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AIM: To determine concurrent changes in serum methylmalonic acid (MMA) and vitamin B12 concentrations of ewes and their lambs on cobalt-deficient properties, subsequent to cobalt supplementation. METHODS: Three experiments were carried out on two farms. Groups of ewes (n=25-50) were either supplemented with cobalt bullets during late pregnancy, 23-47 days before the mean lambing date, or left unsupplemented. In two experiments, lambs from within each group were supplemented directly by vitamin B12 injection at 3-weekly intervals from birth, and in the third experiment by injection with micro-encapsulated vitamin B12 at tailing and 3 months later. Pasture samples were obtained for analysis of cobalt content at each sampling time. Blood samples were obtained and liveweight recorded from ewes and lambs at approximately monthly intervals. On one farm (two experiments), liver and milk samples were obtained from ewes and liver samples from lambs. RESULTS: Serum vitamin B12 concentrations in unsupplemented ewes fell below 250 pmol/L during early lactation in all experiments and mean concentrations as low as 100 pmol/L were recorded. MMA concentration was maintained below 2 micromol/L in serum from supplemented ewes but increased to mean concentrations ranging from 7 to 14 micromol/L at the nadir of serum vitamin B12 concentration during peak lactation. A significant liveweight response to supplementation was recorded in ewes on one property, and the vitamin B12 concentration in the ewes' milk and in the livers of their lambs more than doubled. No liveweight-gain response to supplementation was observed in lambs on this property. Mean serum MMA concentrations in lambs ranged from <2 in supplemented, to 19.2 micromol/L in unsupplemented lambs, and the latter had concurrent serum vitamin B12 concentrations of >300 pmol/L. Pasture cobalt concentration was lowest at 0.04-0.09 microg/kg dry matter (DM) on the property on which responses in lambs occurred but considerably higher (>0.09 microg/kg DM) on the property on which responses in ewes occurred. On the second property, serum vitamin B12 concentrations in lambs at tailing were extremely low (100 pmol/L), irrespective of supplementation of dams with cobalt. Mean serum MMA concentration was increased to 20 and 42 micromol/L in lambs from supplemented and non-supplemented ewes, respectively. Weight-gain response to direct supplementation of lambs with vitamin B12 occurred during suckling in the latter, but not the former. Lambs from ewes supplemented with vitamin B12 showed a much bigger increase in serum vitamin B12 concentrations a month after supplementation than did lambs from unsupplemented ewes (+1,400 pmol/L vs + 650 pmol/L). CONCLUSIONS: Serum MMA concentration gave a more precise indication of responsiveness to vitamin B12 or cobalt supplementation than serum vitamin B12 concentrations in ewes and lambs. Neither very low serum vitamin B12 nor elevated MMA concentrations were necessarily indicative of responsiveness to supplementation in suckling lambs, but the latter gave an early indication of impending responsiveness. Supplementation of the ewe with a cobalt bullet appeared to protect the growth performance of the lamb for 90 days and influence the subsequent serum vitamin B12 response in the lamb to vitamin B12 supplementation. CLINICAL SIGNIFICANCE: Supplementing ewes with cobalt bullets in late pregnancy can improve the vitamin B12 status of their lambs, and modify their response to vitamin B12 supplementation.
Cobalt exposure level and its concentrations in blood and urine were determined for 175 hard metal workers. For control data, the cobalt concentrations in blood and urine were measured for 20 office workers. The exposed workers had significantly higher cobalt concentrations in both blood and urine. The relationships between exposure level and cobalt concentrations in blood and urine were linear and positive. The results clearly showed that the cobalt concentration in the blood or urine can be used as an exposure indicator. With cobalt exposure of 100 micrograms/m3, the cobalt concentration was 0.57 to 0.79 micrograms/dl in blood and 59 to 78 micrograms/l in urine with 95% confidence limits. In workers using respirators, the cobalt concentrations in the blood and urine decreased to 2/5 and 1/8, respectively, of those not using respirators.
Cobalt protoporphyrin generated from 5-amino[4-14C]laevulinate by homogenates or primary cultures of chick embryo liver exposed to CoCl2 was found to be radioactivity unextractable by acid/acetone, when extra protein was added. The activity of ferrochelatase was required for formation of cobalt protoporphyrin since inhibition of ferrochelatase with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (in the presence of cycloheximide) inhibited formation of cobalt protoporphyrin and resulted in accumulation of protoporphyrin. Cobalt protoporphyrin was detected spectrophotometrically in hepatocyte cultures exposed to the combination of 2-allyl-2-isopropylacetamide and CoCl2: (1) as the pyridine haemochrome of the protein pellet remaining after acid-acetone extraction of the cells, or (2) as the material extracted from the protein pellet with acetic acid-pyridine-chloroform. The amount of cobalt protoporphyrin increased with increasing CoCl2 concentration as cellular haem declined. The decrease in haem was about equal to the amount of cobalt protoporphyrin that accumulated. 2-Allyl-2-isopropylacetamide and polychlorinated biphenyls were both powerful inducers of 5-aminolaevulinate synthase. The former led to protoporphyrin accumulation, whereas with the latter, uroporphyrin accumulated, probably due to a concomitant decrease in activity of uroporphyrinogen decarboxylase. The decrease in activity of 5-aminolaevulinate synthase produced by administration of CoCl2 was greater after treatment with 2-allyl-2-isopropylacetamide than after treatment with allylisopropylacetamide and 3,4,3',4'-tetrachlorobiphenyl. We conclude: (a) that cobalt protoporphyrin is readily formed in cultured hepatocytes, and (b) that its formation accounts for the action of cobalt on 5-aminolaevulinate synthase.
CoaR associates with and confers cobalt-dependent activation of the coaT operator-promoter. A CoaR mutant (Ser-Asn-Ser) in a carboxyl-terminal Cys-His-Cys motif bound the coaT operator-promoter but did not activate expression in response to cobalt, implicating thiolate and/or imidazole ligands at these residues in an allosteric cobalt binding site. Deletion of 1 or 2 nucleotides from between near consensus, but with aberrant (20 base pairs) spacing, -10 and -35 elements enhanced expression from the coaT operator-promoter but abolished activation by cobalt-CoaR. It is inferred that cobalt effects a transition in CoaR that underwinds the coaT operator-promoter to realign promoter elements. In the absence of cobalt, CoaR represses expression (approximately 50%). CoaR is a fusion of ancestral MerR (mercury-responsive transcriptional activator)- and precorrin isomerase (enzyme of vitamin B(12) biosynthesis)-related sequences. Expression from the coaT operator-promoter was enhanced in a partial mutant of cbiE (encoding an enzyme preceding precorrin isomerase in B(12) biosynthesis), revealing that this pathway "inhibits" coaT expression. Disruption of coaT reduced cobalt tolerance and increased cytoplasmic (57)Co accumulation. coaT-mediated restoration of cobalt tolerance has been used as a selectable marker.
AIM: To compare serum analyses of vitamin B12 and methylmalonic acid (MMA) as indices of cobalt/vitamin B12 deficiency in lambs around weaning. METHODS: Lambs on five properties, considered to be cobalt- deficient, were supplemented with either cobalt bullets, or short- or long-acting vitamin B12 preparations. Blood samples, and in some cases liver biopsies, and liveweights were obtained at monthly intervals. Serum samples were assayed for vitamin B12 and MMA and liver for vitamin B12 concentrations. Pasture cobalt concentrations were measured on three of the properties. RESULTS: Pasture cobalt concentrations were generally maintained below 0.07 microg/g dry matter (DM) on the properties sampled. Growth responses to supplementation were observed on only 2/5 properties, despite serum vitamin B12 concentrations being within the currently used 'marginal' reference range (336-499 pmol/L) for at least 3 months on all properties and in the deficient reference range (0-335 pmol/L) for at least 2 months on all farms except one. Serum MMA concentrations in supplemented lambs were <2 micromol/L, except in those animals sampled 1 month after receiving treatment with a short-acting vitamin B12 injection. Serum MMA concentrations in unsupplemented animals on properties on which no growth response to supplementation occurred generally reached peak levels of between 4 and 7 micromol/L at the nadir of serum vitamin B12 concentration. When a growth response was observed, differences in weight gain between supplemented and unsupplemented lambs occurred as mean serum MMA concentrations increased from 9 to 14 micromol/L. On one property where supplementation commenced before weaning, normal growth rates were maintained despite serum vitamin B12 concentrations of 140 pmol/L and serum MMA concentrations in excess of 40 micromol/L serum. CONCLUSIONS: The possibility that current serum vitamin B12 references ranges for diagnosis of cobalt deficiency are set too high and lead to over-diagnosis of responsiveness to cobalt/ vitamin B12 supplementation is discussed. The suggestion is made that serum MMA concentrations in excess of 9-14 micromol/L will provide a more reliable diagnostic test for cobalt deficiency. However, there was sufficient variation between properties in the relationships between cobalt concentrations of pasture and serum vitamin B12 or MMA concentrations to require more rigorous testing of the reliability of using serum MMA concentration for this purpose. The possibility that differences in rumen fermentation and therefore propionate and vitamin B12 production could be involved is discussed. The measurement of serum MMA and vitamin B12 appears to be of little value whilst the lamb is still suckling. CLINICAL SIGNIFICANCE: Serum MMA concentration may offer advantages over serum vitamin B12 concentrations in the diagnosis of a cobalt/vitamin B12 responsiveness in weaned lambs.
BACKGROUND: Blood doping is commonplace in competitive athletes who seek to enhance their aerobic performances through illicit techniques. PRESENTATION OF THE HYPOTHESIS: Cobalt, a naturally-occurring element with properties similar to those of iron and nickel, induces a marked and stable polycythemic response through a more efficient transcription of the erythropoietin gene. TESTING THE HYPOTHESIS: Although little information is available so far on cobalt metabolism, reference value ranges or supplementation in athletes, there is emerging evidence that cobalt is used as a supplement and increased serum concentrations are occasionally observed in athletes. Therefore, given the athlete's connatural inclination to experiment with innovative, unfair and potentially unhealthy doping techniques, cobalt administration might soon become the most suited complement or surrogate for erythropoiesis-stimulating substances. Nevertheless, cobalt administration is not free from unsafe consequences, which involve toxic effects on heart, liver, kidney, thyroid and cancer promotion. IMPLICATIONS OF THE HYPOTHESIS: Cobalt is easily purchasable, inexpensive and not currently comprehended within the World Anti-Doping Agency prohibited list. Moreover, available techniques for measuring whole blood, serum, plasma or urinary cobalt involve analytic approaches which are currently not practical for antidoping laboratories. Thus more research on cobalt metabolism in athletes is compelling, along with implementation of effective strategies to unmask this potentially deleterious doping practice.
Twenty-one mixed-ligand complexes of cobalt(II) and cobalt(III) have been screened for their antimicrobial, insect sterilizing and ovicidal activities. Three of these cobalt(III) complexes exhibit broad antimicrobial spectra, including against human bacterial pathogens, dermatophytes and plant pathogenic fungi, while one exhibits feeble activity against a human pathogenic bacterium. These results have been compared with the activity of the corresponding cobalt(II) complexes, which have been found to be inactive, while the free ligands show reduced activity compared with the cobalt(III) complexes. Change in biological activity induced by a particular complex appears to be dependent on the composition of the first co-ordination sphere. Two of these complexes showed 50% inhibition of the conidial germination of Helminthosporium oryzae and Alternaria triticina. These results indicate their potential for use against human and plant pathogenic microbes. Minimum inhibitory concentrations of the cobalt(III) complexes were determined. Three of these cobalt(III) complexes have been tested for insect sterilizing and ovicidal activities on Dysdercus koenigi F. Positive sterilizing and ovicidal actions of [Co(BSOP)(NH3)2]NO3 (where BSOP-H2 is the Schiff base derived from salicylaldehyde and orthophenylene-diamine) were obtained. Possible mechanism(s) of all these activities are discussed qualitatively.
This paper describes the ability of the combination of electrospray ionization mass spectrometry (ESI-MS) and anion-exchange chromatography coupled with inductively coupled plasma atomic emission spectrometry (AEC-ICP-AES) for cobalt speciation study in the binary cobalt-cysteine system. ESI-MS, allowing the identification and the characterization of the analytes, is used as a technique complementary to AEC-ICP-AES, providing elemental information on the separated species. The methods have been developed through the study of samples containing Co2+ and 1-fold to 5-fold molar ratios of cysteine over a pH range 2.5 to 11. In each case, cobalt-cysteine complexes were characterized by ESI-MS in negative ion mode. AEC-ICP-AES allowed further separation and detection of the cobalt species previously characterized. The strong influence of pH and ligand-to-metal ratios on the nature and stoichiometry of the species is demonstrated. For the first time, a direct experimental speciation diagram of cobalt species has been established owing to these analytical techniques. This work is a promising basis for the speciation analysis of cobalt, since a good knowledge of cobalt speciation is of prime importance to better understanding its fate in biological and environmental media.
Metals such as cobalt and nickel are common contact allergens. We studied the mechanisms underlying an allergic reaction with marked synovial inflammation in a patient with a cobalt alloy arthroplasty. After removing the joint prosthesis the adjacent synovial tissue was examined for cobalt-specific T lymphocytes. Synovial membrane mononuclear cells were expanded in interleukin 2 and cloned using a representative cloning protocol. T cell clones were tested for their proliferative response to cobalt and further characterized with regard to cytokine secretion, phenotype, and HLA restriction. Additionally, synovial fibroblasts were tested for their function as antigen presenting cells (APC). Almost 30% of the T cell clones reacted to cobalt, but not to the control nickel. All these T cell clones were CD4 positive. The cobalt induced proliferative response could be blocked by anticlass II antibodies. Also, synovial fibroblasts expressing class II molecules induced by interferon-gamma were able to serve as APC. However, when testing a panel of APC of HLA class II mismatched donors, no requirement for a certain HLA class II molecule could be defined. Further studies are necessary to determine mechanisms of presentation and recognition of cobalt by T lymphocytes, a prerequisite for improved prevention and treatment of metal induced allergic reactions.
During a 3-year period, 146 patients with positive patch tests to nickel and/or cobalt, for whom a systemic cause of dermatitis was suspected, were challenged orally with a single dose of 2.5 mg nickel given as nickel sulphate and 1 mg cobalt given as cobalt sulphate using a double-blind, placebo-controlled method. No following-up was possible for 2 patients. Seventy-five of the remaining 144 (52%) had flares of their dermatitis after challenge with nickel and/or cobalt, while 45 patients (31%) had no reaction and 24 (17%) reacted only to the placebo or to the placebo in combination with nickel or cobalt. Seven out of 13 patients with positive patch tests to cobalt experienced flares of their dermatitis only after challenge with cobalt.
Cobalt protoporphyrin inhibited the drug-induced increase of delta-aminolevulinate synthase as well as its transfer from the cytosol fraction to the mitochondria in rat liver in a similar way to protoheme. Cobalt chloride given to animals in a large dose exhibited similar effects. Cobalt protoporphyrin was isolated from the liver of rats treated with cobalt chloride. The observed regulatory effects of cobalt chloride with respect to the induction and the intracellular translocation of delta-aminolevulinate synthase may be mediated by cobalt protoporphyrin synthesized in vivo.
A series of cobalt(III) complexes of the anticancer antibiotic bleomycin has been prepared. Mass spectrometry and enzymatic analysis show that the green cobalt-bleomycin complex contains a hydroperoxide (-OOH) group bound to cobalt with unusual stability. Under appropriate conditions, cobalt-bleomycins containing other monodentate ligands to cobalt can be formed; fast-atom bombardment mass spectra of such complexes show peaks for cobalt-bleomycin at the expected mass, and also peaks for the intact complexes at the required higher mass.
The synthesis of a cobalt phthalocyanine-cobalt porphyrin heteropentamer (cobalt(II) phthalocyanine-tetrakis(cobalt(II) tetrakis(5-phenoxy-10,15,20-triphenylporphyrin))), (CoPc-(CoTPP)4), containing four units of cobalt tetraphenylporphyrin linked to a central cobalt phthalocyanine macrocycle via ether linkages is reported. Cyclic voltammetry and spectroelectrochemistry were employed to characterize the complexes. Cyclic voltammetry and square wave voltammetry revealed nine processes. Spectroelectrochemistry of the pentamer confirmed that reduction occurs on the individual components in an alternating manner; the first reduction occurring on the CoTPP moieties, the second on the CoPc moiety, the third on the CoTPP moieties and so on. Oxidation occurred first on the CoPc moiety of the pentamer.
The method described by Weisner et al. for stabilizing 99Tcm-hexamethylpropylene amine oxime (99Tcm-HMPAO) with cobalt chloride hexahydrate solution is the most promising developed to date. The aim of our work was to study the behaviour of cobalt during the labelling of leukocytes with 99Tcm-HMPAO stabilized in vitro using this method. Three parallel labellings were carried out using six blood samples taken from polycythaemic patients. The first set of labellings was performed using 99Tcm-HMPAO, the second set using 99Tcm-HMPAO stabilized with cobalt chloride hexahydrate solution "spiked' with 57Co-chloride, and the third set using 57Co-chloride solution alone. Measurements of radioactivity content were made on the leukocyte pellets after washing at five time points post-labelling (t = 0, 30 min, 1 h, 2 h and 4 h). The data show that leukocytes do not retain cobalt during labelling with stabilized 99Tcm-HMPAO. Studies carried out in parallel demonstrated that the presence of cobalt in the cell-labelling medium had no effect on cell viability.
Various cobalt-containing agents (cyanocobalamin, sodium cobaltinitrite, and cobaltous chloride), which formerly had been shown to prevent the onset of cleft palate in CF-1 mice injected with cortisone, were studied to determine whether they would afford similar protection against phenytoin. Phenytoin, however, failed to cause cleft palate in the mouse fetus when given to pregnant animals alone; and cortisone, on the contrary, induced this anomaly in the presence of the so-called cobalt antagonists as well as when administered in their absence. It is suggested from these results that high dietary intake of cobalt prevents cleft palate caused by phenytoin challenge and also negates the protective effects associated with the acute administration of cobalt compounds. Therefore, it is concluded that these well-known teratogens inhibit palatal closure in mice by different mechanisms.