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Immunomodulation by Environmental Chemicals: Insights into Mammalian Immune Responses to Arsenic, Cadmium, and Lead
Abstract
Exposure to different environmental chemicals like arsenic (As), cadmium (Cd), and lead
(Pb) from natural and anthropogenic activity represents a threat to global human health.
Human populations are exposed to these chemicals either through drinking water or
through occupational exposure in various industries. Different organ systems are affected
to varying degrees following exposure in a dose- and time-dependent manner. In this
chapter, we will discuss specific human immune responses as well as immune responses of different mammalian model systems in exposure to three environmental chemicals, As,
Cd, and Pb. Although there are conflicting reports about the immunotoxic potential of
metals and metalloids, but in general, immunomodulatory action exerted by environmental
chemicals is directly dependent on the exposure dose, route, and time. Higher
concentrations exert immunosuppressive action. However, at lower concentration,
immunostimulatory effects can be observed. The focus of this chapter will be on
in vivo and in vitroimmuneresponses to these environmental chemicals, but the potential
mechanisms of biological effects exerted by these chemicals will also be discussed.
... Certain heavy metals, well-documented for their impact on the immune system, are associated with immune-mediated illnesses as environmental contaminants. Among these, cadmium (Cd) stands out as one of the most hazardous [36][37][38]. Analyzing small quantities of heavy metals in a sample pattern can be accomplished for regulatory approval and quality management purposes. We identify the heavy metalloids in actual samples, and we can additionally decide to examine the contaminants in smokers. ...
This study was standardized to investigate the effects of trace metals in smokers' blood samples and find metals' correlation with virulent diseases. An auxiliary finding was used to detect the inflated amount of metal absorption, which was determined by Inductively Coupled Plasma Optical Emission Spectroscopy (ICP-OES). The large metal level does not generate immunity in the smoker's body. Human samples display fickle computation of concentrations of these metals. The Mean±SD of As, B, Pb Sr, and Zn in smoker's samples were (6.1±2.9 ppb), (285.9±118.1 ppb), (60.7±28.5 ppb), (28.6±9.8 ppb), and (420.5±100.4 ppb) reciprocally. The As, B, Pb, Sr, and Zn concentrations in all the smokers' blood samples were over the acceptable limit, withal the P-value= (≥0.05) all the samples have displayed no correlation in smokers against viral inflammation. This examination can be used as a support and quotation for further investigations. These findings declare that the number of metals in the body for long periods contributes to toxicity and promotes viral infections.
... Immune-mediated lung diseases linked to occupational exposure observed in early (immuno) toxicological studies, as well as experimental rodent studies, first revealed an immunomodulatory potential of environmental chemicals, also known as xenobiotics [3]. Among representative environmental pollutants associated with immune-mediated disorders are certain heavy metals that have been reported to affect the immune system, with cadmium (Cd) being one of the most toxic [4,5]. ...
Cadmium (Cd) represents a unique hazard because of the long biological half-life in humans (20-30 years). This metal accumulates in organs causing a continuum of responses, with organ disease/failure as extreme outcome. Some of the cellular and molecular alterations in target tissues can be related to immune-modulating potential of Cd. This metal may cause adverse responses in which components of the immune system function as both mediators and effectors of Cd tissue toxicity, which, in combination with Cd-induced alterations in homeostatic reparative activities may contribute to tissue dysfunction. In this work, current knowledge concerning inflammatory/autoimmune disease manifestations found to be related with cadmium exposure are summarized. Along with epidemiological evidence, animal and in vitro data are presented, with focus on cellular and molecular immune mechanisms potentially relevant for the disease susceptibility, disease promotion, or facilitating development of pre-existing pathologies.
... Generally, Cd exerted various degrees of suppression of components involved in reactions of adaptive immunity both in vitro and in animal immune systems (Gera et al., 2015;Koller, 1998). One of the ways in which Cd might cause immunosuppression was by affecting lymphocyte cell viability. ...
Cadmium (Cd) has been listed as one of the most toxic substances affecting numerous tissues/organs, including the immune system. Due to variations in studies examining Cd effects on the immune system (exposure regime, experimental systems, immune endpoint measured), data on Cd immunotoxicity in humans and experimental animals are inconsistent. However, it is clear that Cd can affect cells of the immune system and can modulate some immune responses. Due to the complex nature of the immune system and its activities which are determined by multiple interactions, the underlying mechanisms involved in the immunotoxicity of this metal are still vague. Here, the current knowledge regarding the interaction of Cd with cells of the immune system, which may affect immune responses as well as potential mechanisms of consequent biological effects of such activities, is reviewed. Tissue injury caused by Cd-induced effects on innate cell activities depicts components of the immune system as mediators/effectors of Cd tissue toxicity. Cd-induced immune alterations, which may compromise host defense against pathogenic microorganisms and homeostatic reparative activities, stress this metal as an important health hazard.
... To our knowledge, there are no data regarding the effect of oral cadmium exposure on lung infection caused by other pathogens, including those which cause opportunistic infections. The effect of cadmium on infections caused by opportunistic microorganisms is particularly important given the fact that cadmium has an immunomodulatory potential (Gera et al., 2015) and that these microorganisms become pathogenic when the immune system is impaired/dysfunctional (Jose and Brown, 2016). ...
Cadmium (Cd) is one of the most toxic environmental heavy metals to which the general population is exposed mainly via the oral route. Owing to its immunomodulatory potential, orally acquired Cd affects antimicrobial immune defense in several organs, including the lungs. While there are data concerning Cd and viral and bacterial pulmonary infections, effects on fungal infections are not studied yet. In the present study, the effect of the Cd (5 mg/L for 30 days, in drinking water, the average daily Cd intake 0.641 ± 0.089 mg/kg) on the immune response of rats to pulmonary A. fumigatus infection was examined. Data obtained showed that orally acquired cadmium does not affect the elimination of the fungus in immunocompetent rats owing to the preservation of some aspects of innate immune responses (lung leukocyte infiltration and NBT reduction) and an increase in other (increased numbers of mucus-producing goblet cells, MPO release). Cd does not affect an IFN-γ response in lung leukocytes during the infection (despite suppression of cytokine production in cells of lung-draining lymph nodes), while it stimulates IL-17 and suppresses IL-10 response to the fungus. As a result, the elimination of the fungus occurs in a milieu with the prevailing proinflammatory response in Cd-exposed animals that preserved fungal elimination from the lungs, though with more intense injury to the lung tissue. Therefore, the proinflammatory microenvironment in the lungs created by Cd that sustains inflammatory/immune response to the fungus to which humans are exposed for a lifetime, raises a concern of orally acquired Cd as a risk factor for the development of chronic low-grade pulmonary inflammation.
Cadmium and Pb are known to enhance immune cell damages and to decrease cellular immunity, promoting higher susceptibility to infectious diseases. Selenium is an essential element involved in immunity and reactive oxygen species scavenging. This study aimed at evaluating how Cd and Pb and low nutritional (Se) quality modulate immune response to a bacterial lipopolysaccharide (LPS) challenge in wood mice (Apodemus sylvaticus). Mice were trapped near a former smelter in northern France in sites of High or Low contamination. Individuals were challenged immediately after capture or after 5 days of captivity, fed standard or Se-deficient diet. Immune response was measured with leukocytes counting and plasma concentration of TNF-α, a pro-inflammatory cytokine. Faecal and plasma corticosterone (CORT), a stress-hormone involved in anti-inflammatory processes, was measured to assess potential endocrine mechanisms. Higher hepatic Se and lower faecal CORT were measured in free-ranging wood mice from High site. LPS-challenged individuals from High site showed higher decrease of circulating leukocytes of all types, higher TNF-α concentrations, and a significant increase of CORT, compared to individuals from Low site. Challenged captive animals fed standard food exhibited similar patterns (high decrease of leukocytes, significant increase of CORT, and detectable levels of TNF-α), with individuals from lowly contaminated site having higher responses than their counterparts from highly polluted site. Animals fed Se-deficient food exhibited lymphocytes decrease, non-significant variation of CORT, and average levels of TNF-α. These results suggest (i) a higher inflammatory response to challenge in free-ranging animals highly exposed to Cd and Pb, (ii) a faster recovery of inflammatory response in animals lowly exposed to pollution when fed non-contaminated standard food than more exposed individuals, and (iii) a functional role of Se in the inflammatory response. The precise role of Se and mechanisms underlying the relationship between glucocorticoid and cytokine remain to be elucidated.
Cadmium (Cd) is a toxic heavy metal that when absorbed into the body causes nephrotoxicity and effects in other tissues.Anatomical barrier tissues are tissues that prevent the entry of pathogens and include skin, mucus membranes and the immune system. The adverse effects of Cd-induced immune cell’s activity are the most extensively studied in the kidneys and the liver. There are though fewer data relating the effect of this metal on the other tissues, particularly in those in which cells of the immune system form local circuits of tissue defense, maintaining immune-mediated homeostasis. In this work, data on the direct and indirect effects of Cd on anatomical barrier tissue of inner and outer body surfaces (the lungs, gut, reproductive organs, and skin) were summarized.
Arsenic (As) is a common metalloid which contaminates drinking water in several regions of the world and chronic exposure is associated with skin, lung, bladder, and kidney cancer. Previous studies suggest that arsenic exposure leads to a diminution of phytohemaglutinin (PHA) stimulated T cell proliferation in humans. In order to understand the mechanism of this suppression, the effect of As was evaluated on the expression of CD25, and IL-2 secretion in human peripheral blood mononuclear cells (PBMC). Inhibition of proliferation was observed in all donors studied. Most of the donors did not show any change in the expression of CD25, but IL-2 secretion was inhibited in 6 of the 7 donors tested. Proliferative inhibition was due to a suboptimal levels of IL-2 secreted by lymphocytes, since the addition of recombinant IL-2 to the cultures reversed in a dose-dependent fashion the inhibitory effect of As. The determination of the mRN A of IL-2 and the intracellular IL-2 levels demonstrated that the inhibition is not at the transcriptional level. Electron microscopy studies revealed that cellular ultrastructure in Golgi apparatus, mitochondria, cytoskeleton, and perinuclear membrane were altered. These alterations suggest that due to sodium arsenite effects on cytoskeleton, the intracellular secretion of proteins is affected, including the one of IL-2, leading to an impaired proliferation of the T cells when stimulated with PHA.
Prevalence and concentration of some toxic (Pb, Cd, and As) and essential metals (Zn, Cu, Cr, Ni, and Co) were determined in the blood samples collected from asthmatic patients in Karachi, Pakistan using atomic absorption spectrophotometer. All selected patients were habitual of taking crude drugs and home remedy as self medication to treat and prevent asthma. We detected large proportion of the patients with detectable levels of heavy metals. The percentage prevalence of Pb, Cr, Ni, and Co, were found 100% while that of As and Cd were 55% and 60% respectively. Atomic absorption spectroscopic data showed the presence of metals in the analyzed samples in the range of 0.00-37.08 μg/dl for As, 8.1-41.4μg/dl for Pb, 0.0-9.6μg/l for Cd, 2.0-55.6μg/l for Cr, 20.0-85.9μg/l for Ni, and 0.15-3.6 μg/l for Co. The study will be helpful in creating awareness regarding the use of quality herbal medicines in asthma. It is suggested that along with avoidance of other risk factors, reliance on the use of quality traditional medicines free from heavy metal contamination is very essential especially incase of bronco asthmatic conditions.
Human exposure to arsenic in drinking water is known to contribute to many different health outcomes such as cancer, diabetes, and cardiopulmonary disease. Several epidemiological studies suggest that T cell function is also altered by drinking water arsenic exposure. However, it is unclear how individual responses differ to various levels of exposure to arsenic. Our laboratory has recently identified differential responses of human peripheral blood mononuclear cell (HPMBC) T cells as measured by polyclonal T cell activation by mitogens during sodium arsenite exposure. T cells from certain healthy individuals exposed to various concentrations (1-100 nM) of arsenite in vitro showed a dose-dependent suppression at these extremely low concentrations (∼0.1-10 ppb) of arsenite, whereas other individuals were not suppressed at low concentrations. In a series of more than 30 normal donors, two individuals were found to be sensitive to low concentration (10 nM equivalent ∼1 ppb drinking water exposure) to sodium arsenite-induced inhibition of T cell proliferation produced by phytohemagglutinin (PHA) and anti-CD3/anti-CD28. In an arsenite-susceptible individual, arsenite suppressed the activation of Th1 (Tbet) cells, and decreased the percentage of cells in the double positive Th17 (RORγt) and Treg (FoxP3) population. While the majority of normal blood donors tested were not susceptible to inhibition of proliferation at the 1-100 nM concentrations of As+3, it was found that all donors were sensitive to suppression by 100 nM monomethylarsonous acid (MMA+3), a key metabolite of arsenite. Thus, our studies demonstrate for the first time that low ppb-equivalent concentrations of As+3 are immunosuppressive to HPBMC T cells in some individuals, but that most donor HPBMC are sensitive to suppression by MMA+3 at environmentally relevant exposure levels.
It is known that exposure to As+3 via drinking water causes a disruption of the immune system and significantly compromises the immune response to infection. The purpose of these studies was to assess the effects of As+3 on bone marrow progenitor cell colony formation and the humoral immune response to a T-dependent antigen response (TDAR) in vivo. In a 30 day drinking water study, mice were exposed to 19, 75, or 300 ppb As+3. There was a decrease in bone marrow cell recovery, but not spleen cell recovery at 300 ppb As+3. In the bone marrow, As+3 altered neither the expression of CD34+ and CD38+ cells, markers of early hematopoietic stem cells, nor CD45-/CD105+, markers of mesenchymal stem cells. Spleen cell surface marker CD45 expression on B cells (CD19+), T cells (CD3+), T helper cells (CD4+) and cytotoxic T cells (CD8+), natural killer (NK+), and macrophages (Mac 1+) were not altered by the 30 day in vivo As+3 exposure. Functional assays of CFU-B colony formation showed significant selective suppression (p<0.05) by 300 ppb As+3 exposure, whereas CFU-GM formation was not altered. The TDAR of the spleen cells was significantly suppressed at 75 and 300 ppb As+3. In vitro studies of the bone marrow revealed a selective suppression of CFU-B by 50 nM As+3 in the absence of apparent cytotoxicity. Monomethylarsonous acid (MMA+3) demonstrated a dose-dependent and selective suppression of CFU-B beginning at 5 nM (p<0.05). MMA+3 suppressed CFU-GM formation at 500 nM, a concentration that proved to be nonspecifically cytotoxic. As+5 did not suppress CFU-B and/or CFU-GM in vitro at concentrations up to 500 nM. Collectively, these results demonstrate that As+3 and likely its metabolite (MMA+3) target lymphoid progenitor cells in mouse bone marrow and mature B and T cell activity in the spleen.
Arsenic is a lung toxicant that can lead to respiratory illness through inhalation and ingestion, although the most common exposure is through contaminated drinking water. Lung effects reported from arsenic exposure include lung cancer and obstructive lung disease, as well as reductions in lung function and immune response. As part of their role in innate immune function, airway epithelial cells provide a barrier that protects underlying tissue from inhaled particulates, pathogens, and toxicants frequently found in inspired air. We evaluated the effects of a five-day exposure to environmentally relevant levels of arsenic {<4μM [~300 μg/L (ppb)] as NaAsO2} on airway epithelial barrier function and structure. In a primary mouse tracheal epithelial (MTE) cell model we found that both micromolar (3.9 μM) and submicromolar (0.8 μM) arsenic concentrations reduced transepithelial resistance, a measure of barrier function. Immunofluorescent staining of arsenic-treated MTE cells showed altered patterns of localization of the transmembrane tight junction proteins claudin (Cl) Cl-1, Cl-4, Cl-7 and occludin at cell-cell contacts when compared with untreated controls. To better quantify arsenic-induced changes in tight junction transmembrane proteins we conducted arsenic exposure experiments with an immortalized human bronchial epithelial cell line (16HBE14o-). We found that arsenic exposure significantly increased the protein expression of Cl-4 and occludin as well as the mRNA levels of Cl-4 and Cl-7 in these cells. Additionally, arsenic exposure resulted in altered phosphorylation of occludin. In summary, exposure to environmentally relevant levels of arsenic can alter both the function and structure of airway epithelial barrier constituents. These changes likely contribute to the observed arsenic-induced loss in basic innate immune defense and increased infection in the airway.
Cadmium (Cd) is a well-established carcinogen, however, the underlying mechanism, especially the role of epigenetics in it, is still poorly understood. Our previous work has disclosed that when rats were exposed to 0.5mg CdCl2 (kg.d) for 8 and 12 weeks, the growth of peripheral white blood cells (WBC) was obviously stimulated but no over-proliferation of granulocyte-monocyte (GM) progenitor cells was observed in the bone marrow, suggesting that the over-proliferation of lymphocyte was promoted by Cd exposure. Is DNA-methylation involved in this Cd-stimulated cell proliferation? The present study found that when human B lymphoblast HMy2.CIR cells were exposed to Cd with a dose lower than 0.1μM for 3 months, both cell proliferation and mRNA expressions of DNA methyltransferases of DNMT1 and DNMT3b were increased, while the mRNA of tumor suppressor gene p16 was remarkably decreased. Furthermore, the level of genomic DNA methylation was increased and the CpG island in p16 promoter was hypermethylated in the Cd-exposed cells. A DNA demethylating agent, 5-aza-2'-deoxycytidine (5-aza-dC), diminished Cd-stimulated cell proliferation associated with p16 overexpression. Our results suggested that the chronic exposure of low dose Cd could induce hypermethylation of p16 promoter and hence suppress p16 expression and then promote cell proliferation, which might contribute to Cd-induced carcinogenesis.
Among the environmental contaminants recognised for their toxicity and their global presence, heavy metals are certainly a major concern. They can elicit a number of immunomodulatory effects leading ultimately to an enhanced susceptibility (sensitivity) of immune cells to microbial agents and the appearance of neoplastic diseases and autoimmune phenomena. Heavy metals also provoke changes in the function(s) of immune cells. A striking biological effect of heavy metals is the induction of intracellular thiols (cysteine, glutathione, metallothioneins). Thiols are involved in many physiological processes, including protection from free radical damage and detoxification of chemicals. The purpose of this study was to assess the differences of susceptibility (sensitivity) in both pre-activated (concanavalin A was used) and non-pre-activated cells in the presence of heavy metals. Five were evaluated on murine splenocytes. The lymphoblastic proliferation test was performed for lymphocytes and a phagocytosis test for macrophages. Data showed that the levels of thiols in the pre-activated cells are greater than non-pre-activated cells following exposure to various heavy metals; macrophages were more resistant than lymphocytes to the toxic effects of heavy metals, and pre-activated cells were more resistant than cells at rest. One possible explanation is that macrophages produce more thiols than lymphocytes and this provides an increased protection from the deleterious effects of heavy metals.
The object of this study was the effect of lead (Pb) exposure on immune and neurobehavioral parameters of 16 women with a mean age of 34 yr who worked for an average of 12 yr in three printing houses in Taiyuan (Shanxi Province, China). The women were not occupationally exposed to toxic agents other than Pb. Mean air Pb in the printing houses was about 25 mug/m(3), mean blood Pb of the workers was 28.6 mug/d/ and that of the referents 12.4. The referent group of 36 women, resident in the same industrialised and traffic busy city, was of similar age, working activity, lifestyle and education of the Pb-exposed group. The Neurobehavioral Core Test Battery (NCTB) was utilised; some of the NCTB scores, including the simple reaction time, Digit Symbol, Pursuit Aiming II (PA) and correct PA, were significantly lower in the Pb exposed group, whereas all the negative Profile Mood States (POMS) scores were slightly higher in the workers (some with a significant difference) indicating a negative psychological effect of Pb. Lymphocyte subsets were determined in 16 of the Pb exposed women and in 16 referent women with similar age and lifestyle of the whole group of 36 controls. CD4(+)-CD45RO(+) "memory" T lymphocytes of the workers were significantly higher than those of control women, whereas NK and B CD3(-)-HLA-DR+ and NK CD16(+)-CD56(+) lymphocytes of the Pb exposed women were much lower than those of the referent group. We suggest that the reduction of blood CD16(+)-CD56(+) lymphocytes in the workers in the printing houses may depend either on a direct effect of Pb exposure on the immune system or on an effect mediated by the neuroendocrine system.
Because of its dual roles in acute toxicity and in therapeutic application in cancer treatment, arsenic has recently attracted a renewed attention. In this study, we report NaAsO2-induced signal cascades from the cell surface to the nucleus of murine thymic T lymphocytes that involve membrane rafts as an initial signal transducer. NaAsO2 induced apoptosis through fragmentation of DNA, activation of caspase, and reciprocal regulation of Bcl-2/Bax with the concomitant reduction of membrane potential. We demonstrated that NaAsO2-induced caspase activation is dependent on curcumin-sensitive c-Jun amino-terminal kinase and barely dependent on SB203580-sensitive p38 kinase or PD98059-sensitive extracellular signal-regulated kinase. Additionally, staurosporine, which severely inhibited the activation of mitogen-activated protein (MAP) family kinases and c-Jun, partially blocked the NaAsO2-mediated signal for poly(ADP-ribose) polymerase (PARP) degradation. Potentially as the initial cell surface event for intracellular signaling, NaAsO2 induced aggregation of GPI-anchored protein Thy-1 and superoxide production. This Thy-1 aggregation and subsequent activation of MAP family kinase and c-Jun and the degradation of PARP induced by NaAsO2 were all inhibited by DTT, suggesting the requirement of interaction between arsenic and protein sulfhydryl groups for those effects. β cyclodextrin, which sequestrates cholesterol from the membrane rafts, inhibited NaAsO2-induced activation of protein tyrosine kinases and MAP family kinases, degradation of PARP, and production of superoxide. In addition, β cyclodextrin dispersed NaAsO2-induced Thy-1 clustering. These results suggest that a membrane raft integrity-dependent cell surface event is a prerequisite for NaAsO2-induced protein tyrosine kinase/c-Jun amino-terminal kinase activation, superoxide production, and downstream caspase activation.
Immunotherapy is a promising antitumor strategy that can successfully be combined with current anticancer treatment. In this study, arsenic trioxide (As(2)O(3)) was shown to increase the antitumor immune response in CT26 colon tumor-bearing mice through the modulation of regulatory T cell (T(reg)) numbers. As(2)O(3) induced T(reg)-selective depletion in vitro. In vivo, tumor-bearing mice injected with 1 mg/kg As(2)O(3) showed a significant decrease in the T(reg)/CD4 cell ratio and in absolute T(reg) count versus controls. As(2)O(3) exerted antitumor effects only in immunocompetent mice and enhanced adoptive immunotherapy effects. Inhibition of As(2)O(3)-induced T(reg) depletion by the NO synthase inhibitor N(G)-nitro-l-arginine methyl ester and the superoxide dismutase mimic manganese [III] tetrakis-(5, 10, 15, 20)-benzoic acid porphyrin suggested that it was mediated by oxidative and nitrosative stress. The differential effect of As(2)O(3) on T(reg) versus other CD4 cells may be related to differences in the cells' redox status, as indicated by significant differences in 2'7'dichlorodihydrofluorescein diacetate and 4,5-diaminofluorescein diacetate fluorescence levels. In conclusion, these results show for the first time, to our knowledge, that low doses As(2)O(3) can delay solid tumor growth by depleting T(regs) through oxidative and nitrosative bursts, and suggest that As(2)O(3) could be used to enhance the antitumor activity of adoptive immunotherapy strategies in human cancer.
Lead is a metal with many recognized adverse health side effects, and yet the molecular processes underlying lead toxicity are still poorly understood. Quantifying the injurious effects of lead is also difficult because of the diagnostic limitations that exist when analyzing human blood and urine specimens for lead toxicity.
We analyzed the deleterious impact of lead on human cells by measuring its effects on cytokine production and gene expression in peripheral blood mononuclear cells. Lead activates the secretion of the chemokine IL-8 and impacts mitogen-dependent activation by increasing the secretion of the proinflammatory cytokines IL-6 and TNF-α and of the chemokines IL-8 and MIP1-α in the presence of phytohemagglutinin. The recorded changes in gene expression affected major cellular functions, including metallothionein expression, and the expression of cellular metabolic enzymes and protein kinase activity. The expression of 31 genes remained elevated after the removal of lead from the testing medium thereby allowing for the measurement of adverse health effects of lead poisoning. These included thirteen metallothionein transcripts, three endothelial receptor B transcripts and a number of transcripts which encode cellular metabolic enzymes. Cellular responses to lead correlated with blood lead levels and were significantly altered in individuals with higher lead content resultantly affecting the nervous system, the negative regulation of transcription and the induction of apoptosis. In addition, we identified changes in gene expression in individuals with elevated zinc protoporphyrin blood levels and found that genes regulating the transmission of nerve impulses were affected in these individuals. The affected pathways were G-protein mediated signaling, gap junction signaling, synaptic long-term potentiation, neuropathic pain signaling as well as CREB signaling in neurons. Cellular responses to lead were altered in subjects with high zinc protoporphyrin blood levels.
The results of our study defined specific changes in gene and protein expression in response to lead challenges and determined the injurious effects of exposures to lead on a cellular level. This information can be used for documenting the health effects of exposures to lead which will facilitate identifying and monitoring efficacious treatments for lead-related maladies.
The effects of cadmium (Cd) on phytohemoagglutinin or phorbol myristate acetate-induced lymphocyte activation were investigated and a dose-dependent inhibition of cell proliferation was found. Kinetic studies revealed that the Cd-sensitive step is an early event of T cell stimulation. Failure of IL2 secretion and reduction of IL2 receptor expression in the Cd-treated cells are also reported. Regardless of which mechanism is responsible for Cd effects, our studies show that the inhibition of lymphocyte activation is associated with reduced [3H]phorbol dibutyrate binding to Ca2+-phospholipid-dependent protein kinase and altered breakdown of phosphatidylinositols. Thus, Cd interferes with two biochemical events which play a critical role in lymphocyte signal transduction and activation.
Examining the complex interactions associated with clinical toxicological events and chemical exposure of drug administration, this updated and revised Second Edition functions as a stand-alone text or reference of clinical toxicology for professionals, students of toxicology and pharmacy, as well as forensic toxicologists, occupational healthcare workers, industrial hygienists, and safety engineers. This all-inclusive source has been updated to include the latest issues and the most current research in clinical toxicology. Key features in Clinical Toxicology: Principles and Mechanisms include: • Convenient and organized categorization of compounds into therapeutic and non-therapeutic agents • Tables, drawings, and figures that provide readily accessible, precise data • Tables for easy usage and cross-reference to names, indications, effects, adverse reactions, and drug interactions for over 70 common herbal products • The brand, generic, and street names of therapeutic agents Topics covered in the Second Edition include: • Symptoms of diseases and pathology caused by toxins and clinical drugs • Biological and chemical toxins, changes in protocols for managing toxic ingestions, new antidotes, changes in treatments, and the pharmacology and toxicology of herbal products • The effects of biological and chemical agents cited by the U.S. and U.N. as potential bioterrorist weapons • General physiology and pharmacology principles • The widely distributed chemical agents and currently used therapeutic drugs that have hazardous effects.
Recent evidence suggests that the development of skin lesions from arsenic exposure may be mediated by increases in the expression of various growth factors, including transforming growth factor-alpha (TGF alpha). To investigate this association in humans, levels of total urinary arsenic and urinary TGF alpha were determined in 41 individuals with and without arsenic-associated skin lesions from Bangladesh who have chronic exposure to arsenic in their drinking water. After adjusting for age and sex, total urinary arsenic was found to be correlated with urinary TGF alpha (R-2 = 0. 37; p < 0.0001), particularly in those individuals with arsenic-associated skin lesions (R-2 = 0.70; p < 0.0001). Stratification of the cohort into quartiles based on urinary TGF alpha levels demonstrated a trend of increasing odds ratios for the presence of arsenic-associated skin lesions with increasing urinary TGF alpha, although this was not significant (p = 0.15). These results suggest that urinary TGF alpha may be a useful biomarker for the epidermal effects of arsenic exposure.
Objective: To study the effect of sodium arsenite exposure on the functions of murine leukocytes and humoral immune response. Methods: Male (BALB/c) mice were continuously exposed to sodium arsenite (NaAsO2) for two weeks. Fractions of peritoneal macrophages were separated and their functional activities were determined. To test the effects of arsenic on the humoral immune response heat killed S. aureus was injected and the titre of the antiserum was measured. results: The mean phagocytic index (P.I) of control macrophage (Mφ) is decreased from 25571.43 ± 1126.26 to 4905.30 ± 556.70 after Sodium arsenite treatment, whereas the mean P.I of S. aureus primed Mφ (47147.44 ± 666.36) is also decreased to 15965.91 ± 1185.95 in case of arsenite exposure followed by S. aureus immunization (P<0.001). Intracellular killing capacity in control cells (68.4%) which is found to 77.3% in case of NaAsO2 treatment and they can kill only 22.7% bacteria. The chemotactic index also decreases significantly in case of arsenic treated cell (2.5±0.02) with respect to that of control cell (9.83±0.22) at 60 min. In S.aureus immunized serum, agglutination titre was obtained at lowest antibody conc(1:512), whereas serum from pre-exposure of arsenite followed by S.aureus immunization showed early agglutination (1:32). Conclusion: Sodium arsenite exposure interferes with the immunological functions and antibody raising capacity of peritoneal macrophages in BALB/C mice.
To assess the immune competence of workers occupationally exposed to lead, several subsets of peripheral lymphocytes, i.e., T, TCD4+, TCD8+, B, NK cells, serum immunoglobulin and complement protein concentrations, chemotaxis, and intracellular killing activity of neutrophils of 25 male storage battery workers have been analyzed and compared to 25 healthy males with no history of lead exposure. The results of this study which indicated that industrial exposure to lead resulting in group mean blood lead concentrations of 75 ± 18 μg/dl are associated with a significant depression of: T helper lymphocytes, Ig G, Ig M and C3, C4 complement levels, chemotaxis, and random migration of neutrophils. No correlation was found between the duration of exposure and the altered immune parameters. The immune system can be a target for lead toxicity and elimination of lead hazard in working places is necessary. Am. J. Ind. Med. 38:349–354, 2000.
Sodium meta-arsenite (SA) is an orally available arsenic compound. We investigated the effects of SA on the development of autoimmune type 1 diabetes. Female non-obese diabetic (NOD) mice were orally intubated with SA (5mg/kg/day) from 8weeks of age for 8weeks. The cumulative incidence of diabetes was monitored until 30weeks of age, islet histology was examined, and lymphocytes including T cells, B cells, CD4+IFN-γ+cells, CD8+IFN-γ+cells, CD4+IL4+ cells, and regulatory T cells were analyzed. We also investigated the diabetogenic ability of splenocytes using an adoptive transfer model and the effect of SA on the proliferation, activation, and expression of glucose transporter 1 (Glut1) in splenocytes treated with SA in vitro and splenocytes isolated from SA-treated mice. SA treatment decreased the incidence of diabetes and delayed disease onset. SA treatment reduced the infiltration of immunocytes in islets, and splenocytes from SA-treated mice showed a reduced ability to transfer diabetes. The number of total splenocytes and T cells and both the number and the proportion of CD4+IFNγ+and CD8+IFNγ+T cells in the spleen were significantly reduced in SA-treated NOD mice compared with controls. The number, but not the proportion, of regulatory T cells was decreased in SA-treated NOD mice. Treatment with SA either in vitro or in vivo inhibited proliferation of splenocytes. In addition, the expression of Glut1 and phosphorylated ERK1/2 was decreased by SA treatment. These results suggest that SA reduces proliferation and activation of T cells, thus preventing autoimmune diabetes in NOD mice.
Copyright © 2015. Published by Elsevier Inc.
The effect of cadmium on splenic T and innate immune cells in rats is explored.•Differential effects of 1 mg/kg on T cell and innate immune activities were shown.•Lower Cd dose (0.5 mg/kg) cause less pronounced immunosuppressive effects.•Proinflammatory effects on innate immune activities were seen at that dose.•Presented data depict complexity of immunomodulatory potential of this metal.
Abstract Although numerous investigations have demonstrated a direct effect of cadmium (Cd) on peripheral blood mononuclear cell (PBMC) activity in humans, there is virtually no data concerning the in vivo impact of this metal on circulatory mononuclear cells. In this study, the effects of a sub-lethal Cd (1 mg/kg) dose were examined in rats 48 h following a single intraperitoneal injection. Cd treatment resulted in increased total peripheral blood leukocyte levels; however, decreases in PBMC numbers were seen. These changes coincided with an accumulation of mononuclear cells in the lungs and an increase in mononuclear cells expressing CD11b. A lack of effect of Cd on spontaneous nitric oxide (NO) production and on iNOS mRNA levels in the PBMC was also noted. Differential effects of Cd on PBMC inflammatory cytokine (IL-1β, TNFα, IL-6, IFNγ, and IL-17) gene expression and production were also seen. Specifically, except for IL-1β (levels increased), there were decreases (relative to controls) in mRNA levels for all the other cytokines examined. While there were no Cd treatment-related changes in spontaneous production of the cytokines assessed, there seemed to be a trend (p = 0.06) toward a decrease in spontaneous IL-6 release. When these harvested cells were stimulated ex vivo, there was no effect from Cd exposure on LPS-stimulated IL-1β and TNFα or on ConA-stimulated IFNγ or IL-17 production, but a decrease in IL-6 production in response to LPS was, again, noted. A preliminary study with a lower Cd dose (0.5 mg/kg) revealed some of the same outcomes noted here (mononuclear cell infiltration into lungs, increases in PBMC IL-1β mRNA levels), but differential (increased IL-17 mRNA levels) or newly detected outcomes (increased levels of IL-1α mRNA) as well. The described effects of the single in vivo exposure to Cd on PBMC might contribute to a better overall understanding of the immunomodulatory potential of this environmental contaminant.
An imbalance between helper T cell type 1 (Th1) and helper T cell type 2 (Th2) activation can result in immunodysregulations leading to impaired cell-mediated immunity with an increased incidence of infectious disease or cancer and/or aberrant humoral immunity that may culminate with an autoimmune disease. Mercury, a heavy-metal toxicant, is known to induce renal autoimmunity characterized by a predominant Th2 response. Lead, another metal toxicant, causes enhanced B cell activities and impairs host resistance to several bacterial and viral infections. In addition, Pb was reported to enhance Th2 proliferation and inhibit Th1 proliferation. The differential effects of Pb on Th subset activation have been further investigated. In vitro IL-4 production by a Th2 clone was significantly increased by the addition of PbCl2, whereas IFN gamma production by a Th1 clone was decreased by the addition of PbCl2. When BALB/c mice were subcutaneously exposed to PbCl2, ex vivo Il-4 production by anti-CD3-stimulated splenic T cells was enhanced, but IFN gamma production was inhibited. Additionally, the plasma IL-4 and IgE levels of Pb-exposed mice were increased, and the plasma IFN gamma levels were significantly lowered in the absence of any additional exogenous antigen. In vitro, ex vivo, and in vivo treatment with HgCl2 produced similar findings. This study is the first report of the preferential activation of a Th2 response by Pb in vivo and suggests that PB, like Hg, may induce autoimmune responses by upsetting the balance between Th1- and Th2-like cells, which could enhance production of antibodies to self antigens.
Serum immunoglobulin (IgG, IgM, and IgE) concentrations of 38 preschool children with blood lead levels > or = 0.48 pmol/L (10 microg/ dL) were examined and compared to 35 preschool children with blood lead levels < or = 0.48 micromol/L. No differences in serum concentrations of IgG, IgM, and IgE in the populations were observed, but IgG, IgM, and IgE of male and female children from the high blood lead level group were compared to those of controls and the results showed that IgG and IgM were significantly lower in the high blood lead level group of females than in the controls, while IgE was significantly higher in the high blood lead level group of females than in the controls (P < 0.05). No correlation between blood lead concentration and serum immunogloblins IgG and IgM was demonstrated, but a statistically significant relationship between IgE and blood lead level was found in this population. These data indicate that the effect of lead on IgG, IgM, and IgE was stronger in females than in males and lead could play a role in this process by stimulating IgE production.
Although cadmium (Cd) is a redox system disruptor, the systematic defensive responses to Cd-induced oxidative stress remain unclear. In this study, we initially determined that when human T cell-derived Jurkat cells were exposed to a low concentration of Cd, the glutathione (GSH) concentration rapidly increased via the transient nuclear accumulation of the transcription factor Nrf2. Therefore, we hypothesized that this increase in the GSH levels was a significant event that occurred in response to the Cd toxicity in the Jurkat T-cells. To test this hypothesis, the expression of Nrf2 in the cells was silenced using siRNA transfection. These restricted expression conditions demonstrated that the sensitivity of the Jurkat T-cells to Cd toxicity was significantly higher in the knockdown cells. While we could not find differences in the metallothionein (MT) expression responses, accumulation of Nrf2 in the nuclei and the GSH increase following Cd exposure were clearly suppressed in the Nrf2 knockdown cells. These findings strongly suggest that the Cd-induced activation of GSH synthesis is initiated as an acute response for Cd detoxification. Furthermore, the Cd remaining in the Jurkat T-cells did not cause a significant inhibition of cell growth after the rapid and transient increase in the GSH concentration returned to its basal level. Additionally, we found that MT expression induced by Cd occurred much later, with the expression seen at least 12h or more after the Nrf2-dependent immediate responses were almost completed. These results indicate that the rapid increase in GSH is an essential defensive response, with the subsequent induction of MT potentially chelating the Cd retained in the cell, thereby leading to continued suppression of the Cd toxicity.
Infiltration of circulatory inflammatory cells is a common histopathological finding in target organs following cadmium administration, but there is paucity of data concerning their activity. In this study, the effects of sublethal (1mg/kg) cadmium on peripheral blood polymorphonuclear (PMN) cells were examined 48h following administration in rats, when tissue (liver and lung) infiltration of these cells was observed. Cadmium administration resulted in systemic inflammatory cytokine and acute phase response with an increase in circulatory neutrophil numbers and cells that express CD11b molecules. Rise in basic aspects of oxidative activity including intracellular myeloperoxidase (MPO), reactive oxygen (nitroblue tetrazolium/NBT cytochemical assay) and nitrogen (Griess assay) species production was observed in PMNs from cadmium-administered rats. A decrease in levels of mRNA for IL-1β, TNF-α and IL-6 was noted, but production of these cytokines was affected differentially. Described effects of cadmium on PMNs add further to the understanding of inflammatory potential of this environmental contaminant.
Lead has been found to depress the immune system in animal studies at levels far below those responsible for overt toxicity. Literature studies in animal systems most clearly showed an effect of lead on response to a specific immunogenic stimulus. Data are sparse concerning the effects of lead on the immune system in the human population at greatest risk for exposure-children up to six years of age. This portion of the Phase I study reports concentrations of IgG, IgM, IgA, and IgE, as well as antibody titers to the specific antigenic stimuli provided by the vaccines against diphtheria, tetanus, and Rubella. The study population consisted of a group of 193 children, ages 9 months to 6 years, who participate in the WIC (Women, Infants and Children) and Lead Poisoning Prevention Programs in the urban area of Springfield-Greene County Missouri. Blood lead levels ranged from 1 to 50 μg dL(-1). Total Ig levels were determined and the data were analysed. No consistent significant differences were observed among the risk categories in the five age groups examined. A single Ig class in each of three age groups showed apparent significant differences among the various risk categories, but these differences were not correlated with blood lead. An analysis of specific antibody titers to diphtheria, tetanus, and Rubella was performed. Regression analyses of current data in Phase I of this study suggest a detrimental effect of lead on the antibody titres to diphtheria and Rubella.
Studies conducted in animal systems have shown that lead is an immunosuppressive agent at levels far below those causing overt toxicity. Children less than six years of age are the population at highest risk for exposure to environmental lead; however little data were available to assess effects on the developing immune system in this age group. Reported here is the completed Phase I study on 193 children, ages 9 months to 6 years, with blood lead levels from 1 to 50 (μg dL(-1), recruited from the urban population of Springfield-Greene County, Missouri, through their participation in the WIC (Women, Infants, and Children) and Lead Poisoning Prevention Programs. This portion of the study dealt with enumeration of cells involved with the immune response andin vitro mitogenic stimulation of lymphocytes. The percent lymphocytes, monocytes, granulocytes, T cells (total), B cells, CD4+T's and CD8+T's and CD4+/CD8+ ratios were determined and the data were analysed. No consistent significant differences were seen among the various risk categories currently identified by the CDC. Though two age groups showed some possible effect of lead, none of the various cellular parameters within these age groups showed significant correlation with blood lead. The lymphocyte response toin vitro mitogenic stimulus was studied on 42 children (including 17 in risk classifications IIA and higher) using the mitogens phytohemagglutinin (PHA), Concanavalin A (Con A), and Pokeweed mitogen (PWM). No consistent statistically significant differences were seen among the various risk categories; the effects of lead, if present, are most likely subtle and obscured by the interindividual and time-dependent variation inherent in this type of study.
Background
The essential metals, chromium (Cr), magnesium (Mg), manganese (Mn) and zinc (Zn), are necessary for many metabolic processes and their homeostasis is crucial for life. The toxic metals, cadmium (Cd) and lead (Pb), have no beneficial role in human metabolism. The aim of this study was to investigate the levels of Cd, Cr, Mg, Mn, Pb, and Zn in scalp hair samples of type 2 diabetes mellitus patients of both genders, ages ranging from 30 to 50 y, and belong to urban areas of Ireland and Pakistan. For comparison purposes, age matched non-diabetic subjects of both countries were selected as referents.Methods
The concentrations of metals in scalp hair samples were measured by inductively coupled plasma atomic emission spectrophotometer and atomic absorption spectrophotometer after microwave-assisted acid digestion. The validity and accuracy of the methodology were checked by conventional wet-acid-digestion method and using certified reference materials.ResultsThe mean values of Cd and Pb were significantly higher in scalp hair samples of both Pakistani and Irish diabetic patients as compared to referents of both countries (P < 0.001). In contrast, lower Cr, Mg, Mn, and Zn (P < 0.01) concentrations were detected in scalp hair derived from patients with type 2 diabetes versus healthy subjects of both countries.Conclusion
This study showed that, increased toxic elements and decreased essential elements are associated with diabetes mellitus. Therefore, these elements may play a role in the development and pathogenesis of diabetes mellitus.
The effect of sodium arsenite (SA) on LPS-induced NO production in RAW 267.4 murine macrophage cells was studied. SA pretreatment of LPS-stimulated RAW cells resulted in a striking reduction in NO production. No significant difference in LPS binding was observed between RAW cells pretreated with SA and control untreated RAW cells, suggesting that SA might impair the intracellular signal pathway for NO production. SA inhibited LPS-induced NF-κB activation by preventing loss of IκB-α and -β. Furthermore, SA blocked phosphorylation of extracellular signal-regulated kinase 1/2 (Erk1/2), but not phosphorylation of p38 and c-Jun N-terminal kinase. SA treatment resulted in the disappearance of Raf-1, suggesting that it might cause the inhibition of the Erk1/2 mitogen-activated protein (MAP) kinase pathway. The SA-mediated loss of Raf-1 also abolished LPS-induced NF-κB activation as well as the Erk1/2 pathway. The dominant negative mutant of MAP kinase kinase 1 inhibited both NO production and NF-κB activation in LPS-stimulated RAW cells. Taken together, these results indicate that the inhibitory action of SA on NO production in LPS-stimulated macrophages might be due to abrogation of inducible NO synthase induction, and it might be closely related to inactivation of the NF-κB and Erk1/2 MAP kinase pathways through loss of Raf-1.
Based on our recent findings that 25 µM cadmium triggers oxidative stress-mediated caspase-dependent apoptosis in murine thymocytes, this study is designed to explore whether Cd also induces caspase-independent apoptosis. We found that pretreatment with caspase inhibitors fails to prevent Cd-induced apoptosis completely, suggesting the possibility of an additional pathway. Western blot and flow cytometry techniques indicated marked expression of apoptosis-inducing factor and endonuclease G in nuclear fraction, signifying their translocation from mitochondria to nucleus. Intracellular Ca(2+) and reactive oxygen species (ROS) levels significantly raised by Cd were restored by ruthenium red, which had no influence on mitochondrial membrane depolarization and caspase activity and apoptosis. Using cyclosporin A, ROS formation and mitochondrial membrane depolarization were completely abolished, whereas apoptosis was partly attenuated. These results clearly demonstrate more than one apoptotic pathway in thymocytes and support the role of mitochondrial permeability transition pore in the regulation of caspase-independent cell death triggered by Cd.
AimDespite increasing concern regarding health problems as a result of environmental pollutants, no association of toxic heavy metals with diabetes has been demonstrated in the general population. We investigated the association of heavy metals, including lead, mercury and cadmium, with diabetes in the Korean population.Methods
This cross-sectional study is based on data from the fourth and fifth Korea National Health and Nutritional Examination Surveys, which were conducted in 2009 and 2010 among members of the Korean population. Participants included 1588 men and 1596 women, 30 years of age or older, who were selected from all of the 16 administrative districts of South Korea. Measurements of blood lead, mercury and cadmium levels were performed. Homeostatic model assessment of insulin resistance and homeostatic model assessment of β-cell function were calculated in participants without diabetes.ResultsBlood concentration of lead, mercury and cadmium were slightly higher, but non-significantly, in participants with diabetes, compared with those without. After adjustment for age, sex, region, smoking, alcohol consumption and regular exercise, the prevalence of diabetes did not differ among quartiles of blood heavy metal concentrations. Correlation analysis of heavy metals with homeostatic model assessment of insulin resistance and β-cell function did not indicate a significant relationship. The relationship of sum of heavy metal mixture with prevalent diabetes was also not significant.Conclusions
Blood lead, mercury and cadmium have no significant relationship with diabetes in the general Korean population.
Experimental studies have demonstrated that the antileukemic trivalent inorganic arsenic prevents the development of severe pro-inflammatory diseases mediated by excessive Th1 and Th17 cell responses. Differentiation of Th1 and Th17 subsets is mainly regulated by interleukins (ILs) secreted from dendritic cells (DCs) and the ability of inorganic arsenic to impair interferon-γ and IL-17 secretion by interfering with the physiology of DCs is unknown. In the present study, we demonstrate that high concentrations of sodium arsenite (As(III), 1-2μM) clinically achievable in plasma of arsenic-treated patients, block differentiation of human peripheral blood monocytes into immature DCs (iDCs) by inducing their necrosis. Differentiation of monocytes in the presence of non cytotoxic concentrations of As(III) (0.1 to 0.5μM) only slightly impacts endocytotic activity of iDCs or expression of co-stimulatory molecules in cells activated with lipopolysaccharide. However, this differentiation in the presence of As(III) strongly represses secretion of IL-12p70 and IL-23, two major regulators of Th1 and Th17 activities, from iDCs stimulated with different toll-like receptor (TLR) agonists in metalloid-free medium. Such As(III)-exposed DCs also exhibit reduced mRNA levels of IL12A and/or IL12B genes when activated with TLR agonists. Finally, differentiation of monocytes with non cytotoxic concentrations of As(III) subsequently reduces the ability of activated DCs to stimulate the release of interferon-γ and IL-17 from Th cells. In conclusion, our results demonstrate that clinically relevant concentrations of inorganic arsenic markedly impair in vitro differentiation and functions of DCs, which may contribute to the putative beneficial effects of the metalloid towards inflammatory autoimmune diseases.
Pb is a common environmental pollutant affecting various organs. Exposure of the immune system to Pb leads to immunosuppression or immunodysregulation. Although previous studies showed that Pb exposure can modulate the function of helper T cells, Pb immunotoxicity remains incompletely understood. In this study, we investigated the effect of Pb exposure on T cell development, and the underlying mechanism of Pb-induced suppression of the delayed-type hypersensitivity (DTH) response in vivo. Sprague-Dawley rats were exposed to 300ppm Pb-acetate solution via the drinking water for six weeks, and we found that Pb exposure significantly increased Pb concentrations in the blood by 4.2-fold (p<0.05) as compared to those in the control rats. In Pb-exposed rats, the amount of thymic CD4(+)CD8(-) and peripheral CD4(+) T cells was significantly reduced, whereas, CD8(+) population was not affected. In contrast to conventional CD4(+) T cells, Foxp3(+) regulatory T cells (Tregs) were increased in both the thymus and peripheral lymphoid organs of Pb-exposed rats. In line with the increase of Tregs, the DTH response of Pb-exposed rats was markedly suppressed. Depletion of Tregs reversed the suppression of DTH response by Pb-exposed CD4(+) T cells in an adoptive transfer model, suggesting a critical role of the increased Tregs in suppressing the DTH response. Collectively, this study revealed that Pb-exposure may upregulate Tregs, thereby leading to immunosuppression.
The article contains sections titled:
Arsenic, although often referred to as a metal, is classified chemically as a nonmetal or metalloid and belongs to Group 15 (VA) of the Periodic Table (as does antimony). The principal valences of arsenic are , , and . Only one stable isotope of arsenic having mass 75 (100% natural abundance) has been observed. Metallic arsenic is stable in dry air, but when exposed to humid air the surface oxidizes, giving a superficial golden bronze tarnish that turns black upon further exposure. The amorphous form is more stable to atmospheric oxidation. Upon heating in air, both forms sublime and the vapor oxidizes to arsenic trioxide, As2O3. Elemental arsenic combines with many metals to form arsenides. Arsenic is widely distributed about the earth and has a terrestrial abundance of approximately 5 g/t. The most important commercial source of arsenic, however, is as a by-product from the treatment of copper, lead, cobalt, and gold ores. Arsenic metal is also offered in high (ranging from 99.99% to in excess of ) purity form for semiconductor applications. The predominant use of arsenic in the United States is in the manufacture of chemicals. The principal use of arsenic in the United States is in the preparation of wood preservatives for the protection of lumber and other wood products. Arsenic trioxide is the basic commodity of commerce from which a number of important chemicals are manufactured. Trace quantities of arsenic are added to lead–antimony grid alloys used in lead acid batteries. Phosphorized deoxidized arsenical copper (alloy 142) is used for heat exchangers and condenser tubes. The toxicity of arsenic ranges from very low to extremely high depending on the chemical state. Metallic arsenic and arsenious sulfide, As2S3, have low toxicity. Arsine is extremely toxic. The toxicity of other organic and inorganic arsenic compounds varies. Arsenic is classified as a carcinogen by the International Agency for Research on Cancer (IARC). The handling of arsenic in the work-place should be in compliance with the U.S. Occupational Safety and Health Administration (OSHA) regulations. Precautions should be taken to avoid accidental generation of arsine gas. Disposal of arsenical products should be in compliance with Federal and local government environmental regulations.
Keywords:
arsenic;
arsenic trioxide;
metallurgy;
wood preservative;
semiconductor;
alloys
The effects of heavy metal exposure on the immune system were determined by measuring cytokine production of human peripheral blood mononuclear cells (h-PBMCs) from a healthy female. The h-PBMCs were exposed for 3 d to CdSO 4 , K 2 Cr 2 O 7 , and HgCl 2 at 1, 5, 10 µM and to (CH 3 COO)Pb at 10, 50, and 100 µM. Concentrations of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β, IL-6, IL-8, and IL-10 were quantified using the ELISA method. The results showed that the cytokines assayed were differentially affected by heavy metal exposure. Chromium significantly increased the production of IL-1β while decreasing the production of IFN-γ, IL-6, IL-8, and IL-10. Mercury at low concentrations increased the levels of TNF-α and IL-1β. At higher concentra-tions, an opposite effect was seen. Cytokines may function as biomarkers in elucidating the mechanisms of the immunotoxic effects of heavy metals.
Cadmium is a highly toxic element responsible for acute and chronic toxicity in man. There is evidence that cadmium induces
pathophysiological effects by modulating components of the immune system. Cytokines are being increasingly recognized as essential
mediators of normal and pathologic immune responses. Cadmium at concentrations varying from 1.0×10−4 to 3.3×10−6 M inhibited the phytohemagglutinin induced production of interleukin-1β and tumour necrosis factor-α, in in vitro activated
human peripheral blood mononuclear cells. The messenger RNA levels of interleukin-1β and tumour necrosis factor-α were examined
during a 24-h culture period, at different time points. The decreased messenger RNA levels at the time points of the maximum
expression of interleukin-1β and tumour necrosis factor-α indicate that cadmium suppresses their production at the transcriptional
level.
At present cadmium (Cd)induced immunotoxicity and the mechanisms involved have not been fully elucidated. The main objective of the present study is to explore the apoptogenic property of Cd in primary cultured mouse thymocytes and its effect on cell surface marker expression and phenotypic changes. Cdinduced thymocyte apoptosis was determined by TdTmediated dUTP nick end labeling (TUNEL) assay, DNA content/cell cycle analysis and DNA gel electrophoresis. The results showed that Cd was able to cause apoptosis in mouse thymocytes in a time and dosedependent manner. Moreover, different subsets of thymocytes possessed different susceptibility to the apoptotic effect of Cd, in the order of CD8+ > CD4–CD8– (double negative cells, DN) > CD4+CD8+ (double positive cells, DP) > CD4+. Cd treatment also altered thymocyte surface marker expression, leading to evident phenotypic changes. Such changes were characterized by a decline in DP cells and a marked decrease in CD4+/CD8+ ratio, mainly due to a significant increase in CD8+ subsets. These observations help to obtain a better understanding of the immunotoxic and immunomodulatory effects of Cd.
Application of lead suppressed the delayed type hypersensitivity (DTH) of mice induced by sheep red blood cells (SRBC). Inhibition of elicitation of DTH in primary as well as in secondary response was correlated with the concentration of lead in the blood of the mice.
Inorganic arsenic is a toxic environmental contaminant to which humans are mainly exposed through drinking water. This metalloid impairs functions of several key immune cells. Particularly, it reduces IL-2 secretion and proliferation of blood peripheral mononuclear cells stimulated by lectins that, however, do not mimic physiological T cell activation. The present study used isolated human T cells activated, in a more physiological manner, through stimulation with CD3/CD28 antibodies, to carefully analyze the impact of arsenic on T cell proliferation and cytokine expression. We demonstrate that non cytotoxic concentrations of sodium arsenite (As(III), 0.25-2μM) significantly reduce T cell proliferation by increasing the percentage of non dividing cells blocked in G1 phase and by preventing cyclin D3 and CDC25A expression. They also markedly, although not totally, reduces IL-2 expression at both mRNA and protein levels; however, metalloid-dependent inhibition of T cells could not be reversed by addition of recombinant IL-2. In addition, As(III) markedly reduces secretion of interferon-γ without impairing that of IL-4 and IL-13; it also decreases interferon-γ mRNA levels but increases those of IL-13. Finally, simultaneously to its immune effects, As(III) rapidly and potently increases expression of the redox-sensitive genes HMOX1, NQO1 and GCLM in activated T cells without altering the levels of reactive oxygen species. In conclusion, our results demonstrate that As(III) inhibits T cell proliferation, independently of IL-2, and alters the Th balance of cytokines secreted by co-stimulated T cells which thus constitute direct targets of this major environmental contaminant.
Heme oxygenase-1 (HO-1, EC 1.14.99.3) is a key enzyme in the cellular response to tissue injury and oxidative stress. It oxidizes heme, a pro-oxidant and toxic species, to biliverdin, CO, and free iron. Cytoprotection during the heat shock response is a complex phenomenon involving multiple inducible mechanisms. Several important pathways involving serine/threonine kinases mediate the induction of HO-1 in response to external stimuli. The objective of the present study was to investigate the mechanism of HO-1 induction during cadmium (Cd)-induced oxidative stress and apoptosis in the lymphocyte B cell line BJAB. To examine the signal pathways involved in HO-1 expression, cells were pre-treated with various inhibitors of key signaling molecules. Increased DNA fragmentation and caspase-3 activity were observed in BJAB cells exposed to 5-40 μM CdCl(2) revealing that Cd induced apoptosis in these cells. Our results indicate that Cd also induces HO-1 expression which is modulated by the thiol redox status, tyrosine kinase and PI3-kinase. The inhibitory effect of calphostin C suggests that Cd induction of HO-1 expression could be mediated by the PKC pathway in the BJAB cells together with the involvement of ERK ½ and JNK in a dose-dependent manner. The molecular and cellular pathways should not be considered separately. They should be viewed as an array of interconnecting signals, all contributing to the final outcome, thereby allowing fine control of the duration and extent of HO-1 induction.
Trivalent inorganic arsenic [As(III)] is an efficient anticancer agent used to treat patients suffering from acute promyelocytic leukemia. Recently, experimental studies have clearly demonstrated that this metalloid can also cure lymphoproliferative and/or pro-inflammatory syndromes in different murine models of chronic immune-mediated diseases. T helper (Th) 1 and Th17 lymphocytes play a central role in development of these diseases, in mice and humans, especially by secreting the potent pro-inflammatory cytokine interferon-γ and IL-17A, respectively. As(III) impairs basic functions of human T cells but its ability to modulate secretion of pro-inflammatory cytokines by differentiated Th lymphocytes is unknown. In the present study, we demonstrate that As(III), used at concentrations clinically achievable in plasma of patients, has no effect on the secretion of interferon-γ from Th1 cells but almost totally blocks the expression and the release of IL-17A from human Th17 lymphocytes co-stimulated for five days with anti-CD3 and anti-CD28 antibodies, in the presence of differentiating cytokines. In addition, As(III) specifically reduces mRNA levels of the retinoic-related orphan receptor (ROR)C gene which encodes RORγt, a key transcription factor controlling optimal IL-17 expression in fully differentiated Th17 cells. The metalloid also blocks initial expression of IL-17 gene induced by the co-stimulation, probably in part by impairing activation of the JNK/c-Jun pathway. In conclusion, our results demonstrate that As(III) represses expression of the major pro-inflammatory cytokine IL-17A produced by human Th17 lymphocytes, thus strengthening the idea that As(III) may be useful to treat inflammatory immune-mediated diseases in humans.
Strain differences were investigated on the proliferative responses of splenic lymphocytes obtained from , , and mice that were treated with cadmium (Cd) for 5 days (0.5 or 1.0 mg Cd/kg/day, sc), and the results were compared with those of in vitro treatment of spleen cells with Cd. Following in vivo treatment, splenocytes from the C3H strain were significantly more susceptible to suppressive effects of Cd exposure on all indices for proliferative responses to mitogens (concanavalin A, phytohemagglutinin, and lipopolysaccharide) and allogeneic lymphocytes, while those from DBA and BALB strains were fairly resistant. Among the three strains, the highest Cd concentrations in plasma and spleen were obtained in the C3H strain with the lowest hepatic concentration of Cd. On the other hand, the Cd exposure hardly affected the splenic concentration of zinc in the C3H strain in contrast to its decrease in the others. When spleen cells obtained from normal mice were treated in vitro with Cd, the C3H strain was more resistant to the suppressive effect of Cd than the other strains. These results indicate that the mouse strain variations in Cd-mediated suppression of lymphocyte proliferation are not based on intrinsic lymphocyte sensitivities, but likely are due to differences in the metabolism of Cd, which is under genetic control.
In these studies the immunotoxicity of arsenic trioxide (ATO, As2O3) was evaluated in mice following 14 days of inhalation exposures (nose only, 3 h per day) at concentrations of 50 μg/m3 and 1 mg/m3. A biodistribution analysis performed immediately after inhalation exposures revealed highest levels of arsenic in the kidneys, bladder, liver, and lung. Spleen cell levels were comparable to those found in the blood, with the highest concentration of arsenic detected in the spleen being 150 μg/g tissue following the 1 mg/m3 exposures. No spleen cell cytotoxicity was observed at either of the two exposure levels. There were no changes in spleen cell surface marker expression for B cells, T cells, macrophages, and natural killer (NK) cells. There were also no changes detected in the B cell (LPS-stimulated) and T cell (Con A-stimulated) proliferative responses of spleen cells, and no changes were found in the NK-mediated lysis of Yac-1 target cells. The primary T-dependent antibody response was, however, found to be highly susceptible to ATO suppression. Both the 50 μg/m3 and 1 mg/m3 exposures produced greater than 70% suppression of the humoral immune response to sheep red blood cells. Thus, the primary finding of this study is that the T-dependent humoral immune response is extremely sensitive to suppression by ATO and assessment of humoral immune responses should be considered in evaluating the health effects of arsenic containing agents.
This study assessed the effects of cadmium on functional lymphopoietic precursor cells and cell size in both spleen and bone marrow. Splenic plaque-forming cell (S-PFC) precursors were stimulated by a thymus independent immunogen (TNP-LPS) and by a thymus dependent immunogen (TNP-BSA plus dextran sulfate). Bone marrow plaque-forming cell (M-PFC) precursors were stimulated by TNP-LPS plus dextran sulfate. Male C57B1/6J mice received either a single ip injection of 5.9 mg/kg CdCl2, and were sacrificed 3 days later (ip group), or 5 daily sc injections of 3.26 mg/kg CdCl2, and were sacrificed either 2 days later (7 day sc group) or 7 days later (12 day sc group). The ip group showed an increase in spleen cellularity which resulted in an enhanced S-PFC (TNP-LPS) response per spleen and compensated for a depressed S-PFC (TNP-BSA) response per 106 cells cultured. Bone marrow cellularity was not significantly decreased but the M-PFC response was drastically depressed. Similar results were obtained in the 7 day sc group. However, a significant increase in spleen cellularity was not seen, resulting in a noncompensated decrease in S-PFC (TNP-BSA) response. The S-PFC (TNP-LPS) response per 106 cells cultured was increased in this group. Responses were similar to controls in the 12 day sc group, but bone marrow cellularity was decreased. The ip and 7 day sc groups showed substantial cadmium-induced shifts in bone marrow cell size distribution profile to larger diameters. Changes in spleen cell size distribution were not as significant. Partial recovery was evident in the 12 day sc group.This study demonstrated that in vivo exposure to cadmium has a greater effect on the in vitro function of immature B-cells in the bone marrow than on more mature B-cells found in the spleen. Bone marrow toxicity should be considered in future investigations of heavy metal toxicity.
Cadmium (Cd) is an environmental pollutant. Chronic exposure of humans to Cd results in various maladies, including anemia and altered immune function. Metallothionein (MT) has been proposed to play an important role in Cd detoxication. Thus, we hypothesized that intracellular MT protects against Cd-induced hematotoxicity and immunotoxicity. Control and MT-I/II knockout (MT-null) mice were given s.c. injections of CdCl2 over a wide range of doses, 6 times/week for up to 10 weeks. Cd-induced anemia was evident after 5 weeks of exposure and progressed with time. MT-null mice were about 10 times more susceptible to Cd-induced anemia, as evidenced by decreased erythrocytes (25%), hemoglobin concentration (30%), and hematocrit (35%) after 10 weeks of Cd injections. Cd produced dose- and time-dependent increases in neutrophils (7×), along with a marked elevation of serum IL-1β (6×) and TNF-α (20×) levels. MT-null mice were more susceptible than controls to Cd-induced alterations in peripheral leukocytes and cytokine levels. Chronic exposure to Cd also produced dose- and time-dependent splenomegaly (5×), with loss of lymphoid structure, inflammation, hyperplasia, appearance of giant cells, and fibrosis. Thymus weights were decreased by Cd in a dose-dependent manner (60%). MT-null mice were also approximately 10 times more susceptible than controls to these lesions. In conclusion, the present study demonstrates that repeated injections of Cd produces hematotoxic and immunotoxic effects, and intracellular MT protects against these chronic Cd-induced effects.