Selenomethionine protects hematopoietic stem/progenitor cells against cobalt nanoparticles by stimulating antioxidant actions and DNA repair functions.

Hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) can differentiate into all blood lineages to maintain hematopoiesis, wound healing, and immune functions. Recently, cobalt-chromium alloy casting implants have been used extensively in total hip replacements; however, cobalt nanoparticles (CoNPs) released from the alloy were toxic to HSCs and HPCs. We aimed to investigate the mechanism underlying the toxic effect of CoNPs on HSCs/HPCs and to determine the protective effect of selenomethionine (SeMet) against CoNPs in vitro and in vivo. Human and rat CD34+ HSCs/HPCs were isolated from cord blood and bone marrow, respectively. CoNPs decreased the viability of CD34+ HSCs/HPCs and increased apoptosis. SeMet attenuated the toxicity of CoNPs by enhancing the antioxidant ability of cells. The protective effect of SeMet was not completely abolished after adding H2O2 to abrogate the improvement of the antioxidant capacity by SeMet. SeMet and CoNPs stimulated ATM/ATR DNA damage response signals and inhibited cell proliferation. Unlike CoNPs, SeMet did not damage the DNA, and cell proliferation recovered after removing SeMet. SeMet inhibited the CoNP-induced upregulation of hypoxia inducible factor (HIF)-1α, thereby disrupting the inhibitory effect of HIF-1α on breast cancer type 1 susceptibility protein (BRCA1). Moreover, SeMet promoted BRCA1-mediated ubiquitination of cyclin B by upregulating UBE2K. Thus, SeMet enhanced cell cycle arrest and DNA repair post-CoNP exposure. Overall, SeMet protected CD34+ HSCs/HPCs against CoNPs by stimulating antioxidant activity and DNA repair.

Chronic copper poisoning in beef cattle in the state of Mato Grosso, Brazil / Intoxicação crônica por cobre em bovinos de corte no Estado de Mato Grosso, Brasil

Copper is an essential micromineral in animal feed; however, when consumed in excess, it can cause liver necrosis, hemolytic crisis, hemoglobinuric nephrosis and death in cattle. Although uncommon in this species, copper poisoning occurs as a result of exacerbated supplementation, deficiency of antagonist microminerals, or previous liver lesions. An outbreak of chronic copper poisoning is reported in semi-confined cattle after supplementation with 50 mg/Kg of dry matter copper. The cattle showed clinical signs characterized by anorexia, motor incoordination, loss of balance, jaundice, brownish or black urine, diarrhea and death, or were found dead, 10 to 302 days after consumption. Of the 35 cattle that died, 20 underwent necropsy, whose frequent findings were jaundice, enlarged liver with evident lobular pattern, black kidneys, and urinary bladder with brownish to blackish content. Microscopically, the liver showed vacuolar degeneration and/or zonal hepatocellular centrilobular or paracentral coagulative necrosis, in addition to cholestasis, mild periacinal fibrosis, apoptotic bodies, and mild to moderate mononuclear inflammation. Degeneration and necrosis of the tubular epithelium and intratubular hemoglobin cylinders were observed in the kidneys. Copper levels in the liver and kidneys ranged from 5,901.24 to 28,373.14 µmol/kg and from 303.72 to 14,021 µmol/kg, respectively. In conclusion, copper poisoning due to excessive nutritional supplementation is an important cause of jaundice, hemoglobinuria, and death in semi-confined cattle.(AU)

Cobre é um micromineral essencial, que quando em excesso induz necrose hepática, crise hemolítica, nefrose hemoglobínurica e morte em bovinos. As intoxicações, apesar de incomuns nessa espécie, ocorrem devido a suplementação exacerbada de cobre, pela deficiência de microminerais antagonistas ou secundária a lesão hepática prévia. Relata-se um surto de intoxicação crônica por cobre em bovinos semiconfinados após suplementação com 50mg/kg de cobre em matéria seca. Os bovinos manifestaram sinais clínicos caracterizados por anorexia, incoordenação motora, perda de equilíbrio, icterícia, urina acastanhada ou negra, diarreia e morte ou foram encontrados mortos, após 10 a 302 dias do início de consumo. De 35 bovinos que morreram 20 foram submetidos à necropsia sendo achada frequente icterícia, fígado aumentado e com padrão lobular evidente, rins pretos e bexiga urinária repleta de conteúdo acastanhado a enegrecida. Microscopicamente, no fígado havia degeneração vacuolar e ou necrose coagulativa hepatocelular zonal, centrolobular ou paracentral, além de degeneração vacuolar com corpúsculos de Councilman, colestase, fibrose periascinar leve, e inflamação de discreta a moderada. Nos rins havia degeneração e necrose do epitélio tubular assim como cilindros de hemoglobina intratubulares. Os níveis de cobre no fígado e rim foram de 5.901,24 a 28.373,14µmol/kg e 303,72 a 14.021µmol/kg respectivamente. A suplementação nutricional excessiva com cobre pode causar doença hemolítica com icterícia, hemoglobinúria e morte de bovinos mantidos em sistema de semiconfinamento.(AU)

Joint effects of cadmium and copper on Apis mellifera forgers and larvae.

Honey bees (Apis mellifera L.) are important ecological and agricultural resources. They are among the most widely available pollinators and provide products as well as services. Unfortunately, honey bee populations are susceptible to several environmental threats, including heavy metal exposure. Honey bees can be exposed to heavy metals when foraging on contaminated honey and pollen resources, and in some cases by airborne exposure. We studied the joint acute and chronic effects of cadmium (Cd) and copper (Cu) on A. mellifera. A 1:1 solution of the two heavy metals increased larval developmental duration and the mortality of both larvae and foragers in a dose-dependent way, decreased forager feeding, increased body metal burdens, and disrupted the sucrose response behavior of foragers. In combination, Cd and Cu demonstrated a weakly synergistic effect on foragers, but for larvae an initially antagonistic effect at low doses changed to strongly synergistic response at higher concentrations. The sucrose response threshold of foragers decreased significantly when they were dosed with increasing concentrations of the metal mixtures. Overall, the fitness of honey bee larvae and foragers is detrimentally affected when these metals co-occur.

Temperature elevation stage-specifically increases metal toxicity through bioconcentration and impairment of antioxidant defense systems in juvenile and adult marine mysids.

Metals are of serious concern due to their toxicity, persistency, and accumulation potential in aquatic animals. However, limited information is available on the combined effects of metal with temperature elevation, which is one of the future climate changes suggested for the oceans. In this study, the effect of temperature elevation was investigated by analyzing toxicity, bioconcentration, and antioxidant response in juvenile and adult marine mysids upon exposure to 20 °C and 25 °C for 48 h and 96 h. Based on LC50 values, toxicity of metals was highly reliant on temperature, exposure period, and age. Elevation in temperature significantly increased the whole metal toxicity in juveniles. Bioconcentration was elevated by increasing exposure period and metal concentration. Significant elevation of malondialdehyde (MDA) and depletion of glutathione (GSH) was measured in juveniles, while significant elevation of both MDA and GSH was detected in adults. Subsequently, enzymatic activities of antioxidant enzymes in catalase (CAT) and superoxide dismutase (SOD) increased significantly in adults at 48 h and 96 h, whereas most activities were significantly lowered in juveniles at 96 h. These results suggest that the early life stage of marine mysids is more sensitive to the combined effect of metal and temperature than adult stage due to an impairment in the induction of the antioxidant defense system.

Zinc Poisoning - Symptoms, Causes, Treatments.

Zinc poisoning has been reported from many parts of the world. It is one of the global health problems that affect many organs, if exposed by inhalation of zinc vapors or by consumption of contaminated food and water. Long term exposure to zinc compounds from different sources such as air, water, soil, and food, lead to toxic effects on body systems, especially digestive, respiratory, and nerve systems, and also causes cancer. Zinc levels can be determined in blood, urine, hair, and nails. Patients with zinc toxicity need chelating agents, other pharmacological treatment, protective lung ventilation, extracorporeal membrane oxygenation (ECMO), and supportive care.

Probiotic mitigates the toxic effects of potassium dichromate in a preclinical study: a randomized controlled trial.

BACKGROUND: The present study aimed to evaluate the nutritional, physiological and biochemical effects of dietary supplementation of an association of probiotic bacteria in rats intoxicated with chromium (VI). Ninety-six male rats, recently weaned, were randomly divided into eight groups (n = 12): Control, DK12, DK24 and DK36 (0, 0.12, 0.24 and 0.36 g kg-1 of K2 Cr2 O7 incorporated in the basal feed, respectively) and groups Prob, DK12 + Prob, DK24 + Prob and DK36 + Prob received a progressive dose of 0, 0.12, 0.24 and 0.36 g kg-1 of K2 Cr2 O7 incorporated in the basal feed and supplemented with 0.02 g kg-1 of an association of probiotic bacteria (Lactobacillus acidophilus, Enterococcus faecium, Bifidobacterium thermophilum and Bifidobacterium longum). RESULTS: After 90 days, we observed significant (P < 0.05) and dose-dependent alterations from incorporation of increasing doses of chromium (VI) related to nutritional, physiological and biochemical parameters. These changes were attenuated (P < 0.05) with probiotic supplementation. CONCLUSION: Supplementation with probiotics in the diet beneficially modified the nutritional and physiological parameters, as well as hepatic, renal, glycemic and lipid profiles, of animals intoxicated with increasing doses of K2 Cr2 O7 . © 2018 Society of Chemical Industry.

Selective basal ganglia vulnerability to energy deprivation: Experimental and clinical evidences.

The basal ganglia (BG) include structures pivotal for motor and cognitive functions. Such structures are affected in neurodegenerative disorders and toxic or ischemic insults. The peculiar vulnerability of BG to toxic and ischemic damage has been the focus of preclinical research for all over the last century. This comprehensive review collects all evidences supporting a specific susceptibility of BG to energy deprivation, highlighting the pathways through which neuronal survival is jeopardized, and the consequent clinical correlates. In particular, we addressed intrinsic and extrinsic factors participating in BG neuronal vulnerability. The terminal blood supply, the main extrinsic factor, is crucial to the low threshold for hypoxic hazard. Specific, the lack of anastomoses between second and third order branches represents the frailty of an archaic terminal network, unable to guarantee collateral supply and resistance to oxygen deprivation. In addition, BG neurons survival is jeopardized by several intrinsic molecular factors. Among them, the subunit composition of ionotropic and metabotropic glutamate receptors, the impairment of mitochondria, the deficit in neurotransmitter clearance, the poor control of intracellular calcium homeostasis and the glutamatergic-dopaminergic pro-excitotoxic interplay, all play a significant role. Intrinsic and extrinsic factors represent two faces of the same coin, producing excitotoxic damage and poor ability to deal with energy deprivation. The clinical correlates of BG vulnerability are represented by ischemic lesions, such as striatocapsular infarcts and lacunar infarcts, and local toxic-induced damage, mainly associated with energy production impairment, due to carbon monoxide, cyanide and manganese.

Differential protein expression of hippocampal cells associated with heavy metals (Pb, As, and MeHg) neurotoxicity: Deepening into the molecular mechanism of neurodegenerative diseases.

Chronic exposure to heavy metals such as Pb, As, and MeHg can be associated with an increased risk of developing neurodegenerative diseases. Our in vitro bioassays results showed the potency of heavy metals in the order of Pb < As < MeHg on hippocampal cells. The main objective of this study was combining in vitro label free proteomics and systems biology approach for elucidating patterns of biological response, discovering underlying mechanisms of Pb, As, and MeHg toxicity in hippocampal cells. The omics data was refined by using different filters and normalization and multilevel analysis tools were employed to explore the data visualization. The functional and pathway visualization was performed by using Gene ontology and PathVisio tools. Using these all integrated approaches, we identified significant proteins across treatments within the mitochondrial dysfunction, oxidative stress, ubiquitin proteome dysfunction, and mRNA splicing related to neurodegenerative diseases. The systems biology analysis revealed significant alterations in proteins implicated in Parkinson's disease (PD) and Alzheimer's disease (AD). The current proteomics analysis of three metals support the insight into the proteins involved in neurodegeneration and the altered proteins can be useful for metal-specific biomarkers of exposure and its adverse effects. SIGNIFICANCE: The proteomics techniques have been claimed to be more sensitive than the conventional toxicological assays, facilitating the measurement of responses to heavy metals (Pb, As, and MeHg) exposure before obvious harm has occurred demonstrating their predictive value. Also, proteomics allows for the comparison of responses between Pb, As, and MeHg metals, permitting the evaluation of potency differences hippocampal cells of the brain. Hereby, the molecular information provided by pathway and gene functional analysis can be used to develop a more thorough understanding of each metal mechanism at the protein level for different neurological adverse outcomes (e.g. Parkinson's disease, Alzheimer's diseases). Efforts are put into developing proteomics based toxicity testing methods using in vitro models for improving human risk assessment. Some of the key proteins identified can also potentially be used as biomarkers in epidemiologic studies. These heavy metal response patterns shed new light on the mechanisms of mRNA splicing, ubiquitin pathway role in neurodegeneration, and can be useful for the development of molecular biomarkers of heavy metals exposure.

Phenotypic and Functional Evaluation of Hematopoietic Stem and Progenitor Cells in Toxicology of Heavy Metals.

All blood cells are differentiated from hematopoietic stem and progenitor cells (HSPCs), a process known as hematopoiesis that can be influenced by a variety of environmental factors. In this unit, we introduce a couple of protocols including phenotypic analysis, mixed bone marrow (BM) chimera and rescue assays, colony-forming unit (CFU), and in vitro OP9 stromal cell differentiation assays for evaluating HSPCs in the BM of mice, and provide some examples of their implications in mouse models treated with heavy metals. The protocols for evaluating hematopoietic stem cells (HSCs) comprise phenotypic analysis and functional transplantation assays. The protocols for assessing hematopoietic progenitor cells (HPCs) consist of phenotypic analysis and in vitro differentiation assays. The main techniques applied in these protocols include flow cytometry (phenotypic analysis and sorting), irradiation, transplantation, and cell culture. © 2018 by John Wiley & Sons, Inc.

Adverse effect of heavy metals (As, Pb, Hg, and Cr) on health and their bioremediation strategies: a review.

Currently, heavy metal pollution becomes a severe problem whole over the world, and these toxic metals enter into the environment either by natural phenomena or due to extensive industrialization. The discharged effluents containing toxic heavy metals mixed with soil/water and change their natural composition. These heavy metals have adverse effects on living beings and cause damage to the vital body organs of animals as well as humans. The heavy metal pollution also inhibits the biodegradation of the chlorinated organic compounds (another type of environmental pollution) by interacting with metabolizing enzymes and inhibits their functioning. Earlier studies described that heavy metals cannot be fully removed from the environment, but they can be effectively neutralized or transformed into less toxic form so that their harmful effect on the environment can be reduced. The distinctive enzymatic apparatus within microbial system plays a major role in the transformation of heavy metals in the environment. A considerable advancement has been made during recent years to transform the heavy metals by utilizing the bioremediation potential of genetically engineered (GE) microorganisms. These transgenics are very much efficient in heavy metal transformations and still, we have to discover more to additionally utilize their full biotransformation potential.In the present review article, the detailed description of the adverse effects of four heavy metals (arsenic, lead, mercury, and chromium) and their adverse effect on our environment and human beings is discussed. Furthermore, the use of microorganisms/GE organisms for the bioremediation of heavy metals from the environment is also discussed along with their detailed bioremediation mechanism.

Zinc-Excess Intake Causes the Deterioration of Renal Function Accompanied by an Elevation in Systemic Blood Pressure Primarily Through Superoxide Radical-Induced Oxidative Stress.

Using rats fed 22 g/d of a control diet containing 0.005% zinc (Zn) or 2 Zn-excess diets containing 0.05% or 0.2% Zn for 4 weeks, we examined the mechanisms involved in the deterioration of renal function induced by Zn-excess intake. An increase in Zn intake elevated mean blood pressure (BP) and reduced renal blood flow (RBF) and inulin clearance in a dose-dependent manner. This decline in inulin clearance may be derived from a fall in RBF. Administration of the nitric oxide (NO) synthase inhibitor, Nω-nitro-l-arginine methyl ester, markedly increased mean BP and significantly decreased RBF in the 3 groups of rats. Administration of the exogenous superoxide radical (OO-) scavenger, tempol, significantly decreased mean BP and substantially increased RBF in all groups of rats. These observations suggest that both an elevation in systemic BP and a reduction in RBF seen in the 2 Zn-excess diet groups result from a decrease in the action of the vasodilator, NO, through the formation of peroxynitrite based on the nonenzymatic reaction of NO and increased OO- Indeed, the activity of the endogenous OO- scavenger, copper/Zn-superoxide dismutase, was significantly reduced in the vessel wall of rats fed 2 Zn-excess diets versus a control diet. 8-Hydroxy-2'-deoxyguanosine formation caused by OO- generation was notably elevated in the kidneys of rats fed 2 Zn-excess diets relatively to rats fed a control diet. Thus, Zn-excess intake leads to the aggravation of renal function concomitantly with an increase in systemic BP predominantly through the oxidative stress caused by OO^.