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      Relationship between Vitamin B12 and Cobalt Metabolism in Domestic Ruminant: An Update

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          Abstract

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          We review the role of cobalt and vitamin B12 in animals, especially in ruminants. Vitamin B12 is an essential part of the enzyme systems involved in multiple metabolic reactions and mainly in the formation of energy from ruminal fermentation. Signs of deficiency, as well as cobalt toxicity, in animals are described. The level of cobalt in ruminants can be assessed by measuring the blood or tissue concentrations of cobalt or vitamin B12, as well as the level of some metabolites such as malonate, homocysteine or transobolamine in blood or methylmalonic acid in urine. The requirement for cobalt (Co) is around 0.11 ppm (mg/kg) dry matter (DM) in the diet, although current recommendations advise supplementing the diet up to 0.20 mg Co/kg DM, which seems to increase animal production, especially in dairy cattle.

          Abstract

          Cobalt, as a trace element, is essential for rumen microorganisms for the formation of vitamin B12. In the metabolism of mammals, vitamin B12 is an essential part of two enzymatic systems involved in multiple metabolic reactions, such as in the metabolism of carbohydrates, lipids, some amino acids and DNA. Adenosylcobalamin and methylcobalamin are coenzymes of methylmalonyl coenzyme A (CoA) mutase and methionine synthetase and are essential for obtaining energy through ruminal metabolism. Signs of cobalt deficiency range from hyporexia, reduced growth and weight loss to liver steatosis, anemia, impaired immune function, impaired reproductive function and even death. Cobalt status in ruminant animals can be assessed by direct measurement of blood or tissue concentrations of cobalt or vitamin B12, as well as the level of methylmalonic acid, homocysteine or transcobalamin in blood; methylmalonic acid in urine; some variables hematological; food consumption or growth of animals. In general, it is assumed that the requirement for cobalt (Co) is expressed around 0.11 ppm (mg/kg) in the dry matter (DM) diet; current recommendations seem to advise increasing Co supplementation and placing it around 0.20 mg Co/kg DM. Although there is no unanimous criterion about milk production, fattening or reproductive rates in response to increased supplementation with Co, in some investigations, when the total Co of the diet was approximately 1 to 1.3 ppm (mg/kg), maximum responses were observed in the milk production.

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          Vitamin B12 as a modulator of gut microbial ecology.

          The microbial mechanisms and key metabolites that shape the composition of the human gut microbiota are largely unknown, impeding efforts to manipulate dysbiotic microbial communities toward stability and health. Vitamins, which by definition are not synthesized in sufficient quantities by the host and can mediate fundamental biological processes in microbes, represent an attractive target for reshaping microbial communities. Here, we discuss how vitamin B12 (cobalamin) impacts diverse host-microbe symbioses. Although cobalamin is synthesized by some human gut microbes, it is a precious resource in the gut and is likely not provisioned to the host in significant quantities. However, this vitamin may make an unrecognized contribution in shaping the structure and function of human gut microbial communities.
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            Microbial production of vitamin B12.

            One of the most alluring and fascinating molecules in the world of science and medicine is vitamin B12 (cobalamin), which was originally discovered as the anti pernicious anemia factor and whose enigmatic complex structure is matched only by the beguiling chemistry that it mediates. The biosynthesis of this essential nutrient is intricate, involved and, remarkably, confined to certain members of the prokaryotic world, seemingly never have to have made the eukaryotic transition. In humans, the vitamin is required in trace amounts (approximately 1 microg/day) to assist the actions of only two enzymes, methionine synthase and (R)-methylmalonyl-CoA mutase; yet commercially more than 10 t of B12 are produced each year from a number of bacterial species. The rich scientific history of vitamin B12 research, its biological functions and the pathways employed by bacteria for its de novo synthesis are described. Current strategies for the improvement of vitamin B12 production using modern biotechnological techniques are outlined.
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              Cobalt metabolism and toxicology--a brief update.

              Cobalt metabolism and toxicology are summarized. The biological functions of cobalt are updated in the light of recent understanding of cobalt interference with the sensing in almost all animal cells of oxygen deficiency (hypoxia). Cobalt (Co(2+)) stabilizes the transcriptional activator hypoxia-inducible factor (HIF) and thus mimics hypoxia and stimulates erythropoietin (Epo) production, but probably also by the same mechanism induces a coordinated up-regulation of a number of adaptive responses to hypoxia, many with potential carcinogenic effects. This means on the other hand that cobalt (Co(2+)) also may have beneficial effects under conditions of tissue hypoxia, and possibly can represent an alternative to hypoxic preconditioning. Cobalt is acutely toxic in larger doses, and in mammalian in vitro test systems cobalt ions and cobalt metal are cytotoxic and induce apoptosis and at higher concentrations necrosis with inflammatory response. Cobalt metal and salts are also genotoxic, mainly caused by oxidative DNA damage by reactive oxygen species, perhaps combined with inhibition of DNA repair. Of note, the evidence for carcinogenicity of cobalt metal and cobalt sulfate is considered sufficient in experimental animals, but is as yet considered inadequate in humans. Interestingly, some of the toxic effects of cobalt (Co(2+)) have recently been proposed to be due to putative inhibition of Ca(2+) entry and Ca(2+)-signaling and competition with Ca(2+) for intracellular Ca(2+)-binding proteins. The tissue partitioning of cobalt (Co(2+)) and its time-dependence after administration of a single dose have been studied in man, but mainly in laboratory animals. Cobalt is accumulated primarily in liver, kidney, pancreas, and heart, with the relative content in skeleton and skeletal muscle increasing with time after cobalt administration. In man the renal excretion is initially rapid but decreasing over the first days, followed by a second, slow phase lasting several weeks, and with a significant long-term retention in tissues for several years. In serum cobalt (Co(2+)) binds to albumin, and the concentration of free, ionized Co(2+) is estimated at 5-12% of the total cobalt concentration. In human red cells the membrane transport pathway for cobalt (Co(2+)) uptake appears to be shared with calcium (Ca(2+)), but with the uptake being essentially irreversible as cobalt is effectively bound in the cytosol and is not itself extruded by the Ca-pump. It is tempting to speculate that this could perhaps also be the case in other animal cells. If this were actually the case, the tissue partitioning and biokinetics of cobalt in cells and tissues would be closely related to the uptake of calcium, with cobalt partitioning primarily into tissues with a high calcium turn-over, and with cobalt accumulation and retention in tissues with a slow turn-over of the cells. The occupational cobalt exposure, e.g. in cobalt processing plants and hard-metal industry is well known and has probably been somewhat reduced in more recent years due to improved work place hygiene. Of note, however, adverse reactions to heart and lung have recently been demonstrated following cobalt exposure near or slightly under the current occupational exposure limit. Over the last decades the use of cobalt-chromium hard-metal alloys in orthopedic joint replacements, in particular in metal-on-metal bearings in hip joint arthroplasty, has created an entirely new source of internal cobalt exposure. Corrosion and wear produce soluble metal ions and metal debris in the form of huge numbers of wear particles in nanometric size, with systemic dissemination through lymph and systemic vascular system. This may cause adverse local reactions in peri-prosthetic soft-tissues, and in addition systemic toxicity. Of note, the metal nanoparticles have been demonstrated to be clearly more toxic than larger, micrometer-sized particles, and this has made the concept of nanotoxicology a crucial, new discipline. As another new potential source of cobalt exposure, suspicion has been raised that cobalt salts may be misused by athletes as an attractive alternative to Epo doping for enhancing aerobic performance. The cobalt toxicity in vitro seems to reside mainly with ionized cobalt. It is tempting to speculate that ionized cobalt is also the primary toxic form for systemic toxicity in vivo. Under this assumption, the relevant parameter for risk assessment would be the time-averaged value for systemic cobalt ion exposure that from a theoretical point of view might be obtained by measuring the cobalt content in red cells, since their cobalt uptake reflects uptake only of free ionized cobalt (Co(2+)), and since the uptake during their 120 days life span is practically irreversible. This clearly calls for future clinical studies in exposed individuals with a systematic comparison of concurrent measurements of cobalt concentration in red cells and in serum. Copyright © 2012 Elsevier B.V. All rights reserved.
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                Author and article information

                Journal
                Animals (Basel)
                Animals (Basel)
                animals
                Animals : an Open Access Journal from MDPI
                MDPI
                2076-2615
                12 October 2020
                October 2020
                : 10
                : 10
                : 1855
                Affiliations
                [1 ]Medicine, Surgery and Anatomy Veterinary Department, Veterinary Faculty, University of León, 24071 León, Spain; ajalod@ 123456unileon.es (A.J.A.); roblesdellano@ 123456gmail.com (R.R.)
                [2 ]Academic Unit of Veterinary Medicine and Zootechnics, Autonomous University of Nayarit, Tepic 69130, Nayarit, Mexico; fescalera@ 123456uan.edu.mx
                [3 ]Production and Health Animal, Public Health Veterinary and Science and Technology of Food Department, Veterinary Faculty, Cardenal Herrera-CEU University, 46115 Valencia, Spain; juan.lomillos@ 123456uchceu.es
                [4 ]Animal Production Department, Veterinary Faculty, Veterinary Faculty, University of León, 24071 León, Spain; marta.alonso@ 123456unileon.es
                Author notes
                [* ]Correspondence: jrgonm@ 123456unileon.es ; Tel.: +34-987-2941214
                Author information
                https://orcid.org/0000-0002-8976-3332
                https://orcid.org/0000-0002-3792-2733
                https://orcid.org/0000-0002-3810-0176
                Article
                animals-10-01855
                10.3390/ani10101855
                7601760
                33053716
                0c04bc78-8adc-444c-9678-be35148ba0e9
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 02 September 2020
                : 01 October 2020
                Categories
                Review

                cobalt,vitamin b12,deficiency,ruminant,cattle
                cobalt, vitamin b12, deficiency, ruminant, cattle

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