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Cobalt (Co) and its compounds are widely distributed in nature and are part of numerous anthropogenic activities. Although cobalt has a biologically necessary role as metal constituent of vitamin B 12 , excessive exposure has been shown to induce various adverse health effects. This review provides an extended overview of the possible Co sources and related intake routes, the detection and quantification methods for Co intake and the interpretation thereof, and the reported health effects. The Co sources were allocated to four exposure settings: occupational, environmental, dietary and medical exposure. Oral intake of Co supplements and internal exposure through metal-on-metal (MoM) hip implants deliver the highest systemic Co concentrations. The systemic health effects are characterized by a complex clinical syndrome, mainly including neurological (e.g. hearing and visual impairment), cardiovascular and endocrine deficits. Recently, a biokinetic model has been proposed to characterize the dose-response relationship and effects of chronic exposure. According to the model, health effects are unlikely to occur at blood Co concentrations under 300 μg/l (100 μg/l respecting a safety factor of 3) in healthy individuals, hematological and endocrine dysfunctions are the primary health endpoints, and chronic exposure to acceptable doses is not expected to pose considerable health hazards. However, toxic reactions at lower doses have been described in several cases of malfunctioning MoM hip implants, which may be explained by certain underlying pathologies that increase the individual susceptibility for Co-induced systemic toxicity. This may be associated with a decrease in Co bound to serum proteins and an increase in free ionic Co 2+ . As the latter is believed to be the primary toxic form, monitoring of the free fraction of Co 2+ might be advisable for future risk assessment. Furthermore, future research should focus on longitudinal studies in the clinical setting of MoM hip implant patients to further elucidate the dose-response discrepancies. [ABSTRACT FROM AUTHOR]

Objectives Cobalt (Co) exposure has been documented to result in increased erythropoiesis. To evaluate the potential for implant-derived Co toxicity, we examined the relationship between serum Co (sCo) and erythrocyte counts (ERY) in a metal-containing total-hip arthroplasty implant population. Methods Retrospective review of sCo concentrations identified 77 patients with concomitant ERY. Statistical analysis was performed to determine if there was a significant difference in ERY for patients divided into clinically relevant sCo ranges. A single detailed case review of a patient with a loose mal-positioned acetabular component and significantly elevated sCo was also performed for symptoms thought to arise from Co toxicity. Results Statistical difference in ERY was not observed between patients with significantly elevated (> 10 ng/mL), elevated (4–10 ng/mL), modestly elevated (1.0–3.9 ng/mL), or normal (< 1.0 ng/mL) sCo. While the detailed case report was unremarkable for any of the clinical symptoms previously reported to be associated with Co toxicity and no increase in ERY was observed, this patient's sCo was 84 ng/mL. Conclusions Increased erythropoiesis was not observed in patients with implant-derived increased sCo. Even with a sCo 100× the upper-limit of normal, the patient presented did not have increased ERY nor exhibit any symptoms ascribed with Co toxicity. [ABSTRACT FROM AUTHOR]

Abstract: Background: Cobalt has a rare occurrence in nature, but may accumulate in cells to toxic levels. In the present study, we have investigated how the transcription factor Yap1 mediates tolerance to cobalt toxicity. Methods: Fluorescence microscopy was used to address how cobalt activates Yap1. Using microarray analysis, we compared the transcriptional profile of a strain lacking Yap1 to that of its parental strain. To evaluate the extent of the oxidative damage caused by cobalt, GSH was quantified by HPLC and protein carbonylation levels were assessed. Results: Cobalt activates Yap1 under aerobiosis and anaerobiosis growth conditions. This metal generates a severe oxidative damage in the absence of Yap1. However, when challenged with high concentrations of cobalt, yap1 mutant cells accumulate lower levels of this metal. Accordingly, microarray analysis revealed that the expression of the high affinity phosphate transporter, PHO84, a well-known cobalt transporter, is compromised in the yap1 mutant. Moreover, we show that Yap1 is a repressor of the low affinity iron transporter, FET4, which is also known to transport cobalt. Conclusions: Cobalt activates Yap1 that alleviates the oxidative damage caused by this metal. Yap1 partially controls cobalt cellular uptake via the regulation of PHO84. Although FET4 repression by Yap1 has no effect on cobalt uptake, it may be its first line of defense against other toxic metals. General significance: Our results emphasize the important role of Yap1 in mediating cobalt-induced oxidative damages and reveal new routes for cell protection provided by this regulator. [Copyright &y& Elsevier]

Abstract: Cobalt (Co) is an essential trace element well known as a constituent of vitamin B12, but different compounds of Co are also described as highly toxic and/or radiotoxic for individuals or the environment. In nuclear power plants, 58Co and 60Co are radioactive isotopes of cobalt present as activation products of stable Co and Ni used in alloys. Skin exposure is a current occupational risk in the hard metal and nuclear industries. As biochemical and molecular cobalt-induced toxicological mechanisms are not fully identified, we investigated cobalt toxicity in a model human keratinocyte cell line, HaCaT. In this study, we propose a model to determine the in vitro chemical impact on cell viability of a soluble form of cobalt (CoCl2) with or without γ-ray doses to mimic contamination by 60Co, to elucidate the mechanisms of cobalt intracellular chemical and radiological toxicity. Intracellular cobalt concentration was determined after HaCaT cell contamination and chemical toxicity was evaluated in terms of cellular viability and clonogenic survival. We investigated damage to DNA in HaCaT cells by combined treatment with chemical cobalt and a moderate γ-ray dose. Additive effects of cobalt and irradiation were demonstrated. The underlying mechanism of cobalt toxicity is not clearly established, but our results seem to indicate that the toxicity of Co(II) and of irradiation arises from production of reactive oxygen species. [Copyright &y& Elsevier]

Cobalt is an important metal cofactor of many living cells. However, excessive cobalt is toxic and can cause cell death and even several diseases in humans. Saccharomyces cerevisiae is a useful tool for studying metal homeostasis and many of the genes and pathways are highly conserved in higher eukaryotes including humans. The intracellular cobalt and reactive oxygen species (ROS) levels were measured by an atomic absorption spectrometer and DHE staining method, respectively. The expression of genes involved in scavenging oxidative stress was tested by qPCR method, while the expression of UPRE - lac Z report gene was analyzed via β-galactosidase activity assay. Using a genome-scale genetic screen, 153 cobalt-sensitive and 37 cobalt-tolerant gene deletion mutants were identified from Saccharomyces cerevisiae. We showed that 101 of the cobalt-sensitive mutants accumulated higher intracellular cobalt compared to wild-type. The intracellular ROS levels in 112 of the mutants were induced by cobalt, which might be caused by the decreased expression of genes involved in scavenging oxidative stress in response to cobalt. Moreover, more than one-third of the cobalt-sensitive mutants were also sensitive to tunicamycin, and cobalt stress might induce the unfolded protein response (UPR) through serine/threonine kinase and endoribonuclease Ire1. This study reinforced the fact that cobalt toxicity might be due to the high intracellular cobalt and ROS levels, and the endoplasmic reticulum stress responses induced by cobalt. Elucidating the toxicity mechanisms of cobalt stress response will help reveal new routes for the treatment of the diseases induced by cobalt. Suggested model for the toxicity mechanisms of cobalt stress. Cells uptake the extracellular cobalt via the plasma membrane transporters Smf2, Fet4 and Pho84. Once inside the cell, cobalt generates ROS, causing DNA damage and lipid/protein oxidation, thus inducing the ER stress. The oxidative damage caused by cobalt can be alleviated by inducing the genes involved in oxidative stress scavenging. Unlabelled Image • Cobalt-sensitive and -tolerant mutants were both identified • Cobalt generates ROS by inducing genes involved in scavenging oxidative stress • Cobalt induces UPR through Ire1 • Cobalt toxicity was caused by High intracellular cobalt and ROS levels, ER stress [ABSTRACT FROM AUTHOR]

• Growth, water content and osmotic potential decreased under Co stress. • Stress caused a disruption in the photosynthetic capacity in wheat leaves. • Hydrogen peroxide and lipid peroxidation were induced under stress. • SNP/NaHS together with cobalt ameliorated the toxic effect on chloroplast of wheat. • SNP/NaHS maintain of the redox state of ascorbate-glutathione cycle in chloroplast. The role of hydrogen sulfide (H 2 S)/nitric oxide (NO) in mitigating stress-induced damages has gained interest in the past few years. However, the protective mechanism H 2 S and/or NO has towards the chloroplast system through the regulation of redox status and activation of antioxidant capacity in cobalt-treated wheat remain largely unanswered. Triticum aestivum L. cv. Ekiz was treated with alone/in combination of a H 2 S donor (sodium hydrosulfide (NaHS,600μM)), a NO donor (sodium nitroprusside (SNP,100μM)) and a NO scavenger (rutin hydrate (RTN,50μM)) to assess how the donors affect growth, water relations, redox and antioxidant capacity in chloroplasts, under cobalt (Co) concentrations of 150-300 μM. Stress decreased a number of parameters (growth, water content (RWC), osmotic potential (Ψ Π), carbon assimilation rate, stomatal conductance, intercellular CO 2 concentrations, transpiration rate and the transcript levels of rubisco, which subsequently disrupt the photosynthetic capacity). However, SNP/NaHS counteracted the negative effects of stress on these aforementioned parameters and RTN application with stress/non-stress was reversed these effects. Hydrogen peroxide (H 2 O 2) and TBARS were induced under stress in spite of activated ascorbate peroxidase (APX). SNP/NaHS under stress increased activation of superoxide dismutase (SOD), peroxidase (POX), APX, glutathione reductase (GR), monodehydroascorbate reductase (MDHAR), dehydroascorbate reductase (DHAR), ascorbate (tAsA) and glutathione (GSH). In conclusion, NaHS/SNP are involved in the regulation and modification of growth, water content, rubisco activity and up-regulation of ascorbate-glutathione cycle (AsA-GSH) in chloroplast under stress. [ABSTRACT FROM AUTHOR]

The mechanisms underlying cobalt toxicity in aquatic species in general and cnidarians in particular remain poorly understood. Herein we investigated cobalt toxicity in a Hydra model from morphological, histological, developmental, and molecular biological perspectives. Hydra, exposed to cobalt (0-60 mg/L), were altered in morphology, histology, and regeneration. Exposure to standardized sublethal doses of cobalt impaired feeding by affecting nematocytes, which in turn affected reproduction. At the cellular level, excessive ROS generation, as the principal mechanism of action, primarily occurred in the lysosomes, which was accompanied by the upregulation of expression of the antioxidant genes SOD, GST, GPx, and G6PD. The number of Hsp70 and FoxO transcripts also increased. Interestingly, the upregulations were higher in the 24-h than in the 48-h time-point group, indicating that ROS overwhelmed the cellular defense mechanisms at the latter time-point. Comet assay revealed DNA damage. Cell cycle analysis indicated the induction of apoptosis accompanied or not by cell cycle arrest. Immunoblot analyses revealed that cobalt treatment triggered mitochondria-mediated apoptosis as inferred from the modulation of the key proteins Bax, Bcl-2, and caspase-3. From this data, we suggest the use of Hydra as a model organism for the risk assessment of heavy metal pollution in aquatic ecosystems. [ABSTRACT FROM AUTHOR]

Cobalt-containing hip prosthesis may cause systemic toxicity due to the release of cobalt from metal-on-metal (MoM) joint arthroplasty into the bloodstream. High cobalt blood levels can lead to a variety of clinical manifestations, mimicking other disorders, especially autoimmune, hematologic, and infectious diseases. Our purpose is to describe a clinical case of cobalt hip prosthesis intoxication mimicking an autoimmune disease, with systemic inflammation signs, arthro-myalgias unrelated to overt synovitis, and multiple autoantibody positivity. A 69-years-old woman presented with a 1-year history of right coxalgia, recurrent fever, arthro-myalgias, mediastinal and right iliac reactive lymphadenopathy. She underwent hip replacement surgery seven years earlier. The physical examination was unremarkable except for right hip pain. Laboratory tests showed markedly increased inflammatory indices and microbiological tests were all negative. Ultrasound-guided arthrocentesis of right hip yielded limpid fluid with negative cultures. Increased cobalt levels in plasma and urine showed metal intoxication. Magnetic resonance imaging with metal artifact reduction sequence (MARS) confirmed a periprosthetic mass as usually seen in reaction to metal debris. Prosthesis substitution was performed with a resolution of the clinical picture and normalization of cobalt levels. [ABSTRACT FROM AUTHOR]

High levels of circulating cobalt ions in blood have been reported to induce systemic reactions in patients with metal-on-metal (MoM) hip implants. We still lack information regarding these adverse effects, which may specifically impact on patients showing adverse neurological symptoms. To investigate this, we used a battery of in vitro viability and proliferation assays to identify toxic cobalt chloride (CoCl 2) concentrations in two different brain cell types: SH-SY5Y neuroblastoma and U-373 astrocytoma cells. Cobalt cytotoxicity was characterised by MTT and Neutral Red (NR) assays at concentrations ranging from 0 to 500 μM after 24, 48, and 72 h exposure. MTT and NR showed a dose- and time-dependent toxicity with cobalt decreasing cell viability at high concentrations. IC50s for MTT at 72 h (astrocytes: 333.15 ± 22.88; neurons: 100.01 ± 5.91 μM) and for BrdU proliferation assays (astrocytes: 212.89 ± 9.84; neurons: 88.86 ± 19.03 μM) demonstrate that SH-SY5Y neurons are significantly more vulnerable to cobalt than astrocytes. Increased BrdU and MTT assay sensitivity suggested that DNA synthesis and metabolism disruption were involved in Co toxicity. Intracellular cobalt level measured by ICP-MS was significant after 100 μM treatment. Astrocytes displayed improved resistance to cobalt toxicity and higher uptake, which may reflect their neuroprotective nature. In summary, exposure to high concentrations of extracellular cobalt has deleterious effects in neurons and astrocytes, with neurons showing particular sensitivity. • We investigated the effects of cobalt on viability and uptake in CNS cell lines. • MTT and NR assays show that cobalt ions are toxic at high concentrations in vitro. • MTT and BrdU sensitivity suggests that Co jeopardises metabolism and DNA synthesis. • Cobalt metal uptake is dose-dependent in neuroblastoma and astrocytoma cells. • Astrocytoma exhibit greater resistance to cobalt toxicity despite a higher uptake. [ABSTRACT FROM AUTHOR]

Although cobalt is a required nutrient, it is toxic due to its ability to generate reactive oxygen species (ROS) and damage DNA. ROS generation by Co2+ often has been compared to that of Fe2+ or Cu+, disregarding the reduction potential differences among these metal ions. In plasmid DNA damage studies, a maximum of 15% DNA damage is observed with Co2+/H 2 O 2 treatment (up to 50 μM and 400 μM, respectively) significantly lower than the 90% damage observed for Fe2+/H 2 O 2 or Cu+/H 2 O 2 treatment. However, when ascorbate is added to the Co2+/H 2 O 2 system, a synergistic effect results in 90% DNA damage. DNA damage by Fe2+/H 2 O 2 can be prevented by polyphenol antioxidants, but polyphenols both prevent and promote DNA damage by Cu+/H 2 O 2. When tested for cobalt-mediated DNA damage affects, eight of ten polyphenols (epicatechin gallate, epigallocatechin gallate, propyl gallate, gallic acid, methyl-3,4,5-trihydroxybenzoate, methyl-4,5-dihydroxybenzoate, protocatechuic acid, and epicatechin) prevent cobalt-mediated DNA damage with IC 50 values of 1.3 to 27 μM and two (epigallocatechin and vanillic acid) prevent little to no DNA damage. EPR studies demonstrate cobalt-mediated formation of •OH, O 2 •ˉ, and •OOH, but not 1O 2 in the presence of H 2 O 2 and ascorbate. Epigallocatechin gallate and methyl-4,5-dihydroxybenzoate significantly reduce ROS generated by Co2+/H 2 O 2 /ascorbate, consistent with their prevention of cobalt-mediated DNA damage. Thus, while cobalt, iron, and copper are all d -block metal ions, cobalt ROS generation and its prevention is significantly different from that of iron and copper. In contrast to Fe(II), Co(II) does not damage DNA in the presence of hydrogen peroxide alone. Instead, it generates reactive oxygen species (ROS) and damages DNA in the presence of both hydrogen peroxide and ascorbate. Some polyphenols can bind Co(II) and scavenge these ROS to prevent cobalt-mediated DNA damage. [Display omitted] • Unlike Fe(II), Co(II) does not damage DNA in the presence of only hydrogen peroxide. • With H 2 O 2 and ascorbate, Co(II) generates hydroxyl and ascorbyl radicals to damage DNA. • Some polyphenols prevent Co-mediated DNA damage and compete with ascorbate to bind Co(II). • Antioxidant-metal binding may be one way to prevent cobalt toxicity. [ABSTRACT FROM AUTHOR]

The effect of two concentrations of cobalt (Co 2+ ) on photosynthetic activity and antioxidative response in Lemna minor L. were assessed 24, 48 and 72 h after the start of the exposure. Higher concentration of cobalt (1 mM) induced growth inhibition while lower concentration (0.01 mM) increased photosynthetic pigments content. Analysis of chlorophyll a fluorescence transients revealed high sensitivity of photosystem II primary photochemistry to excess of Co 2+ especially at the higher concentration where decreased electron transport beyond primary quinone acceptor Q A − and impaired function of oxygen evolving complex (OEC) was observed. Due to impairment of OEC, oxygen production was decreased at higher Co 2+ concentration. Activity of superoxide dismutase was mainly inhibited while lipid peroxidation increased, at both concentrations, indicating that cobalt-induced oxidative damage after short exposure and moreover, susceptibility of the membranes in the cell to cobalt toxicity. Results obtained in this study suggest possible application of used parameters as tools in assessment of early damage caused by metals. [ABSTRACT FROM AUTHOR]

Abstract: 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 (Co2+) 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 (Co2+) 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 (Co2+) have recently been proposed to be due to putative inhibition of Ca2+ entry and Ca2+-signaling and competition with Ca2+ for intracellular Ca2+-binding proteins. The tissue partitioning of cobalt (Co2+) 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 (Co2+) binds to albumin, and the concentration of free, ionized Co2+ is estimated at 5–12% of the total cobalt concentration. In human red cells the membrane transport pathway for cobalt (Co2+) uptake appears to be shared with calcium (Ca2+), 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 (Co2+), and since the uptake during their 120days 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 &y& Elsevier]

Abstract: Cobalt ions can enhance the generation of reactive oxygen species (ROS), which may be the reason for cobalt toxicity. This study aimed to determine whether Co2+ toxicity in goldfish is related to induced oxidative stress in gills, heart and spleen, and to assess responses of antioxidant systems. Exposure of goldfish to 50, 100 and 150mgL−1 of Co2+ for 96h elevated total hemoglobin in blood by 23, 44 and 78%, respectively. In gills, cobalt exposure enhanced lipid peroxide levels and activities of primary antioxidant enzymes; superoxide dismutase (SOD) rose by 125% and glutathione peroxidase (GPx) increased by 53–296%. Glutathione-S-transferase (GST) activity also increased by 117–157% and glucose-6-phosphate dehydrogenase (G6PDH) enhanced by 46–96%. Heart showed limited effects of fish exposure to 50 or 100mgL−1 of Co2+, but the exposure to 150mgL−1 of Co2+ elevated concentrations of lipid peroxides by 123% and activities of GPx by 98% and SOD by 208%. The most substantial effects of goldfish exposure to Co2+ were observed in spleen: a decrease in total protein concentration by 44–60% and high molecular mass thiols by 59–82%, reduced activities of catalase by 24–58% and GR by 25–68%, whereas the level of low molecular mass thiols increased by 153–279% and activities of GPx, GST, G6PDH were enhanced by 114–120%, 192–769%, and 256–581%, respectively. The data show that fish exposure to 50–150mgL−1 of Co2+ elevates blood hemoglobin level, mimicking effects of hypoxia, and causes the activation of defense systems against ROS. [Copyright &y& Elsevier]

Abstract: Cobalt is suspected to cause memory deficit in humans and was reported to induce neurotoxicity in animal models. We have studied the effects of cobalt in primary cultures of mouse astrocytes. CoCl2 (0.2–0.8mM) caused dose-dependent ATP depletion, apoptosis (cell shrinkage, phosphatidylserine externalization and chromatin rearrangements) and secondary necrosis. The mitochondria appeared to be a main target of cobalt toxicity, as shown by the loss of mitochondrial membrane potential (ΔΨ m) and release from the mitochondria of apoptogenic factors, e.g. apoptosis inducing factor (AIF). Pre-treatment with bongkrekic acid reduced ATP depletion, implicating the involvement of the mitochondrial permeability transition (MPT) pore. Cobalt increased the generation of oxygen radicals, but antioxidants did not prevent toxicity. There was also an impaired response to ATP stimulation, evaluated as a lower raise in intracellular calcium. Similarly to hypoxia and dymethyloxallyl glycine (DMOG), cobalt triggered stabilization of the α-subunit of hypoxia-inducible factor HIF-1 (HIF-1α). This early event was followed by an increased expression of HIF-1 regulated genes, e.g. stress protein HO-1, pro-apoptotic factor Nip3 and iNOS. Although all of the three stimuli activated the HIF-1α pathway and decreased ATP levels, the downstream effects were different. DMOG only inhibited cell proliferation, whereas the other two conditions caused cell death by apoptosis and necrosis. This points to cobalt and hypoxia not only inducing HIF-1α regulated genes but also affecting similarly other cellular functions, including metabolism. [Copyright &y& Elsevier]

Developing brain is very sensitive to the influence of environmental factors during gestation and the neonatal period. The aim of the study is to assess cobalt and iron accumulation in the brain as well as changes in the expression of iron-regulatory proteins transferrin receptor 1, hepcidin, and ferroportin in suckling mice. Perinatal exposure to cobalt chloride increased significantly cobalt content in brain tissue homogenates of 18-day-old (d18) and 25-day-old (d25) mice inducing alterations in brain iron homeostasis. Higher degree of transferrin receptor 1 expression was demonstrated in cobalt chloride-exposed mice with no substantial changes between d18 and d25 mice. A weak ferroportin expression was found in 18-day-old control and cobalt-treated mouse brain. Cobalt exposure of d25 mice resulted in increased ferroportin expression in brain compared to the untreated age-matched control group. Hepcidin level in cobalt-exposed groups was decreased in d18 mice and slightly increased in d25 mice. The obtained data contribute for the better understanding of metal toxicity impact on iron homeostasis in the developing brain with further possible implications in neurodegeneration. • Late prenatal and early postnatal exposure to cobalt chloride increases significantly brain Co content in suckling mice. • CoCl 2 provokes changes in the expression of iron-regulatory proteins transferrin receptor 1, hepcidin and ferroportin. • Cobalt toxicity affects iron homeostasis in the developing brain with further possible implications in neurodegeneration. [ABSTRACT FROM AUTHOR]

Nickel and cobalt are essential elements that become toxic at high concentrations. Little is known about nickel and cobalt toxicity in aquatic animals. This study aimed to investigate acute and chronic toxicity of nickel and cobalt in Japanese flounder (Paralichthys olivaceous), with emphasis on oxidative stress reactions, histopathological changes, and differences in gene expression. The lethal concentration for 50% mortality (LC 50) in 3 and 8 cm Japanese flounder exposed to nickel for 96 h was found to be 86.2 ± 0.018 and 151.3 ± 0.039 mg/L; for cobalt exposure, LC 50 was 47.5 ± 0.015 and 180.4 ± 0.034 mg/L, respectively. Chronic nickel and cobalt exposure caused different degrees of oxidative enzyme activity changes in gill, liver, and muscle tissues. Erythrocyte deformations were detected after acute or chronic exposure to nickel and cobalt. the nickel and cobalt exposure also caused pathological changes such as spherical swelling over other gill patches, rod-like proliferations in the gill patch epithelial cell layer, and disorder in hepatocyte arrangement, cell swelling, and cytoplasm loosening. RNA-Seq indicated that there were 184 upregulated and 185 downregulated genes in the liver of Japanese flounder exposed to 15 mg/L nickel for 28 d. For cobalt, 920 upregulated and 457 downregulated genes were detected. Among these differentially expressed genes, 162 were shared by both nickel and cobalt exposure. In both nickel and cobalt, pathways including fatty acid elongation, steroid biosynthesis, unsaturated fatty acid biosynthesis, fatty acid metabolism, PPAR signaling, and ferroptosis were significantly enriched. Taken together, these results aided our understanding of the toxicity of nickel and cobalt in aquatic animals. Image 1 • Heterozygous clonal Japanese flounder with genetic similarity of 1.00 were used. • Lethal concentration for 50% mortality that exposed to nickel and cobalt were determined in Japanese flounder. • Chronic nickel and cobalt exposure changed oxidative enzyme activity in Japanese flounder. • Nickel and cobalt induced stress response signaling pathways were explored in Japanese flounder. Chronic nickel and cobalt exposure induced ferroptosis in the liver of Japanese flounder. [ABSTRACT FROM AUTHOR]