Genotoxic effects of potassium dichromate, sodium arsenite, cobalt chloride and lead nitrate in diploid yeast

4 metal salts, potassium dichromate, sodium arsenite, cobalt chloride and lead nitrate were tested for their genotoxic effects in Saccharomyces cerevisiae. Potassium dichromate was the most potent agent for induction of gene conversion and reverse mutation. Sodium arsenite was virtually ineffective as a convertogen but gave a positive result for reversion. Cobalt chloride was the least toxic, exhibited a convertogenic activity but was only marginally active for reverse mutation. Lead nitrate was the most toxic salt but was genetically inactive.     

Selective and effective bactericidal activity of the cobalt (II) cation against Helicobacter pylori

BACKGROUND: Although the anti-Helicobacter pylori activity of bismuth is well established, the therapeutic potential of other metal ions against the organism is not known. MATERIALS AND METHODS: We measured the minimum inhibitory concentrations of a series of metal ions, including several cobalt (II) compounds against four type strains and seven clinical isolates of H. pylori using three standard broth culture media and a defined medium. Other intestinal bacteria were also investigated for specificity of action. RESULTS: Cobalt chloride had marked activity against H. pylori (minimum inhibitory concentration range was 0.03-1.0 mg/l). The effect was specific because other transition metals had no effect and other intestinal bacteria were not affected by cobalt chloride. Activity was attributable to free cobalt ions as ligands inhibited activity in proportion to their affinity for the ions. Inhibition of cobalt activity was also observed in the presence of nickel, in a dose dependent fashion. However, cobalt activity was not directed towards the nickel-dependent urease enzyme because its effect was similar in wild-type and urease negative mutant strains of H. pylori. Finally, the viability of H. pylori was reduced at the same rate with 2 mg/l cobalt as with 1 mg/l amoxicillin. CONCLUSIONS: Cobalt competes for nickel in its acquisition by H. pylori, but mediates toxicity in a nonurease dependent fashion. As cobalt MIC is similar to some antibiotics and 10 to a hundred times lower than for bismuth, cobalt may represent an effective form of therapy for H. pylori infection.     

Inhibition of proteasomal degradation of Mcl-1 by cobalt chloride suppresses cobalt chloride-induced apoptosis in HCT116 colorectal cancer cells

Cobalt promotes apoptosis in multiple cell systems, however, the molecular mechanisms that influence cobalt-induced apoptosis are not fully understood. We investigated mechanisms of cobalt chloride induced apoptosis in HCT116 colorectal cancer cells. Cobalt chloride induced dose dependent apoptosis in HCT116 cells (250–750 μM) which, at higher concentrations (500–750 μM), was associated with an increase in the expression of the Bcl-2-related Mcl-1 survival protein. Cobalt chloride caused the accumulation of higher molecular weight ubiquitin-conjugates of Mcl-1 in intact HCT116 cells and inhibited the activity of the trypsin-like site of the 20S proteasome in an in vitro assay. Although siRNA-mediated knockdown of Mcl-1 increased apoptosis in HCT116 cells, the combination of Mcl-1 siRNA and cobalt chloride induced very high levels of cell killing. Therefore, inhibition of the proteasome by cobalt chloride leads to the accumulation of Mcl-1 which acts to limit cobalt chloride induced apoptosis.     

The detection of high-risk groups among workers in contact with heavy metals based on an analysis of chromosome aberrations and sister chromatid exchanges

Heavy metal salts, the workers from molybdenum, tungsten and cobalt plants to make in contact with, reveal their mutagenic activity. Individual sensitivity to heavy metal salts has been analyzed through the example of molybdenum. Chromosome aberrations and sister chromatid exchanges have been studied for the regularities of their formation in lymphocytes of workers depending on the length of service. Sensitivity of tests of chromosome aberrations and sister chromatid exchanges has been compared to reveal genetic consequences of these types of the effects.     

Effect of cobalt on the oxidative status in heart and aorta of streptozotocin-induced diabetic rats

Effects of cobalt on the antioxidant status of control and streptozotocin diabetic rat heart and aorta were examined at the second, fourth and sixth week of treatment. Rats were divided into four groups: control, diabetic, control treated with cobalt chloride and diabetic treated with cobalt chloride. Diabetes was induced by tail vein injection of streptozotocin (STZ). Cobalt treatment groups were given 0.5 mM of CoCl(2) in drinking water. The rats in both groups were further subdivided into three groups of six rats each. Rats in these subgroups were studied at 2-week intervals up to 6 weeks. At the end of the experiment, all animals were sacrificed by decapitation, heart and aorta samples were removed for determination of thiobarbituric acid reactive substance (TBARS) level and superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities. It was found that lipid peroxidation levels and antioxidant enzyme activities were increased in the streptozotocin-induced diabetic rats at all times studied. Cobalt treatment of diabetic rats (0.5 mM in drinking water) resulted in attenuation of the increased levels of TBARS and antioxidant enzyme activities in heart and aorta. Thus, the effect of oral administration of cobalt at this dose during the early stage of experimental diabetes can be considered as a consequence of altered endogenous defence mechanisms in heart and aorta.     

Mutagenicity of a series of hexacoordinate cobalt(III) compounds

15 cobalt(III) compounds have been tested for DNA-damaging capabilities using an E. coli differential repair assay and for mutagenicity in strains of Salmonella typhimurium. 4 of these compounds were active in both systems. Although the general ligand requirements for genetic activity of cobalt(III) appear to closely parallel those of chromium(III) and rhodium(III), the genetic activity of cobalt compounds seems particularly dependent upon the structure of the ligands coordinated about the metal ion. By a simple methyl substitution on the organic ligands, a compound completely devoid of activity, e.g. trans-[Co(pyr)4Cl2]Cl, could be made slightly mutagenic in Salmonella typhimurium strains e.g. trans-[Co(3-pic)4Cl2]Cl. Substitution at the 4-position rather than the 3-position on the same pyridine ring, e.g. trans-[Co(4-pic)4Cl2]Cl, results in a 50-fold enhancement of activity in both repair and mutagenesis systems. The difference in genetic activity is attributed to the influence of the ligands on the relative lability of the metal complex.     

Inverse correlation between combined mutagenicity in Salmonella typhimurium and strength of coordinate bond in mixtures of cobalt(II) chloride and 4-substituted pyridines

Cobalt(II) chloride (CoCl₂), non-mutagenic by itself, has been tested for mutagenic activity in the presence of 4-substituted pyridines in the test strains of Salmonella typhimurium. CoCl₂ was found to be mutagenic in strains TA1537 and TA2637, when combined pyridine, with methyl isonicotinate, 4-methylpyridine, 4-ethylpyridine, 4-chloropyridine or 4-bromopyridine. Mixtures of CoCl₂ and isonicotinic acid, 4-cyanopyridine, 4-aminopyridine, or 4-dimethylaminopyridine exhibited no mutagenicity. Judging from the spectral observations, such combined mutagenicity may be due to the formation of moderate to weak complexes between these compounds and the Co(II) cation.     

Cobalt and antimony: genotoxicity and carcinogenicity

The purpose of this review is to summarise the data concerning genotoxicity and carcinogenicity of Co and Sb. Both metals have multiple industrial and/or therapeutical applications, depending on the considered species. Cobalt is used for the production of alloys and hard metal (cemented carbide), diamond polishing, drying agents, pigments and catalysts. Occupational exposure to cobalt may result in adverse health effects in different organs or tissues. Antimony trioxide is primarily used as a flame retardant in rubber, plastics, pigments, adhesives, textiles, and paper. Antimony potassium tartrate has been used worldwide as an anti-shistosomal drug. Pentavalent antimony compounds have been used for the treatment of leishmaniasis. Co(II) ions are genotoxic in vitro and in vivo, and carcinogenic in rodents. Co metal is genotoxic in vitro. Hard metal dust, of which occupational exposure is linked to an increased lung cancer risk, is proven to be genotoxic in vitro and in vivo. Possibly, production of active oxygen species and/or DNA repair inhibition are mechanisms involved. Given the recently provided proof for in vitro and in vivo genotoxic potential of hard metal dust, the mechanistic evidence of elevated production of active oxygen species and the epidemiological data on increased cancer risk, it may be advisable to consider the possibility of a new evaluation by IARC. Both trivalent and pentavalent antimony compounds are generally negative in non-mammalian genotoxicity tests, while mammalian test systems usually give positive results for Sb(III) and negative results for Sb(V) compounds. Assessment of the in vivo potential of Sb2O3 to induce chromosome aberrations (CA) gave conflicting results. Animal carcinogenicity data were concluded sufficient for Sb2O3 by IARC. Human carcinogenicity data is difficult to evaluate given the frequent co-exposure to arsenic. Possible mechanisms of action, including potential to produce active oxygen species and to interfere with DNA repair systems, still need further investigation.     

Effects of cobalt on plants

Cobalt, a transition element, is an essential component of several enzymes and co-enzymes. It has been shown to affect growth and metabolism of plants, in different degrees, depending on the concentration and status of cobalt in rhizosphere and soil. Cobalt interacts with other elements to form complexes. The cytotoxic and phytotoxic activities of cobalt and its compounds depend on the physico-chemical properties of these complexes, including their electronic structure, ion parameters (charge-size relations) and coordination. Thus, the competitive absorption and mutual activation of associated metals influence the action of cobalt on various phytochemical reactions. The distribution of cobalt in plants is entirely species-dependent. The uptake is controlled by different mechanisms in different species. Biosorption involves ion-exchange mechanism in algae, but in fungi both metabolism-independent and -dependent processes are operative. Physical conditions like salinity, temperature, pH of the medium, and presence of other metals influence the process of uptake and accumulation in algae, fungi, and mosses.     

Effects of supplementation with a combination of cobalt and ascorbic acid on antioxidant enzymes and lipid peroxidation levels in streptozocin-diabetic rat liver

The effect of cobalt(II) chloride (CoCl2) and CoCl2 with ascorbic acid (AA) on components of the antioxidant defense system and lipid oxidative damage were studied in controls and streptozotocin-induced diabetic rat livers. Three days after injection, rats received either 0.5 mM CoCl2 or 0.5 mM CoCl2 with a combination of 1 g/L AA in drinking water up to 6 wk. The elevated blood glucose levels in diabetic rats were about 12% restored by oral administration of CoCl2 (0.05 mM) and were significant reduced (46%) following AA addition (1 g/L) to CoCl2. Cobalt therapy effectively decreased the increased activities of catalase (CAT), superoxide dismutase (SOD), and thiobarbituric acid reactant substances (TBARS) but could not restore the increased glutathione peroxidase (GSH-Px) in the liver of diabetic rats. Our findings suggest that cobalt therapy may prove effective in improving the impaired antioxidant status during the early state of diabetes, and ascorbic acid supplementation at this dose potentiates the effectiveness of cobalt action.     

Effect of cobalt and nickel on growth and carboxymethyl cellulase activity ofCellulomonas spp

ACellulomonas spp isolated from soil produced carboxymethyl cellulase (CMCase) and xylanase enzymes. Cobalt (0.1mm) and nickel (0.1mm) decreased the growth rate ofCellulomonas spp. These metal ions activated CMCase activity but not xylanase activity; cobalt being the greater stimulatory ion than nickel. A predominant long lag phase was observed in adapted cells when compared with the non-adapted cells. However, the growth level of control cells was never obtained by the adapted cells.     

Effect of cobalt on synthesis and activation of Bacillus licheniformis alkaline phosphatase.

The effect of CO2+ on the synthesis and activation of Bacillus licheniformis MC14 alkaline phosphatase has been shown by the development of a defined minimal salts medium in which this organism produces 35 times more (assayable) alkaline phosphatase than when grown in a low-phosphate complex medium or in the defined medium without cobalt. Stimulation of enzyme activity with cobalt is dependent on a low phosphate concentration in the medium (below 0.075 mM) and continued protein synthesis. Cobalt stimulation resulted in alkaline phosphate production being a major portion of total protein synthesized during late-logarithmic and early-stationary-phase culture growth. Cells cultured in the defined medium minus cobalt, or purified enzyme partially inactivated with a chelating agent, showed a 2.5-fold increase in activity when assayed in the presence of cobalt. Atomic spectral analysis indicated the presence of 3.65 +/- 0.45 g-atoms of cobalt associated with each mole of purified active alkaline phosphatase. A biochemical localization as a function of culture age in this medium showed that alkaline phosphatase was associated with the cytoplasmic membrane and was also found as a soluble enzyme in the periplasmic region and secreted into the growth medium.     

Spring Time and Fall Time Effects of 1,25-Dihydroxyvitamin D3, Cobalt (II) and (CoCl2(1,25(OH)2D3)4) Complex on Renal and Cerebral Enzymatic Markers in Rats

In this work, we studied the chronesthesia of 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), cobalt (II) chloride and of the complex [CoCl 2 (1,25(OH) 2 D 3 ) 4 ]. The study was carried out in spring and autumn on AP and ?-GT activities in brain and kidney of rats during the rodents' active period. In rat brain, in both seasons, 1,25(OH) 2 D 3 enhanced AP activity by 59 % in spring and 21 % in autumn and ?-GT by 39 and 35 % respectively. Cobalt (II) stimulated AP activity by 34 and 29 % respectively. The complex was mainly active on ?-GT activity (70 and 36 %) showing a synergic effect on ?-GT activity in June. In rat kidney, during spring, the induction of AP activity for 1,25(OH) 2 D 3 , cobalt (II) chloride and their complex was, respectively 21, 18 and 12 %. The ?-GT activity was not modified during this period, whereas in autumn, it was inhibited by -33, -50 and -28 %. The AP activity in autumn was not altered. We conclude that the effects on the two enzymatic markers of the three compounds 1,25(OH) 2 D 3 , cobalt (II) chloride and [CoCl 2 (1,25(OH) 2 D 3 ) 4 ] are quite different in Spring and Autumn, and this is explained on the basis of chronesthesia.     

Activity of Ca(2+)-dependent neutral proteinases in rat organs under cobalt and mercury chloride injection

The activity of Ca(2+)-dependent neutral proteinases in rats under cobalt and mercury chloride injection was investigated. The calpains activity increase in the lungs, heart, liver and kidneys was revealed after 2 h cobalt chloride action. The mercury chloride gives a reliable increase of calcium-dependent neutral proteinases only in the kidneys.     

Acute toxicity and hematological and serum changes caused by various cobalt salts in rats

The acute toxicities of chloride, acetate, cobalt nitrate and cobalt sulphate (II) were investigated in rats. The values obtained for the LD50 (7 days) were 133, 194, 198 and 279 mg of Co/kg respectively, when the salts were given orally. The values for intraperitoneal administration were 10.6, 8.8, 8.3 and 11.5 mg of Co/kg. The majority of deaths occurred during the first 48 hours. The physical and clinical signs appearing after the intoxication disappeared for the most part after the first 72 hours. Also, the effect produced by chloride and cobalt acetate (II) given orally and intraperitoneally, in some hematological parameters and serum parameters during the first 24 hours after intoxications, has been studied at several doses. A noteworthy increase was observed in the hemoglobin and hematocrit as well as in the plasma proteins. There was significant hyperglycemia and also significant changes in the lipid parameters such as triglycerides and cholesterol. The duration and degree of the change depended on the dose. As a general rule, no significant differences were registered between the results obtained for the two salts.     

Effect of cobalt on the liver glycogen content in the streptozotocin-induced diabetic rats

Cobalt decreases blood glucose in diabetic rats but the mechanisms involved are unclear. To determine the contribution of glycogen metabolism to glycemia-lowering effect, glycogen contents of liver and muscle in the streptozotocin-induced diabetic rats were determined. The liver glycogen was depleted in diabetic rats. But when cobalt was administered to the rats, the glycogen returned to the level of healthy rats, concomitantly with the decrease in blood glucose. The cobalt treatment had no effect on the muscle glycogen in the diabetic rats. The tissue-specific responses of glycogen metabolism suggest the involvement of suppressed glucagon signaling due to cobalt treatment.     

Effect of long-term cobalt deprivation on methanol degradation in a methanogenic granular sludge bioreactor

The effect of the trace metal cobalt on the conversion of methanol in an upflow anaerobic sludge bed (UASB) reactor was investigated by studying the effect of cobalt deprivation from the influent on the reactor efficiency and the sludge characteristics. A UASB reactor (30 degrees C; pH 7) was operated for 261 days at a 12-h hydraulic retention time (HRT). The loading rate was increased stepwise from 2.6 g chemical oxygen demand (COD) x L reactor(-1) x d(-1) to 7.8 g COD x L reactor(-1) x d(-1). Cobalt deprivation had a strong impact on the methanogenic activity of the sludge. In batch tests, the methanogenic activity of the sludge with methanol as the substrate increased 5.3 (day 28) and 2.1 (day 257) times by addition of 840 nM of cobalt. The sludge had an apparent K(m) for cobalt of 948 nM after 28 days of operation and 442 nM at the end of the run. Cobalt deprivation during 54 days of operation led to a methanol conversion efficiency of only 55%. Continuous addition of cobalt (330 nM) for 33 days improved the methanol removal efficiency to 100%. In this period of cobalt dosing, the cobalt concentration in the sludge increased 2.7 times up to 32 microg x g TSS(-1). Upon omission of the cobalt addition, cobalt washed-out at a stable rate of 0.1 microg x g VSS(-1) x d(-1). At the end of the run, the cobalt concentration of the sludge was similar to that of the seed sludge.     

Increase of free cysteine and citric acid in plant cells exposed to cobalt ions

Cobalt complexation was investigated in a suspension cell culture of the cobalt hyperaccumulator Crotalaria cobalticola. C. cobalticola cells were more tolerant towards cobalt ions than the suspension cells of the non-accumulators Rauvolfia serpentina and Silene cucubalus. While the concentration of various compounds increased in cells of C. cobalticola challenged with cobalt ions, phytochelatin biosynthesis was not induced. Instead, the exposure to cobalt ions resulted in the increase of citrate and cysteine in cells. Size exclusion chromatography demonstrated the co-elution of cobalt and cysteine in C. cobalticola cell extracts. A significant increase in cysteine was observed also in cells of R. serpentina and S. cucubalus when they were exposed to cobalt ions. These results suggest that free cysteine is involved in cobalt ion complexation in plant cells.     

Evidence that hemorrhagic hypotension is mediated by the ventrolateral periaqueductal gray region

Severe hemorrhage lowers arterial pressure by suppressing sympathetic activity. This study tested the hypothesis that the decompensatory phase of hemorrhage is mediated by the ventrolateral periaqueductal gray (vlPAG), a region importantly involved in the autonomic and behavioral responses to stress and trauma. Neuronal activity in the vlPAG was inhibited with either lidocaine or cobalt chloride 5 min before hemorrhage (2.5 ml/100 g body wt) was initiated in conscious, unrestrained rats. Bilateral injection of lidocaine (0.5 microl of a 2% or 1 microl of a 5% solution) into the caudal vlPAG delayed the onset and reduced the magnitude of the hypotension produced by hemorrhage significantly. In contrast, inactivation of the dorsolateral PAG with lidocaine was ineffective. Cobalt chloride (5 mM; 0.5 microl), which inhibits synaptic transmission but not axonal conductance, also attenuated hemorrhagic hypotension significantly. Microinjection of lidocaine or cobalt chloride into the vlPAG of normotensive, nonhemorrhaged rats did not influence cardiovascular function. These data indicate that the vlPAG plays an important role in the response to hemorrhage.