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PubMed2005

Beryllium-stimulated reactive oxygen species and macrophage apoptosis.

Beryllium (Be), the etiologic agent of chronic beryllium disease, is a toxic metal that induces apoptosis in human alveolar macrophages. We tested the hypothesis that Be stimulates the formation of reactive oxygen species (ROS) which plays a role in Be-induced macrophage apoptosis. Mouse macrophages were exposed to 100 microM BeSO4 in the absence and presence of the catalytic antioxidant MnTBAP (100 microM). Apoptosis was measured as the percentage of TUNEL+ and caspase-8+ cells. ROS production was measured by flow cytometry using the fluorescence probes, dihydroethidine (DHE) and dichlorofluorescein diacetate (DCFH-DA). Be-exposed macrophages had increased TUNEL+ cells (15+/-1% versus controls 1+/-0.2%, P<0.05) and increased caspase-8+ cells (18.7+/-2% versus controls 1.8+/-0.4%, P<0.05). Be-induced caspase-8 activation, and a 4-fold increase in ROS formation, was ameliorated by exposure to MnTBAP. Hydrogen peroxide (30 microM) exposure potentiated Be-induced caspase-8 activation, and was also attenuated by MnTBAP. Our data are the first to demonstrate that Be stimulates macrophage ROS formation which plays an important role in Be-induced macrophage apoptosis.

Animals↗
PubMed2004

Beryllium-specific immune response in primary cells from healthy individuals.

The effect of beryllium (Be) exposure has been extensively studied in patients with chronic beryllium disease (CBD). CBD patients carry mutated MHC class II alleles and show a hyperproliferation of T cells upon Be exposure. The exact mechanism of Be-induced T-cell proliferation in these patients is not clearly understood. It is also not known how the inflammatory and suppressive cytokines maintain a balance in healthy individuals and how this balance is lost in CBD patients. To address these issues, we have initiated cellular and biochemical studies to identify Be-responsive cytokines and other cellular markers that help maintain a balance in healthy individuals. We have established an immune cell model derived from a mixture of peripheral blood mononuclear cells (PBMCs) and dendritic cells (DCs). In this article, we demonstrate that pro-inflammatory cytokine IL6 shows decreased release whereas suppressive cytokine IL10 shows enhanced release after 5-10 h of Be treatment. Furthermore, the Be-specific pattern of IL6 and IL10 release is dependent upon induction of threonine phosphorylation of a 45 kDa cytosolic protein (p45), as early as 90 min after Be treatment. Pharmacological inhibition of phosphatidylinositol 3' kinase (PI3'K) by wortmannin and p38 mitogen-activated protein kinase (MAPK) by SB203580 reveal that PI3'K mediates Be-specific p45 phosphorylation and IL6 release, whereas p38 MAPK regulates the release of IL6 and IL10 and the phosphorylation of p45 independent of metal-salt treatment. While the IL10 and IL6 release pathways are uncoupled in these cells, they are linked to phosphorylation of p45. These findings suggest that the balance between IL10 and IL6 release and the correlated p45 phosphorylation are important components of the Be-mediated immune response in healthy individuals.

Beryllium↗
PubMed2005

Chemokine regulation in response to beryllium exposure in human peripheral blood mononuclear and dendritic cells.

Exposure to beryllium (Be) induces a delayed-type hypersensitivity immune reaction in the lungs of susceptible individuals, which leads to the onset of Be sensitivity and Chronic Beryllium Disease (CBD). Although some mechanistic aspects of CBD have begun to be characterized, very little is known about the molecular mechanisms by which Be activates the host immune response. To gain insight into the cellular response to Be exposure, we have performed global microarray analysis using a mixture of peripheral blood mononuclear and dendritic cells (PBMC/DCs) from a non-CBD source to identify genes that are specifically upregulated in response to BeSO(4) stimulation, compared to a control metal salt, Al(2)(SO(4))(3). We identified a number of upregulated immunomodulatory genes, including several chemokines in the MIP-1 and GRO families. Using PBMC/DCs from three different donors, we demonstrate that BeSO(4) stimulation generally exhibits an increased rate of both chemokine mRNA transcription and release compared to Al(2)(SO(4))(3) exposure, although variations among the individual donors do exist. We show that MIP-1 alpha and MIP-1 beta neutralizing antibodies can partially inhibit the ability of BeSO(4) to stimulate cell migration of PBMC/DCs in vitro. Finally, incubation of PBMC/DCs with BeSO(4) altered the binding of the transcription factor RUNX to the MIP-1 alpha promoter consensus sequence, indicating that Be can regulate chemokine gene activation. Taken together, these results suggest a model in which Be stimulation of PBMC/DCs can modulate the expression and release of different chemokines, leading to the migration of lymphocytes to the lung and the formation of a localized environment for development of Be disease in susceptible individuals.

Beryllium↗
PubMed1999

Beryllium-stimulated in vitro migration of peripheral blood lymphocytes.

Inhalation of beryllium (Be) induces both inflammatory and metal antigen-specific immune responses in the lungs characterized by mononuclear cell infiltration and granuloma formation (chronic beryllium disease, CBD). We tested the hypothesis that Be-salts might increase the in vitro migration of peripheral blood mononuclear cells (PBMC). PBMC are mixed cells, consisting of lymphocytes and monocytes. We compared their responses to populations of both purified blood lymphocytes, and purified blood monocytes. Purified blood monocytes and lymphocytes, isolated by Percoll gradients and centrifugal elutriation from normal human subjects (n = 6), were exposed to graded concentrations (0.01 to 100 microM) of BeSO4 or to the control metal-salt Al2(SO4)3. Migratory responses of stimulated PBMC were measured in Boyden Chambers. As controls, PBMC mixed cells or purified lymphocytes or purified monocytes were unstimulated or stimulated with a positive chemoattractant, Zymosan-A treated pooled, normal human serum (ZAS). The migration index (MI) was defined as the distance (micrometers) that cells migrated through a 5 micron filter. The MI for unstimulated PBMC mixed cells was 75+/-4 whereas the MI for ZAS-stimulated PBMC mixed cells was 124+/-4 (P < or = 0.05, Tukey-Kramer). The MI for BeSO4 -stimulated (100 microM) PBMC mixed cells was 136+/-4. The observed increase in the BeSO4-stimulated PBMC mixed cell migration was significant down to 0.1 microM BeSO4. BeSO4, BeCl2 and BeF2, tested at 100 and 10 microM, were equally effective at inducing PBMC mixed cell migration. Equimolar concentrations of Al2(SO4)3 were not as effective at inducing PBMC mixed cell migration, MI < 100 at 100 microM, and did not induce PBMC mixed cell migration at concentrations below 1 microM. The migration of purified monocytes through filters was not increased in response to either BeSO4 or Al2(SO4)3 compared to controls, but did respond to ZAS (MI = 100+/-4). Purified lymphocytes migrated in response to stimulation with all concentrations of BeSO4 tested (100 microM MI = 133+/-9), and Al2(SO4)3 (100 microM MI = 85+/-8). There were no significant differences in the MI for PBMC mixed cells or for purified lymphocytes at the concentrations of BeSO4 tested. Our data show that Be directly induces the in vitro migration of PBMC mixed cells and purified blood lymphocytes, and not purified blood monocytes, across a broad range of Be concentrations. This induction of migration was independent of the molecular form of the Be-salt. Inhaled Be, by promoting lymphocyte emigration to the lung, may create a microenvironment that favors a Be-antigen-specific T-lymphocyte response, chronic inflammation, and CBD.

Adult↗
PubMed2000

The pathogenesis of beryllium-induced pulmonary granulomatosis. A scanning secondary ion analytical microscopy study.

Chronic granulomatous pneumonitis was induced in rats with beryllium to study the pathogenesis of that disease, by identifying and localizing the beryllium in histological sections of the pulmonary tissues. This was done with scanning secondary ion mass spectrometry (SIMS). Thus, our observations suggest that the route of the Be from the site of injection into the lung, passes first by the blood, through the vascular wall and into the surrounding pulmonary tissues where Be was phagocytized by macrophages. There resulted in acute vasculitis throughout the lung. It was noted that the granuloma were focal inflammatory sites, solely observed within the vascular wall, distributed along the course of the affected vessel. These findings raise the question as to whether pulmonary granulomatous lesions of other origins are also localized within the vascular wall.

Animals↗
PubMed1997

Correlations between 9Be magic-angle spinning nuclear magnetic resonance spectra and the geometry of beryllium containing framework structures.

A range of sodalite framework structures containing beryllium with general formula M8[BeZO4]6X2; M = Cd, Zn, Z = Si, Ge and X = S, Se or Te have been synthesised. The structures of these materials, which contain a single beryllium environment, have been refined from powder neutron diffraction or powder X-ray diffraction data and the compounds further characterised using 9Be magic-angle spinning nuclear magnetic resonance (MASNMR). Spectra show a single sharp resonance for 9Be(OSi)4 in the chemical shift range +/- 1 ppm from 0.1 M BeCl2. Correlations between the Be-O-Z bond angles and the 9Be chemical shift are reported and show upfield shifts for larger angles as seen previously in MASNMR spectra for 29Si and 27Al.

Beryllium↗
PubMed2002

Chronic beryllium disease: a model interaction between innate and acquired immunity.

Beryllium (Be) is a lightweight and durable metal useful to a variety of manufacturing processes. With the use of Be in industrial settings, a number of health effects were noted including acute pneumonitis, sensitization to Be, interstitial lung disease and dermatological disease. Interstitial mononuclear cell inflammation and granuloma formation are the primary processes that occur in the lungs of Be-exposed workers, resulting in chronic beryllium disease (CBD). Recent studies have begun to describe the role of Be in the pathogenesis of CBD. These studies reveal that the host's response to Be involves components of the innate immune system or inflammatory responses. Inflammatory responses to Be can establish a state of acquired, Be antigen-specific, cell-mediated immunity. Despite triggering both the innate and acquired immune responses, Be is not eliminated from the host. Rather, it establishes pathways leading to chronic granulomatous inflammation. We will examine recent studies describing the host's cellular and molecular responses to Be, responses that promote granuloma formation.

Acute Disease↗
PubMed2004

The structure of bovine F1-ATPase inhibited by ADP and beryllium fluoride.

The structure of bovine F1-ATPase inhibited with ADP and beryllium fluoride at 2.0 angstroms resolution contains two ADP.BeF3- complexes mimicking ATP, bound in the catalytic sites of the beta(TP) and beta(DP) subunits. Except for a 1 angstrom shift in the guanidinium of alphaArg373, the conformations of catalytic side chains are very similar in both sites. However, the ordered water molecule that carries out nucleophilic attack on the gamma-phosphate of ATP during hydrolysis is 2.6 angstroms from the beryllium in the beta(DP) subunit and 3.8 angstroms away in the beta(TP) subunit, strongly indicating that the beta(DP) subunit is the catalytically active conformation. In the structure of F1-ATPase with five bound ADP molecules (three in alpha-subunits, one each in the beta(TP) and beta(DP) subunits), which has also been determined, the conformation of alphaArg373 suggests that it senses the presence (or absence) of the gamma-phosphate of ATP. Two catalytic schemes are discussed concerning the various structures of bovine F1-ATPase.

Adenosine Diphosphate↗
PubMed1991

Flame atomic absorption spectrometric method for the determination of beryllium in natural waters after separation with N-benzoyl-N-phenylhydroxylamine.

A procedure for the determination of beryllium in natural waters is proposed. A solvent extraction step was performed in order to overcome interferences and isolate beryllium before it was atomized by direct nebulization of the organic phase in a dinitrogen oxide-acetylene flame. N-Benzoyl-N-phenylhydroxylamine was used as the extractant whilst isobutyl methyl ketone was the organic solvent. The effects of pH, amine concentration in the organic phase, shaking time, stability of the complex and nature of the extracted species were studied. The detection limit and linear response range are 2 ng ml-1 and 0-1.0 microgram ml-1, respectively. The result obtained for a standard reference material compared well with the quoted value.

Beryllium↗
PubMed2006

Comparison of collection efficiencies of sampling methods for removable beryllium surface contamination.

The primary goal of this study is to compare wet versus dry sampling methods for three different media, (Whatman 41 filter papers, GhostWipes, and SKC Smear Tabs), These media were selected because they are the most commonly used means for the collection of beryllium from contaminated surfaces within the DOE Complex. A range of known concentrations of beryllium was introduced onto a smooth nonporous surface. All three types of media were tested for collection efficiency in both the wet and dry mode and analyzed by inductively-coupled plasma atomic emission spectrometry (ICP-AES).

Beryllium↗
PubMedDate not supplied

Lung clearance of 4-micron particles coated with silver, carbon, or beryllium.

Lung clearance in rabbits during the first week after inhalation of 4-micron teflon particles tagged with chromium-51 and coated with silver, carbon, or beryllium was studied by external measurements of the radioactivity in the lungs. Ten rabbits were exposed to silver- and carbon-coated particles on two separate occasions within 3 weeks. Clearances of the two types of particles were quite similar. Clearance in eight other rabbits that had inhaled silver-coated particles was quite similar to clearance in eight rabbits that had inhaled beryllium-coated particles. The result is regarded as evidence that alveolar macrophages do not play an active role in removing intact particles from the lung the first week after inhalation.

Animals↗
PubMed1984

Overview of analysis of carcinogenic and/or mutagenic metals in biological and environmental samples. I. Arsenic, beryllium, cadmium, chromium and selenium.

One of the most dangerous and pernicious forms of pollution arises from the potential mobilization of a spectrum of toxic trace metals and metalloids in our environment. Among the most important elements in this regard are arsenic, beryllium, cadmium, chromium and selenium whose adverse toxic effects are now well recognized including their carcinogenicity and/or mutagenicity. These agents (and their derivatives) can be widely dispersed throughout the environment as a result of fossil fuel combustion, industrial and agricultural processes and natural processes. The trend for the immediate future appears to be of greater exposure to these metals not only as a result of generally increased usage patterns but also because of prospective enhanced use of fossil fuels for space heating and electricity generation. In order to more readily evaluate trends of human exposure as well as the toxicity, bioavailability, bioaccumulation and transport of these elements, sensitive analytical procedures are required for the determination of their various oxidation states (as well as their organic derivatives) in complex matrices such as those found in both environmental and biological samples. Hence, the principal objective of this overview is to highlight the more recent trends and state-of-the-art methodologies for the determination of arsenic, beryllium, cadmium, chromium and selenium (in their various forms) in environmental compartments such as air, water, soil and in human tissues (primarily blood, urine, and milk). Techniques to be discussed primarily include atomic absorption spectrometry, neutron activation analysis, gas chromatography, differential pulse polarography and electrochemical analysis. The importance of quality control and differentiation according to speciation will also be stressed.

Air↗
PubMed2001

Variability, predictive value, and uses of the beryllium blood lymphocyte proliferation test (BLPT): preliminary analysis of the ongoing workforce survey.

The beryllium blood lymphocyte proliferation test (BLPT) is used as a medical surveillance tool for assessment of persons at risk for developing clinical and subclinical chronic beryllium disease (CBD). Three laboratories, coded "A," "B," and "C," were used to perform the BLPTs, which involved two simultaneous tests on a split specimen. The intra-laboratory agreement analysis compared the first and the second test performed by the same laboratory. The interlaboratory agreement analysis compared test results performed by different laboratories on the same sample. The level of agreement was expressed as a kappa statistic. The positive predictive value (PPV) analysis compared BLPT results against the results of a bronchoscopy used to detect CBD. The data included 5483 records representing 3081 samples from 1510 persons. Intra-laboratory agreement was fair to moderate, with kappa values between 0.3 and 0.6. Inter-laboratory agreement was moderate (kappa = 0.5) for Labs A and B, moderate (kappa = 0.6) for Labs B and C, and poor (kappa = 0.2) for Labs A and C. A single unconfirmed abnormal test had a PPV for CBD of 39 percent, a confirmed (based on subsequent testing) abnormal test had a PPV for CBD of 45 percent, and a first-time double abnormal test had a PPV for CBD of 49 percent. Substantial inter- and intralaboratory disagreement exists between and within major laboratories that conduct this test.

Berylliosis↗
PubMed2005

Physical and chemical characterization of beryllium particles from several workplaces in Québec, Canada--part B: time-of-flight secondary-ion mass spectroscopy.

The problems associated with detecting and characterizing beryllium (Be) particles in industrial samples from Québec were addressed in the companion article (Rouleau et al., 2005). The present study is a continuation of the work aimed at redefining the current occupational exposure level for beryllium. The goals were to determine the principal chemical forms and the principal physical characteristics of Be particles sampled in four Québec industries. Bulk particle chemistry was determined using inductively coupled plasma-mass spectroscopy (ICP-MS) and flame atomic absorption spectrophotometry (FAAS). Time-of-flight secondary-ion mass spectroscopy (TOF-SIMS) was used to characterize particle surface chemistry and physical particle size. The dust samples collected had Be concentrations varying from 58 to 146 microg/g. Results showed that numerous fine Be particles or aggregates were evenly dispersed throughout the samples. Thus, Be does not appear to be concentrated in large particles. However, it was not possible to confirm if these fine particles were combined to specific compounds, chemically or physically, or independent Be particles. Most of the particles containing Be were fine, with diameters less than 10 microm, which is important from an occupational health and safety standpoint. TOF-SIMS should be considered as an appropriate technique for qualitative characterization of Be particles, and a valuable complement to the recognized quantitative methods ICP-MS and FAAS.

Beryllium↗
PubMed1991

C-myc expression is maintained during the G1 phase cell cycle block produced by beryllium.

Salts of the toxic metal beryllium have been shown previously to prevent the synthesis of several enzymes essential for DNA replication in proliferating rat hepatic cells in vivo, and to inhibit the division of rat liver-derived BL9L epithelial cells in vitro, specifically during the G1 phase of the cell cycle. The present study shows, however, that exposure of serum-stimulated sub-confluent monolayer cultures of synchronized BL9L cells to inhibitory concentrations of the beryllium salt BeSO4 (50 microM) did not impair expression of the cell proliferation associated nuclear proto-oncogene c-myc. On the contrary, the increased c-myc mRNA levels normally observed during the G1 phase were maintained by continuous exposure of the cells to BeSO4. This response was specific in that other colloid forming metal salts (ZnSO4 and ZrSO4), which did not inhibit cell division, had no affect on c-myc expression, and mRNA levels for the constantly expressed H-2Kb major histocompatibility complex gene (3'Kb) were unaltered by BeSO4 treatment of the cells. The prevention by Be2+ of the down-regulation of c-myc expression in serum-stimulated BL9L cells appears to result from a modulation of the endogenous transcriptional control process for c-myc, which allows a maintained expression of the gene.

Animals↗
PubMed1984

Beryllium coating for biological X-ray microanalysis.

Beryllium is ideal for coating biological specimens for light element X-ray microanalysis at low temperature. It has higher electrical and thermal conductivity at 100 K and lower absorption of X-rays of biological interest than carbon, aluminium or chromium. It produces no detectable characteristic X-rays. When adequate precautions are taken beryllium is a valuable alternative to other coating materials. Because of its toxicity, however, it should not be used indiscriminately.

Beryllium↗
PubMed1989

Progressive lung injury over a one-year period after a single inhalation exposure to beryllium sulfate.

The chronic pulmonary toxicity of beryllium sulfate was examined in rats over a 1-yr period after a single, 1-h exposure. Male rats, exposed in a nose-only inhalation chamber to an aerosol of 4.05 micrograms Be/L, were evaluated for lung toxicity by the methods of bronchoalveolar lavage, lung cell kinetics, and histopathologic analysis. Bronchoalveolar lavage activities for alkaline phosphatase (Alk Pase) and acid phosphatase (Ac Pase) were elevated 3 wk after exposure; lactate dehydrogenase (LDH) and Alk Pase activities peaked 3 months after exposure. Histopathologic analysis revealed progressive focal interstitial pneumonitis with a prominent alveolar component of heteromorphic macrophages, neutrophils, and debris. No increase was noted in the overall labeling index in the alveolar cell population at any of the time points sampled. This study demonstrates the effectiveness of bronchoalveolar lavage fluid analysis in monitoring lung damage over a prolonged period and shows that the pulmonary toxicity of beryllium manifests itself as a progressive lesion from a single 1-h inhalation exposure to BeSO4.

Acid Phosphatase↗