supplements and the interaction of these two factors on serum lipid profiles and antioxidant status in cashmere goats during the cashmere fiber growing period.

Thirty-six Liaoning cashmere goats (approximately 1.5years of age; 27.5 31.38kg of body weight) were assigned to one of six treatments in a completely randomized design involving a 2*3 factorial arrangement. Goats were housed in individual pens and fed with Chinese wild rye- and alfalfa hay-based diet containing 4.72mg Cu/kg, 0.16mg Mo/kg, and 0.21% S for 84days. Blood samples were collected on day 84.

The triglyceride concentration did not differ among treatments (P>0.05).

Supplemental Cu, regardless of Mo level, decreased (P<0.05) the concentrations of serum total cholesterol and low density lipoprotein cholesterol, and increased (P<0.05) the concentration of serum high density lipoprotein cholesterol, but there were no differences (P>0.05) in these values between Cu-supplemented groups.

Supplemental Cu increased (P<0.05) the activities of serum ceruloplasmin (Cp), Cu-zinc superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px), and decreased (P<0.05) the malondialdehyde content.

The serum GSH-Px activity was also increased (P<0.05) by Mo supplementation.

There was a tendency of the interaction effects of Cu and Mo on the activities of Cp (P=0.094), SOD (P=0.057), and GSH-Px (P=0.062), and goats fed with 19mg Cu/kg in the absence of Mo tended to show the highest serum SOD activity, while goats fed with 38mg Cu/kg with 5mg Mo/kg tended to show the highest values of serum Cp and GSH-Px.

Addition of Cu, Mo, or their interaction had no influence (P>0.05) on the activities of serum glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, and lactate dehydrogenase, and the concentrations of serum glucose and total protein.

In conclusion, addition of 19mg Cu/kg in the absence of Mo (the total dietary Cu level of 23.72mg/kg) was recommended for altering the fat metabolism and obtaining the optimal antioxidant activity of cashmere goats, while 38mg Cu/kg should be supplemented when 5mg Mo/kg was added in the basal diet (the total dietary level of 42.72mg Cu/kg, 5.16mg Mo/kg, and 0.21% S) during the cashmere growing period.

Zhang, Wei, Zhang, Yu, Zhang, Shi W., Song, Xian Z., Jia, Zhi H., and Wang, Run L., Effect of different levels of copper and molybdenum supplements on serum lipid profiles and antioxidant status in cashmere goats, Biological trace element research, 2012, 148, 309-315.

The fictile coordination chemistry of cuprous-thiolate sites in copper chaperones

Copper plays vital roles in the active sites of cytochrome oxidase and in several other enzymes essential for human health.

Copper is also highly toxic when dysregulated; because of this an elaborate array of accessory proteins has evolved which act as intracellular carriers or chaperones for the copper ions. In most cases chaperones transport cuprous copper.

This review discusses some of the chemistry of these copper sites, with a view to some of the structural factors in copper coordination which are important in the biological function of these chaperones.

The coordination chemistry and accessible geometries of the cuprous oxidation state are remarkably plastic and we discuss how this may relate to biological function.

This article is part of a Special Issue entitled: Biogenesis/Assembly of Respiratory Enzyme Complexes. (C) 2011 Elsevier B.V. All rights reserved

Pushie, M. Jake, Zhang, Limei, Pickering, Ingrid J., and George, Graham N., The fictile coordination chemistry of cuprous-thiolate sites in copper chaperones, Biochimica et Biophysica Acta-Bioenergetics, 2012, 1817, 938-947.

[Fictile: Capable of being moulded, suitable for making pottery. Now rare.

< Latin fictil-em, < fingĕre to fashion

Oxford English Dictionary

Dysregulation: Impairment of a physiological regulatory mechanism (as that governing metabolism, immune response, or organ function)


Molybdenum toxicity in the rabbit

Dutch rabbits were fed molybdenum added as sodium molybdate (Na2Mo04-2H20) to a commercial ration. When 0.1% or more molybdenum was fed, gross toxic symptoms were pro duced. The toxic syndrome was characterized by anorexia, loss of weight, alopecia, dermatosis, anemia and death. In some young rabbits a deformity of the front legs developed. The addition of copper to the ration prevented the develop ment of toxicity and the administration of copper caused rapid recovery in rabbits with severe toxic symptoms.

Arrington L. R., Davis G. K..J Nutr. 1953 51 295-304. Molybdenum toxicity in the rabbit.

Molybdenum and magnesium: metabolism rats effect
The Effects of Magnesium Deficiency on Molybdenum Metabolism in Rats

Our previous report indicated that magnesium (Mg) deficiency increased molybdenum (Mo) concentration in the rat liver, suggesting the possibility that Mg deficiency affects Mo metabolism. Growing male rats were given a control diet or a Mg-deficient diet for 4 weeks. Urine and feces were collected during the second and fourth weeks of the feeding trial. The liver, kidney, spleen, skeletal muscle, and blood were collected at the end of the feeding trial. Mg deficiency did not affect the apparent absorption of Mo, but it reduced urinary excretion of Mo. The retention of Mo tended to be higher in the Mg-deficient group than in the control group. Hepatic Mo concentration was higher in the Mg-deficient group than in the control group, but Mg deficiency did not affect Mo concentration in other tissues and plasma. Mg deficiency downregulated the mRNA expression of Mo transporter 2 (MOT2) in the liver, but not in the kidney. These results suggest that Mg deficiency decreases urinary Mo excretion, which is too slight to affect plasma Mo concentration, and that Mg deficiency selectively disturbs the homeostatic mechanism of Mo in the liver, which is not related to the mRNA expression of MOT2 in the liver.

Kim, K. H., Funaba, M., Yoshida, M., and Matsui, T., The Effects of Magnesium Deficiency on Molybdenum Metabolism in Rats, Biological Trace Element Research, 2013, 151, 100-104.

The effects of 3,3',4,4'-tetrabromobiphenyl on rats fed diets containing a constant level of copper and varying levels of molybdenum

Copper (Cu) metabolism is altered in rats fed diets high in molybdenum (Mo) and low in Cu.
This 10-week study was carried out to examine the effects of supplemental Mo (7.5-240mug/g diet) on male Sprague-Dawley rats fed diets adequate in Cu (5mug/g diet) and to determine the susceptibility of Mo-treated animals to the environmental pollutant 3,3',4,4'-tetrabromobiphenyl (TBB).
After 7 weeks of dietary treatment, half of the rats in each group received a single IP injection of TBB (150muM/kg bw), while the other half received the corn oil vehicle.
Rats sacrificed at 10 weeks showed no effects of Mo on growth, feed efficiency, or selected organ or tissue weights. Dose-dependent effects on plasma Mo (0-5.1mug/mL), plasma Cu (0.95-0.20mug/mL), and bone Cu (3.4-10mug/g) in control through the high dose were found. Cu sequestration in the bone of Mo-treated rats is a new finding.
TBB treatment resulted in dramatic weight loss and loss of absolute organ mass. Relative organ weights were increased, except for the thymus. TBB altered the concentrations of certain amino acids. Compared to control rats, this polybrominated biphenyl congener significantly decreased plasma Cu and ceruloplasmin at higher concentrations of dietary Mo and promoted the process of plasma Cu decrease by Mo, suggesting a combined effect.

Salman, Kadhim N., Stuart, Mary A., Schmidt, Jack, Borges, T., McClain, Craig J., Robinson, Farrel R., Li, Miao, and Robertson, Larry W., - The effects of 3,3',4,4'-tetrabromobiphenyl on rats fed diets containing a constant level of copper and varying levels of molybdenum, Environmental science and pollution research international, 2014, 21, 6400-9.

Using sodium molybdate to treat chronic copper toxicity in dairy cows: A practical approach

Case history: A Jersey herd of 350 cows and 70 heifers located in the Taranaki region of New Zealand ceased milking in June 2011. Ten cows died during the subsequent 14 days. For at least 9 months, the cows had received palm kernel expeller (PKE) and molasses supplements. Additional Cu supplementation was provided through the water system. Total Cu intake was calculated to be 400 mg/day/cow.

Clinical and pathological findings: Half of the cows died suddenly while others presented with anorexia, depression and ataxia, which progressed to recumbency and death after 1 to 3 days. Clinical signs were mild dehydration, cyanosis and firm faeces which were covered in dark blood. Mean concentrations of Cu in liver and kidney in three of the dead cows were 3,900 and 440 mu mol/kg fresh weight (FW), respectively. Haemorrhages were observed throughout the alimentary tracts and in muscles, and there were ecchymotic haemorrhages on the epi- and endocardia. The livers were swollen and the gall bladder walls were inflamed.

Diagnosis: High concentrations of Cu in the liver and kidney are characteristic findings of chronic Cu toxicity.

Treatment: The remaining herd was fed 200 mg Mo, as sodium molybdate, per cow per day and all Cu supplements were removed including those provided by the water supply. This reduced mean concentrations of Cu in liver from 3,100 to 1,320 mu mol/kg FW within 26 days in the five live animals that were biopsied. There were no further deaths.

Clinical relevance: In dairy herds where excessive Cu intakes have resulted in high liver Cu concentrations and caused chronic Cu toxicity, the removal of all Cu supplements and provision of high intakes of Mo (200 mg/cow/day) can markedly reduce liver Cu stores within 4 weeks.

Morgan, P. L., Grace, N. D., and Lilley, D. P., Using sodium molybdate to treat chronic copper toxicity in dairy cows: A practical approach, New Zealand Veterinary Journal, 2014, 62, 167-170.

Evaluation of Bioaccumulation and Toxic Effects of Copper on Hepatocellular Structure in Mice

The present study was to evaluate the hepatotoxicity effects in mice exposed to copper (Cu) used as dietary supplements for 95 days.

Cu-treated mice showed increased body weight, and no toxic symptoms were observed at the beginning, but the tendency gradually changed with progress of experiment.

In the liver, beneficial metals [Cu, iron (Fe), zinc (Zn), manganese (Mn), and molybdenum (Mo)] were analyzed by flame atomic absorption spectrometry. The content of Cu maintained at the same level during the experiments, but not resulting in the imbalance of Fe, Zn, Mn, and Mo being distributed.

The activities of alkaline phosphatase (AKP) and super oxidase dismutase (SOD) showed significantly improvement during the first 30 days in Cu-supplemented group (P < 0.01) but declined rapidly from 30th to 60th days, and later, they stabilized and were not statistically significant compared with control (P > 0.05).
No statistically significant correlation of ceruloplasmin (CPL) activity was appreciated during the experiment.
The histopathological and ultrastructural abnormalities changes were observed in the liver of mice including vacuolar degeneration, necrosis, karyorrhexis, and endolysis.

Many hepatocytes showed increased collagenic fibers, appearance of triglyceride droplets, and swollen mitochondria due to oral route of copper, which may lead to lipid peroxidation and free radicals.
In conclusion, our study showed that exposure to copper influenced behavioral pattern and body weight, affected several enzymatic activities, and led to the physiological and considerable structural changes in the liver of mice. The public should pay more attention to avoid being exposed to copper.

Wang, X. Z., Wang, H., Li, J. X., Yang, Z. Q., Zhang, J. Y., Qin, Z., Wang, L., and Kong, X. J., Evaluation of Bioaccumulation and Toxic Effects of Copper on Hepatocellular Structure in Mice, Biological Trace Element Research, 2014, 159, 312-319.

High dietary sulfur decreases the retention of copper, manganese, and zinc in steers

To examine the effects of dietary S on diet digestibility and apparent mineral absorption and retention, 16 steers [8 ruminally fistulated (368 +/- 12 kg BW) and 8 unmodified (388 +/- 10 kg BW)] were paired within modification status and BW, and within each of the 2 consecutive 28-d periods, 4 pairs of steers were randomly assigned to either a low-S (0.24%) or high-S (0.68%) pelleted diet.

Bromegrass hay was fed at 5 or 7% of the diet, during periods 1 and 2, respectively.
Sodium sulfate was used to increase the S content of the high-S diet.

The low-S steers were fed the amount of feed their high-S counterpart consumed the previous day, while the high-S steers received 110% of the previous day's intake.

Steers were adapted to individual metabolism stalls for 4 d (d-3 to 0 of period), acclimated to diet for 7 d (d 1 to 7 of period), and after high-S steers were consuming ad libitum intake for 7 d (d 14 of period), total urine and feces were collected for 5 d. Feed intake and orts were recorded daily. Dry matter and OM digestibility were determined. Jugular blood was collected before and after each collection period on d 14 and 20, and liver biopsies were collected on d 0 and 27. Macromineral (Ca, K, Mg, and Na) and micromineral (Cu, Mn, and Zn) concentrations were determined for pellets and hay, orts, feces, urine, and plasma and liver samples from each steer via inductively coupled plasma spectrometry.

Dry matter intake, DM and OM digestibility, and urine volume were not affected (P >= 0.11) by dietary treatment, but fecal output was greater (P = 0.02) in the low-S steers than the high-S steers.

A high-S diet decreased plasma Cu (P = 0.04) and liver Zn (P = 0.03) compared to low-S steers.

No differences (P >= 0.20) were noted among urinary excretion of Cu, Mn, and Zn.
Sodium absorption was greater (P < 0.01) and Cu, Mn, and Zn retention was lesser (P <= 0.01) in the high-S steers than the low-S steers. Apparent absorption of Ca, K, and Mg was not affected (P >= 0.18) by dietary treatment, while absorption of Cu, Mn, and Zn in the high-S treatment was lesser (P <= 0.06).

In conclusion, consumption of a high-S diet for 28 d had limited effects on Ca, K, Mg, and Na absorption and retention, but decreased Cu, Mn, and Zn retention, which may limit growth and production of cattle consuming a high-S diet long-term.

Pogge, D. J., Drewnoski, M. E., and Hansen, S. L., High dietary sulfur decreases the retention of copper, manganese, and zinc in steers, Journal of Animal Science, 2014, 92, 2182-2191.