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Arsenic immunotoxicity: a review

Environmental Health volume 12, Article number: 73 (2013) Cite this article

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Abstract

Exposure to arsenic (As) is a global public health problem because of its association with various cancers and numerous other pathological effects, and millions of people worldwide are exposed to As on a regular basis. Increasing lines of evidence indicate that As may adversely affect the immune system, but its specific effects on immune function are poorly understood. Therefore, we conducted a literature search of non-cancer immune-related effects associated with As exposure and summarized the known immunotoxicological effects of As in humans, animals and in vitro models. Overall, the data show that chronic exposure to As has the potential to impair vital immune responses which could lead to increased risk of infections and chronic diseases, including various cancers. Although animal and in vitro models provide some insight into potential mechanisms of the As-related immunotoxicity observed in human populations, further investigation, particularly in humans, is needed to better understand the relationship between As exposure and the development of disease.

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Background

Exposure to arsenic (As) is a global public health concern because As is widely distributed and associated with numerous adverse effects. As is a well-established cause of skin, lung and bladder cancers in humans [1], and is associated with skin lesions, diabetes, cardiovascular disease and other disorders [1–3]. Well over 100 million people worldwide are exposed to As, particularly through ingestion of contaminated food and water in countries such as India, Bangladesh, Taiwan, Chile, and the United States [1, 4]. Exposures also occur through inhalation, especially in agricultural and industrial settings [4].

Inorganic As exists in the environment as arsenite (AsIII) or arsenate (AsV) and is metabolized in humans via conversion of AsV to AsIII with subsequent methylation to mono- and di-methylated arsenicals (MMA and DMA, respectively) [5]. MMAIII is considered the most toxic arsenical in vitro[6–9] and individuals who excrete a higher proportion of ingested As as urinary MMA have increased risks of As-associated cancers [10, 11], suggesting a key role for MMA in As toxicity. Proposed mechanisms of toxicity include oxidative stress, inhibition of DNA repair, chromosomal aberrations, micronuclei formation, induction of apoptosis, modification of cellular signaling via altered activation, expression and DNA binding activity of transcription factors, epigenetic modifications resulting in aberrant gene expression, and altered phenotype of stem cell populations [12–16]. As toxicity is thus complex and multifaceted, but is not yet well understood.

Although extensive research has focused on investigating As carcinogenicity, growing evidence indicates that As also has deleterious effects on the immune system [17, 18]. This may potentially play a role in As carcinogenesis of various tissues through reduced immune surveillance. However, the specific effects of As on immune function remain poorly understood. Therefore, we considered that further investigation of As immunotoxicity is warranted and conducted a PubMed search of As exposure and non-cancer immune-related effects through October 2012. Here, we summarize the known toxicological effects of As on immune function in humans, laboratory animals and in vitro models, and identify possible future research directions to help close the gaps in knowledge.

Epidemiological findings

Effects in adults

Gene expression

Microarray-based assays are widely used for identifying differentially expressed genes in investigations of As carcinogenicity. However, a limited number of reported epidemiological studies have employed this powerful method to investigate As toxicity in immune cells from otherwise healthy persons. A microarray-based genome-wide expression study of peripheral blood mononuclear cells (PBMC) from 21 subjects in New Hampshire whose drinking-water As averaged 0.7 μg/L (range 0.007–5.3 μg/L, n = 10) and 32 μg/L (range 10.4-74.7 μg/L, n = 11) showed significant differences between exposure groups in transcripts with functions in T-cell receptor signaling, cell cycle regulation and apoptosis, and most strikingly defense and immune response [19]. Notably, higher As exposure was associated with increased expression of killer cell immunoglobulin-like receptors that inhibit natural killer cell-mediated cytotoxicity, as well as decreased expression of MHC class II molecules, HLA-DQB1, HLA-DPA1, and HLA-DRB1; defense response genes, CD69, HSPA9B and MALT1; and inflammatory genes, IL2RA and IL1B[19]. Exposure was determined by levels of drinking-water As combined with urinary or toenail As as internal markers of exposure, and control and exposed subjects were matched for age, sex and smoking status.

Down-regulated IL1B was also identified in a microarray study of PBMC from an As-exposed Bangladeshi population with (n = 11) and without skin lesions (n = 5) [20]. An overall suppression of 467/468 differentially expressed genes was observed. These findings contradict those from a microarray analysis of PBMC from 24 individuals in Taiwan with low (0–4.32 μg/L), intermediate (4.64–9 μg/L), and high (9.6–46.5 μg/L) blood As levels [21]. Among 62/708 significantly altered genes were several inflammatory molecules that were up-regulated, including IL1B, IL6, CCL2 and CD14, indicating that prolonged exposure may induce ongoing inflammation that could contribute to As-associated disease [21].

More recently, a cDNA microarray study of PBMC from 10 individuals in Mexico having urinary As levels between 117.23 and 435.12 mg/g creatinine (n = 5) revealed significant differences in expression of apoptosis- and inflammation-related genes compared to unexposed subjects (n = 5) [22]. Exposure was associated with down-regulated inflammatory genes, including TNF, IL11, IL10RB, CCR1, and CXCL2[22], which is in stark contrast with up-regulated inflammatory genes reported in chronically-exposed persons in Taiwan [21]. However, the finding of decreased TNF concurs with data from the Bangladeshi study [20]. Some apoptosis-related genes were significantly up-regulated, including BCL2L1 and CASP2, whereas others, namely TRAIL and FASLG, were suppressed [22]. Such contradictory results could be influenced by differences in exposures, sampling, methodology, population genetics and/or environmental factors. For instance, the Mexican study [22] analyzed individual RNA samples from each subject, whereas the Taiwanese study [21] used pooled samples. Additionally, the small number of participants may not be large enough to draw definitive conclusions.

One caveat is that changes in expression may not necessarily be viewed as toxic responses; some changes may occur following chemical exposure as adaptive responses, e.g. acquired resistance to acute toxicity, over time [23]. However, changes reported at the gene and/or protein level are provided to illustrate possible effects resulting from As exposure that may alter cellular function and ultimately the immune system’s ability to defend the host.

Lymphocyte activation

Impaired T-cell activation and functional responses have been observed in As-exposed persons. Analysis of 11 exposed and 13 control individuals in Mexico indicated that chronic exposure significantly decreased proliferation of mitogen-stimulated lymphocytes [24], which is supported by a later study identifying delayed cell cycle progression from S- to M-phase in chronically-exposed persons whose drinking-water levels averaged 412 μg As/L compared with persons consuming water averaging 37.2 μg As/L [25]. Similarly, a cross-sectional study in West Bengal, India of 18 controls and 20 As-exposed individuals with skin lesions found significant reductions in lymphoproliferation and Th1/Th2 secretion of IL-2, IL-4, IL-5, IL-10, IFN-γ and TNF-α in As-exposed compared with unexposed individuals [26]. In contrast, lymphocytes from Chilean copper smelter workers exposed to As-contaminated air (n = 40) displayed higher proliferation rates than those of As-unexposed individuals from the same region (n = 32) [27]. While reasons for the observed differential effects on T-cell proliferation remain unclear, it is plausible that differences in population genetics, metabolism, and/or exposure could be involved. The study also found that urinary As levels positively correlated with oxidative stress markers serum superoxide dismutase (SOD) and lymphocyte malondialdehyde (MDA), and negatively correlated with serum vitamin E levels, suggesting that chronic exposure induces lymphocyte oxidative damage [27].

Lymphocyte subpopulations

Increasing evidence indicates that As affects numerous immune cell subpopulations. Subjects exhibiting dermatological symptoms (n = 30) from exposure to > 100 μg As/L for > 10 years in Eastern India demonstrated significantly increased eosinophil numbers and decreased monocyte counts compared to unexposed persons (n = 25) [28]. As also disrupts macrophage function: monocyte-derived macrophages from As-exposed individuals with skin lesions (n = 70) demonstrated cell rounding and significantly reduced adhesion, nitric oxide anion (NO-) production and phagocytic capacity compared to macrophages from non-exposed persons (n = 64) [29]. Down-regulated F-actin and CD54 adhesion molecule, and altered Rho A-ROCK signaling likely contributed to impaired macrophage function.

Investigation of As influence on immune regulation revealed that in chronically-exposed but otherwise healthy individuals (n = 47), urinary As levels (range, 8.1 – 448 μg/g creatinine) significantly inversely correlated with the number and function of natural T regulatory (nTreg) lymphocytes but not other regulatory T-cells [30]. nTreg lymphocytes are CD25+Foxp3+ T-cells that constitute approximately 10% of circulating CD4+ T-cells and play a critical role in immune homeostasis by suppressing immune response [31]. Although increased apoptotic PBMC were evident in exposed subjects, no significant correlation was found with urinary As levels, suggesting that the effect on nTreg cells was not mediated by apoptosis induction [30]. Alternatively, this could be due to individual differences in As susceptibility. Exposure positively correlated with monocyte innate immune receptor complex TLR4/CD14 and TNF-α secretion [30], which may be causally associated with As effects on nTreg lymphocytes given their inhibitory effect on pro-inflammatory TNF-α release [32]. These results concur with previous findings that chronic human As exposure induces inflammation, including CD14[21].

Humoral immunity

Studies evaluating antibody levels in As-exposed individuals yield conflicting results. One study observed no changes in serum IgM, IgA or IgG in 47 adult male workers exposed to As in a coal-burning power plant compared to 27 workers from another plant in the same district whose As coal content was > 10 times lower [33]. It should be noted that exposure duration and internal As doses are unknown; thus, negative results could be due to acute or low-dose internal As levels. In contrast, Bangladeshi subjects (n = 125) chronically exposed to drinking-water As demonstrated significantly elevated serum IgA, IgG and IgE compared to unexposed persons [34]. IgG and IgE levels were significantly higher during initial stages of skin manifestations, and IgE continued to increase with prolonged exposure. Moreover, increased prevalence of respiratory complications including cough, chest sound, bronchitis and asthma were evident in exposed individuals, and mean serum IgE was higher in subjects with respiratory symptoms relative to exposed subjects without [34]. No effect on eosinophils was observed [34], in contrast with a reported As-associated increase in eosinophil numbers [28], suggesting that increased serum IgE may be due to direct inflammatory effects of As rather than allergic disease [34].

Pulmonary effects

Health outcomes of As immunosuppression are evidenced by increased prevalence of opportunistic infections such as tuberculosis and fungal and respiratory tract infections (RTI) [26, 29, 35]. A recent report from Chile revealed increased mortality from As-associated pulmonary tuberculosis [35]. Reports of As-associated pulmonary effects [26, 29, 34–36] support growing evidence indicating that long-term exposure increases risk of reduced lung function and non-malignant lung disease [36–41]. Moreover, epidemiological investigations provide compelling evidence that As increases the incidence of bronchiectasis [42, 43], a pulmonary disease characterized by chronic infection, inflammation, irreversible bronchial damage, and respiratory failure [44, 45]. Chronically-exposed subjects from West Bengal, India with As-related skin lesions (n = 108) demonstrated a 10-fold higher prevalence of bronchiectasis compared with subjects without lesions (n = 150) [42]. A later report from Chile indicated elevated mortality rates for bronchiectasis in adults aged 30–49 resulting from early-life As exposure; compared with controls, mortality rates for those with childhood and in utero exposure were 12- and 46-fold higher, respectively [43]. Also observed were 6- to 7-fold increases in lung cancer mortality rates resulting from early-life exposures. Studies on this As-exposed Chilean population indicate long latency patterns of increased lung, kidney and bladder cancer mortality continuing for > 25 years after exposures ended [46, 47]. Overall, these reports indicate that As not only exerts severe respiratory effects, but that early-life exposures have pronounced long-term consequences that may include higher prevalence of and mortality from cancers of different tissues. Intriguingly, women appear to be somewhat protected from skin and respiratory manifestations [36, 48], possibly due to sex hormone-related increased methylation capacity of As in women than in men [49].

HBD1 involvement

Interestingly, we previously reported in two As-exposed populations from Nevada and Chile a significant inverse correlation in men between urinary levels of As and antimicrobial peptide human β-defensin-1 (HBD1) [50]. Studies suggest a primary role for HBD1 against pulmonary pathogens relevant to bronchiectasis [44, 45] and an association between HBD1 antimicrobial inactivation and recurrent airway infections in cystic fibrosis patients [51, 52]. Further, observations from transgenic mice deficient in the mouse ortholog of HBD1 indicate that β-defensin-1 serves as an initial barrier to pulmonary bacterial colonization [53]. Given growing evidence that DEFB1, the gene encoding HBD1, is a putative tumor suppressor whose down-regulation may be involved in tumorigenesis of multiple tissues [54–62], it is tempting to speculate that HBD1 suppression may contribute to As-induced carcinogenesis or bronchiectasis. Although our ongoing studies demonstrate As-induced reductions in DEFB1 mRNA and protein in human cell lines (unpublished data), confirmatory evidence of HBD1 inhibition is needed from other As-exposed populations. Thus, it remains to be determined whether HBD1 is suppressed in lungs of As-exposed individuals, and further investigations are needed to elucidate the role of down-regulated HBD1 in As immunotoxicity and carcinogenicity.

Effects in children and infants

The fetus, infant and young child, each at critical stages in development, are particularly sensitive to stressors that could have short- and long-term effects. Yet, few epidemiological studies have investigated the influence of early-life As exposure on immunological outcomes in children and even fewer in newborns and infants. Evidence indicates that early-life As exposure may have consequences that manifest much later in adulthood [18, 63], as evidenced by increased prevalence of and mortality from bronchiectasis and lung cancer in young adults [43]. Therefore, biomarkers indicative of future disease following early-life exposure could be evident in young subjects.

Induction of apoptosis

Indeed, studies of early-life As exposure have detected markers of immune dysfunction in infants and children. Studies of Mexican children aged 4–13 have reported higher incidences of apoptotic PBMC in As-exposed children relative to controls [64, 65]. Although apoptosis is important in immune homeostasis, abnormal immune cell apoptosis can contribute to dysregulated immune function, which may result in immunodeficiency, autoimmune disease or malignant transformation [66]; thus, induced apoptosis may be important in As-mediated immunosuppression. The larger study of 40 children (high and low mean urinary As levels = 46.3 and 14.2 μg/g creatinine, respectively) found a significant positive association between As exposure and apoptotic PBMC [65]. However, despite elevated apoptotic PBMC in chronically-exposed children from the smaller study of 7 highly-exposed and 5 non-exposed children (mean urinary As levels = 143.9 and 24.8 μg/g creatinine, respectively), no significant correlation was observed between exposure and apoptotic cells [64], in agreement with a study on adults [30], possibly due to small sample size or individual differences in As susceptibility [64].

Lymphocyte activation

Consistent with findings from adults [24–26], significant reductions in PBMC IL-2 secretion and proliferation were observed in As-exposed children aged 6–10 (n = 90, mean urinary As levels of high- and low-exposure group = 194.9 and 29.3 μg/L, respectively) [67]. Also noteworthy were increased granulocyte-macrophage colony stimulating factor (GM-CSF) secretion and reduced CD4+ cell count and CD4/CD8 ratio without altered CD8+ cell proportion [67]. Because low CD4/CD8 is considered a surrogate marker of immunosuppression [68–70], the observed decrease in CD4/CD8 may be an early indicator of As-mediated immunosuppression. Furthermore, the increased GM-CSF secretion may indicate chronic inflammation given growing evidence of elevated GM-CSF levels in initiating/mediating chronic inflammation [71], and is consistent with a previous study of As-exposed adults demonstrating up-regulated inflammatory molecules [21].

ROS production

Production of the reactive oxygen species (ROS) NO- and superoxide anion (O2 -) by activated PBMC is an important innate immune response to destroy invading microbes. Cross-sectional studies assessing As influence on ROS production in children have yielded conflicting results. Analysis of 87 children in Mexico ingesting As-contaminated water showed that exposure positively associated with O2 - production by mitogen-stimulated monocytes and basal NO- and O2 - levels in PBMC and monocytes [72]. This is inconsistent with an earlier study of 65 children living near a primary smelter in Mexico in which As exposure was negatively associated with NO- and O2 - production by stimulated monocytes [73]. The discrepancy may be due to differences in exposure; children in the earlier study had lower urinary As levels (range 16.7-465.7 μg/g creatinine) [73] than those in the more recent study (range 12.3-1411 μg/g creatinine) [72]. Regardless of the source of variation in results, these studies suggest that As could alter circulating cells’ ability to respond to immunological challenge. For example, elevated ROS levels in un-stimulated PBMC indicate As-induced oxidative stress, concurrent with findings from copper smelter workers [27]; ROS overproduction by activated PBMC could cause oxidative damage to surrounding tissues, whereas diminished ROS production could weaken PBMC defense against pathogens.

Prenatal exposure

Because As readily crosses the placenta [74], it could potentially alter prenatal development. Indeed, gestational As exposure is linked to increased fetal loss and infant mortality [75, 76]. However, reports on immune-related effects of prenatal exposure in newborns and infants are scarce. In a mother-child cohort study in Bangladesh (n = 140), maternal urinary As levels were significantly negatively correlated with child thymic index and breast milk trophic factors IL-7 (needed for thymic and T-cell development) and lactoferrin (an antioxidant and factor in innate immunity), and positively correlated with maternal morbidity and male infant RTI [77]. These findings are supported by a more recent prospective population-based cohort study of 1,552 infants born in Bangladesh, which revealed dose-dependent increases of 69% and 20% in infant lower RTI and diarrhea, respectively, related to exposure during pregnancy (maternal urinary As levels, lowest quintile < 39 μg/L; highest quintile = 262–977 μg/L) [78]. The observed increased prevalence of infant respiratory illness is consistent with As-associated adult non-malignant lung disease [35, 42] and marked increased risk of such disease following early-life exposures [43]. Moreover, enhanced male infant susceptibility to RTI is consistent with increased As-related pulmonary effects in men and not in women [36].

Another study of women delivering babies in Bangladesh (n = 130) found that gestational As exposure induced placental inflammation (IL-1β, TNF-α and IFN-γ) via oxidative stress (8-oxoguanine), reduced placental CD3+ T-cell numbers, and increased umbilical cord blood IL-8, IL-1β, TNF-α and IFN-γ [79]. These findings concur with reports of elevated oxidative stress [27] and inflammation [21] in chronically-exposed adults. In a follow-up study (n = 44), As levels in maternal urine and placental and cord blood positively associated with cord blood 8-hydroxy-2'-deoxyguanosine and inversely associated with infant thymic function at birth, as measured by signal-joint T-cell receptor-rearrangement excision circles in cord blood mononuclear cells (CBMC) [80]. Further, prenatal As exposure was associated with down-regulated oxidative-stress defense genes, including SOD3, and up-regulated apoptosis-related genes in CBMC, including CASP2[80], the latter consistent with results from adults [22].

Overall, these data indicate that in utero As exposure reduces infant thymic size and function, likely through inhibiting breast milk trophic factors and/or inducing apoptosis and oxidative stress. These effects may contribute to infant immune deficiency evidenced by increased RTI prevalence. Lack of data supporting a relationship between early-life As exposure and non-pulmonary infections suggests that the developing lung is specifically targeted by As. Furthermore, given increasing evidence of As-associated adverse immune-related outcomes, it is likely that immune disruption resulting from early-life As exposure will have long-term detrimental consequences well into adulthood, as seen in increased prevalence of bronchiectasis and lung, kidney and bladder cancers.

Experimental animal studies

Gene expression

Gene expression

In various animal models, As exposure is associated with altered expression of genes involved in immune response. In lungs of mice exposed to AsIII (< 100 ppb) for 5–6 weeks, significant changes were identified in transcripts encoding humoral immune response, antigen binding, TLRs, cytokines, cytokine receptors and genes involved in cell adhesion and migration [81, 82]. Specifically, down-regulated expression of genes encoding TLR/IL1R signaling pathway, including Il1b, was identified [82]. In zebrafish embryos, As significantly inhibited induction of genes involved in regulating innate immune responses against viral and bacterial infection, including il1b[83], tnfa, ifnphi1 (type1 interferon) and mx (interferon-inducible Mx) [84, 85]. As also disrupted JAK/STAT pathway, which is critical in cytokine regulation [84]. These effects concur with epidemiological findings of As-associated decreased expression of IL1B[19, 20] and TNF[22].

Lymphocyte subpopulations

Studies in rats [86–88], mice [89], catfish [90] and chickens [91] show that As can suppress the weight, index and/or cellularity of major immunocompetent organs, including spleen and thymus. In chronically-exposed mice, reduced CD4+ T-cell populations and CD4/CD8 ratio were evident, concurrent with observations in As-exposed children [67], as well as increased percentage of monocytes in splenic mononuclear cells (SMC) [92]. In catfish, As increased atypical lymphocytes and depleted lymphoid and melano-macrophage populations in head kidney (HK), a major immunocompetent organ [90, 93]. Interestingly, a single intra-tracheal exposure of mice to 200 mg/kg gallium arsenide (GaAs) markedly decreased peritoneal lymphocyte counts [94] and splenic T-cell, B-cell and macrophage numbers by 58, 61 and 30%, respectively, without affecting their proportions [89].

Lymphocyte activation

Consistent with epidemiological observations [24–26, 67], chronic As exposure inhibits mitogen-stimulated proliferation of PBMC and SMC in broiler chickens [91] and SMC in mice [92], and T-cell and B-cell proliferation in catfish spleen and HK [90, 93]. Consequently, decreases have been observed in secretion of IFN-γ, IL-2, IL-6 and IL-12 in mice [92], and “IL-4-like factors” from HK T-cells in catfish [93]. An important consideration regarding animal studies is that As concentrations administered typically far exceed human exposures, which may account for differential effects observed.

Humoral and hypersensitivity responses

As can inhibit humoral immunity, as evidenced by suppressed in vitro primary and/or secondary antibody-forming cell (AFC) responses of rodent splenocytes [87, 89, 94–97]. IL-2 is a primary target of this inhibition in mice [98]. Further, As suppressed delayed-type hypersensitivity reaction, a response to cutaneous sensitization, in mice [94, 99], rats [88, 100] and chickens [91]. Compared to controls, AsIII-exposed sensitized mice demonstrated reduced lymph node cell proliferation, ear swelling, activated Langerhans cells (LC) in cervical lymph nodes, peritoneal macrophages and circulating neutrophils [99], suggesting that As inhibits LC migration to lymph nodes and subsequent T-cell activation.

Macrophages

Similar to humans [29], As exposure in animals suppresses macrophage production of NO- and/or O2 -[91, 101–103], release of TNF-α [104], and phagocytosis [90, 102, 103]. In chronically-exposed animals, such effects may be long-term. Exposure of freshwater bivalve L. marginalis to AsIII (1–5 ppm) for < 30 days resulted in time- and dose-dependent decreases in phagocytic efficiency and NO- production in haemocytes, the major phagocytes and immune-effector cells in bivalves [102]. In a recovery assay, animals were maintained in As-free water for the same duration as exposure to evaluate immune efficiency. They demonstrated partial recovery of phagocytic potential, but inhibitory effects were still apparent; whereas NO- production was restored to control levels in animals exposed to 1 ppm AsIII for < 4 days, NO- generation remained suppressed in high-dose- and long-term-exposed animals [102]. As can also induce apoptosis in macrophages, as seen in 3-fold increased DNA fragmentation in splenic macrophages from AsIII-exposed mice [103]. Further, splenic macrophages from As-treated mice demonstrated reduced adhesion and chemotactic index [105], surface I-Ak (MHC) class II molecule expression and antigen presentation to T-cells [106]. Similar observations have been made in humans [19, 29], thus giving these results biological plausibility.

Immune surveillance

Altogether, these data indicate that in vivo As exposure can disrupt innate and humoral immunity. Studies of As influence on allogeneic immune response, i.e. rejection of MHC-mismatched allografts, suggest As disrupts the immune system’s ability to distinguish “self” from “non-self” [107, 108]. In a mouse heart transplantation model, arsenic trioxide (As2O3) significantly reduced allograft rejection relative to control [107]. Similarly, As2O3 radically reduced severe symptoms of graft-versus-host disease in mice following allogeneic hematopoietic stem cell transplantation [108]. Together with reported decreased macrophage I-Ak class II expression and antigen presentation [106], these findings provide potential mechanisms whereby As can suppress the immune system’s ability to discriminate self from non-self antigens.

Investigation of As influence on immune system regulation revealed redistributed nTreg lymphocytes following 3-week AsIII exposure in a rat model of multiple sclerosis, an autoimmune disease characterized by decreased nTreg cell number and function [30]. Whereas low AsIII doses increased nTreg cell number in spleen and alleviated severity of the autoimmune condition, concentrations > 100 μg/L reduced cell numbers in blood and spleen, consistent with epidemiological findings from that study [30]. Evidently, low-dose As-mediated increased number of splenic nTreg lymphocytes inhibited generation of (auto-) immune responses, hence the beneficial effect of immunosuppression by low-dose As. Thus, two possible scenarios whereby As can interfere with self/non-self recognition exist: by i) preventing immune surveillance from recognizing “non-self” from “self”, leading to increased non-self antigen survival, as in allograft transplantation; or ii) inhibiting recognition of self antigens as “self”, which could arise from As-induced reduction of nTreg cell inhibitory activity, leading to “anti-self” antibody production indicative of autoimmune disease. Such effects would likely render the host immunocompromised and could have detrimental health consequences.

Several models indicate that As compromises the immune system’s ability to rid the host of pathogens and tumors. As-exposed mice demonstrating depressed humoral and cellular immunity displayed significantly impaired resistance against B16F10 melanoma, which resulted in 7-fold increased tumor burden [94]. AsIII-exposed zebrafish embryos and larvae exhibited significant 57- to 80-fold increased viral titers and 17- to 19-fold increased bacterial loads [85], and decreased ROS production [84, 85]. Exposure-challenge studies in catfish revealed efficient pathogen colonization in distant tissues [93] and increased ulcer and septicemia susceptibility following A. hydrophilia infection [90]. Investigations in mice yield conflicting results on As influence on clearance of infection. Whereas As delayed splenic clearance of S. aureus in one study [105], in another As apparently enhanced resistance to G. muris gastrointestinal infection [109]. While reasons for these inconsistencies are unclear, it should be noted that As inhibited splenic macrophage adhesion and chemotaxis by > 50% in the earlier study [105], which could explain increased bacterial survival. However, the later study did not examine other immune functional parameters [109]; thus, it stands to reason that As concentrations used were insufficient to achieve immunosuppressive effects.

Chronic low-dose AsIII (< 100 ppb) exposure of mice aggravated H1N1 influenza A infection severity, increasing morbidity and respiratory viral titers [110]. Early in the infection, As suppressed lymphocyte, macrophage and neutrophil migration to lungs and dendritic cell (DC) recruitment to lymph nodes, and inhibited production of 9/10 cytokines, including TNF-α and IL-1β [110], concurrent with down-regulated cytokines and adhesion- and migration-related genes in lungs of uninfected As-exposed mice [81, 82]. As depressed DC migration in in vitro assays of bone marrow-derived DC from uninfected As-exposed relative to unexposed mice [110]. Similarly, As2O3 reduced DC density, T helper 17 (Th17) cells, which play a major role in defense against infections, and levels of the major pro-inflammatory cytokine IL-17 in airways of asthmatic mice [111, 112]. Although cell counts and cytokine levels in lungs of As-exposed mice were similar to or higher than those of controls by day 7 post-infection [110], these results show that prolonged As exposure can impair immune responses against infection, and suggest that impaired response to repeated infections could promote chronic human diseases such as bronchiectasis.

In vitro studies

In vitro studies

Lymphocyte activation

In vitro As exposure suppressed IL-2 secretion and proliferation of mitogen-stimulated lymphocytes from humans and various animal species [113–118]. A biphasic dose-dependent response was observed following AsIII or AsV exposure of mitogen-stimulated human and bovine PBMC [119], demonstrating As immunosuppressive effects depend on the dose. As markedly suppressed lymphocyte secretion and/or mRNA levels of IFN-γ, IL-4 and IL-10 in different in vitro models [114, 116, 117]. AsIII also significantly impaired differentiation of human Th17 cells by repressing their expression and release of IL-17 and decreasing expression of RORγt, which regulates IL-17, through inactivation of JNK/c-Jun pathway [120]. AsIII further impaired Th17 cells by disrupting functions of DC, which regulate Th17 cell differentiation, via i) blocking DC differentiation through induced necrosis; ii) decreasing DC endocytotic activity; iii) repressing secretion of IL-12p70 and IL-23, two major regulators of Th17 activities, by activated DC; and iv) reducing ability of activated DC to stimulate IFN-γ and IL-17 release from Th17 cells [121].

In contrast with reduced CD4+ and unaltered CD8+ T-cell populations in children [67] and mice [92], in vitro AsIII treatment of mitogen-stimulated mouse T-lymphocytes decreased CD8+ counts without affecting CD4+ counts [115]. Additionally, AsIII inhibited early activation of mouse CD4+ and CD8+ cells, as evidenced by reduced surface CD69 expression [115], an effect that was reported at the protein level in in vitro As-exposed human CD4+ and CD8+ lymphocytes [122] and also at the mRNA level in lymphocytes of As-exposed humans [19].

Induction of apoptosis and humoral immunity

As immunosuppressive effects are further demonstrated in vitro by increased apoptotic rates in B-cells, T-cells, macrophages and neutrophils [64, 123–127]. Prior to inducing apoptosis in TA3 mouse antigen-presenting B-cells, AsIII inhibited activity of lysosomal protease cathepsin L, which is important in antigen processing/presentation to elicit T-cell responses [125]. This could possibly potentiate As-induced suppression of humoral immunity, for in vitro As exposure inhibits AFC responses of mouse splenocytes [128, 129], consistent with animal studies.

Macrophages

As exposure disrupts monocyte/macrophage survival, development and function in vitro. As2O3-exposed human blood monocytes and U937 promonocytic cells underwent marked apoptosis during macrophagic differentiation, an important event in immune response, likely through inhibition of NF-κB-related survival pathways [126]. Further, As inhibited differentiation of human monocytes into macrophages, reversed macrophage-specific features, and impaired endocytosis/phagocytosis, essentially leading to macrophagic “de-differentiation” [130–134]. Interestingly, As2O3 enhanced LPS-induced macrophage TNF-α and IL-8 mRNA and secretion [130], suggesting As toxicity toward macrophages is complex, and supporting epidemiological findings of As-associated inflammation [21]. Altogether, these data support epidemiological evidence of disrupted macrophage function [29] and impaired phagocytosis/antimicrobial responses by macrophages of As-exposed mice [105].

Pulmonary effects

Proposed mechanisms for As-associated compromised respiratory immunity include impaired pulmonary alveolar macrophage (PAM) function, demonstrated by markedly reduced LPS-stimulated TNF-α and O2 - production [104], and decreased airway epithelial (AE) chloride secretion cystic fibrosis transmembrane conductance regulator (CFTR), an essential chloride channel for mucociliary clearance of pathogens, as seen in human CFBE41o- AE cells [135] and killifish gills [136]. In human 16HBE14o- AE cells, As restricted wound response, i.e. monolayer reformation following scraping of cultures, through MMP9 up-regulation [137] and inhibition of paracrine Ca2+ signaling [138], consistent with down-regulated adhesion- and migration-related genes in lungs of mice [81, 82] and altered airway proteins in mice and humans [139–141]. Collectively, these data suggest As disrupts pulmonary defense through mechanisms involving i) altered PAM function, ii) decreased AE chloride secretion resulting in depressed clearance of pathogens, and iii) AE remodeling due to impaired wound response, ultimately promoting chronic lung diseases such as bronchiectasis.

Discussion

Studies reviewed here show that As significantly impacts both innate and adaptive immune defenses. Likely mechanisms involve altered expression of key immune regulators, induced apoptosis, oxidative stress and inflammation in circulating PBMC, impaired lymphocyte activation and macrophage function, and altered cellular and humoral immunity (Table 1). Specific examples of concordance between epidemiological and experimental data are i) reduced expression of MHC class II molecules, CD69, IL-1β and TNF-α; ii) altered expression of airway adhesion- and migration-related genes/proteins; iii) decreased stimulated lymphocyte proliferation and IL-2 secretion; iv) impaired macrophage adhesion, phagocytosis and stimulated ROS production involving altered Rho A-ROCK signaling; v) induced apoptosis of PBMC; and vi) decreased stimulated ROS production by PBMC (Table 1). These effects can result in immunosuppression, as evidenced by reduced microbial clearance in animals and increased prevalence of opportunistic infections in humans, particularly RTI. Furthermore, epidemiological data suggest marked susceptibility of the lung to perturbation by As, especially during prenatal and childhood development, which results in unprecedented rates of chronic lung diseases, notably lung cancer and bronchiectasis. Experimental data suggest that such pulmonary effects could involve disrupted PAM function and airway remodeling resulting in impaired clearance of pulmonary pathogens. The pleiotropic effects of As on the immune system, including specific examples of compromised immune surveillance such as decreased rejection of MHC mismatched allografts and reduced migration of PBMC, neutrophils and DC to sites of infection in various animal models (Table 2), lend biological plausibility to increased rates of infection, cancers and other immune-related illnesses observed in As-exposed human populations, and are illustrated in Figure 1.

Table 1 Major findings of As-associated immune-related effects that are consistent across multiple studies
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Table 2 Summary of specific observations of As-associated immune-related effects
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Figure 1
figure1

Simplified scheme of select As-induced alterations of immune responses. Also illustrated is how such effects might contribute to development of As-associated illnesses. Antigen (Ag) can be foreign or tumor cell.

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Conclusions

In vivo and in vitro studies depict As as an immunomodulator that could render the host immunocompromised. Such immune alterations could help explain increased risk of infections and several cancers observed in chronically-exposed human populations. As-mediated alterations of cellular and humoral immunity reported in animal and in vitro models generally agree with immunological outcomes in humans. However, more work is needed to close the gap between experimental data and risk of human immunotoxicity. Moreover, inconsistencies in epidemiological findings, possibly due to differences in dose, sampling, genetic background, and environmental/nutritional factors, indicate need for larger participant numbers and diverse ethnic populations. Due to differential effects of exposures, populations having low, intermediate and high exposure should be evaluated to better understand dose-dependent relationships. Furthermore, strong evidence for an association between developmental As exposure and elevated risk of human disease necessitates more investigations of early-life exposure outcomes. Finally, comprehensive genomic, proteomic and metabolomic profiling will be critical for identifying and validating potential molecular targets of As to monitor progression of As-associated diseases and elucidate mechanisms of As immunotoxicity.

Abbreviations

AE:

Airway epithelial

AFC:

Antibody-forming cell

As:

Arsenic

AsIII:

Arsenite

AsV:

Arsenate

As2O3:

Arsenic trioxide

CBMC:

Cord blood mononuclear cells

CFTR:

Cystic fibrosis transmembrane conductance regulator

DC:

Dendritic cells

GaAs:

Gallium arsenide

GM-CSF:

Granulocyte-macrophage colony stimulating factor

HBD1:

Human β-defensin-1

HK:

Head kidney

LC:

Langerhans cells

MDA:

Malondialdehyde

nTreg:

Natural T regulatory

NO-:

Nitric oxide anion

O2-:

Superoxide anion

PAM:

Pulmonary alveolar macrophages

PBMC:

Peripheral blood mononuclear cells

ROS:

Reactive oxygen species

RTI:

Respiratory tract infections

SMC:

Splenic mononuclear cells

SOD:

Superoxide dismutase.

References

  1. 1.

    IARC: A Review of Human Carcinogens: Arsenic, Metals, Fibres, and Dusts vol. 100C. 2012, Geneva, Switzerland: World Health Organization

  2. 2.

    Liu J, Waalkes MP: Liver is a target of arsenic carcinogenesis. Toxicol Sci. 2008, 105: 24-32. 10.1093/toxsci/kfn120.

  3. 3.

    Hughes MF, Beck BD, Chen Y, Lewis AS, Thomas DJ: Arsenic exposure and toxicology: a historical perspective. Toxicol Sci. 2011, 123: 305-332. 10.1093/toxsci/kfr184.

  4. 4.

    Nordstrom DK: Public health. Worldwide occurrences of arsenic in ground water. Science. 2002, 296: 2143-2145.

  5. 5.

    Drobna Z, Naranmandura H, Kubachka KM, Edwards BC, Herbin-Davis K, Styblo M, Le XC, Creed JT, Maeda N, Hughes MF, Thomas DJ: Disruption of the arsenic (+3 oxidation state) methyltransferase gene in the mouse alters the phenotype for methylation of arsenic and affects distribution and retention of orally administered arsenate. Chem Res Toxicol. 2009, 22: 1713-1720. 10.1021/tx900179r.

  6. 6.

    Mass MJ, Tennant A, Roop BC, Cullen WR, Styblo M, Thomas DJ, Kligerman AD: Methylated trivalent arsenic species are genotoxic. Chem Res Toxicol. 2001, 14: 355-361. 10.1021/tx000251l.

  7. 7.

    Petrick JS, Ayala-Fierro F, Cullen WR, Carter DE, Vasken Aposhian H: Monomethylarsonous acid (MMA(III)) is more toxic than arsenite in Chang human hepatocytes. Toxicol Appl Pharmacol. 2000, 163: 203-207. 10.1006/taap.1999.8872.

  8. 8.

    Petrick JS, Jagadish B, Mash EA, Aposhian HV: Monomethylarsonous acid (MMA(III)) and arsenite: LD(50) in hamsters and in vitro inhibition of pyruvate dehydrogenase. Chem Res Toxicol. 2001, 14: 651-656. 10.1021/tx000264z.

  9. 9.

    Styblo M, Del Razo LM, Vega L, Germolec DR, LeCluyse EL, Hamilton GA, Reed W, Wang C, Cullen WR, Thomas DJ: Comparative toxicity of trivalent and pentavalent inorganic and methylated arsenicals in rat and human cells. Arch Toxicol. 2000, 74: 289-299. 10.1007/s002040000134.

  10. 10.

    Chen YC, Guo YL, Su HJ, Hsueh YM, Smith TJ, Ryan LM, Lee MS, Chao SC, Lee JY, Christiani DC: Arsenic methylation and skin cancer risk in southwestern Taiwan. J Occup Environ Med. 2003, 45: 241-248. 10.1097/01.jom.0000058336.05741.e8.

  11. 11.

    Steinmaus C, Bates MN, Yuan Y, Kalman D, Atallah R, Rey OA, Biggs ML, Hopenhayn C, Moore LE, Hoang BK, Smith AH: Arsenic methylation and bladder cancer risk in case–control studies in Argentina and the United States. J Occup Environ Med. 2006, 48: 478-488. 10.1097/01.jom.0000200982.28276.70.

  12. 12.

    Flora SJ: Arsenic-induced oxidative stress and its reversibility. Free Radic Biol Med. 2011, 51: 257-281. 10.1016/j.freeradbiomed.2011.04.008.

  13. 13.

    IARC: Some drinking-water disinfectants and contaminants, including arsenic. IARC Monogr Eval Carcinog Risks Hum, vol. 84. 2004, Geneva, Switzerland: World Health Organization, 1-477.

  14. 14.

    NRC: Arsenic in Drinking Water: 2001 Update. 2001, Washington, D C: National Academy Press

  15. 15.

    Reichard JF, Schnekenburger M, Puga A: Long term low-dose arsenic exposure induces loss of DNA methylation. Biochem Biophys Res Commun. 2007, 352: 188-192. 10.1016/j.bbrc.2006.11.001.

  16. 16.

    Tokar EJ, Qu W, Waalkes MP: Arsenic, stem cells, and the developmental basis of adult cancer. Toxicol Sci. 2011, 120 (Suppl 1): S192-203.

  17. 17.

    Selgrade MK: Immunotoxicity: the risk is real. Toxicol Sci. 2007, 100: 328-332. 10.1093/toxsci/kfm244.

  18. 18.

    Vahter M: Health effects of early life exposure to arsenic. Basic Clin Pharmacol Toxicol. 2008, 102: 204-211. 10.1111/j.1742-7843.2007.00168.x.

  19. 19.

    Andrew AS, Jewell DA, Mason RA, Whitfield ML, Moore JH, Karagas MR: Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008, 116: 524-531. 10.1289/ehp.10861.

  20. 20.

    Argos M, Kibriya MG, Parvez F, Jasmine F, Rakibuz-Zaman M, Ahsan H: Gene expression profiles in peripheral lymphocytes by arsenic exposure and skin lesion status in a Bangladeshi population. Cancer Epidemiol Biomarkers Prev. 2006, 15: 1367-1375. 10.1158/1055-9965.EPI-06-0106.

  21. 21.

    Wu MM, Chiou HY, Ho IC, Chen CJ, Lee TC: Gene expression of inflammatory molecules in circulating lymphocytes from arsenic-exposed human subjects. Environ Health Perspect. 2003, 111: 1429-1438. 10.1289/ehp.6396.

  22. 22.

    Salgado-Bustamante M, Ortiz-Perez MD, Calderon-Aranda E, Estrada-Capetillo L, Nino-Moreno P, Gonzalez-Amaro R, Portales-Perez D: Pattern of expression of apoptosis and inflammatory genes in humans exposed to arsenic and/or fluoride. Sci Total Environ. 2010, 408: 760-767. 10.1016/j.scitotenv.2009.11.016.

  23. 23.

    Tokar EJ, Qu W, Liu J, Liu W, Webber MM, Phang JM, Waalkes MP: Arsenic-specific stem cell selection during malignant transformation. J Natl Cancer Inst. 2010, 102: 638-649. 10.1093/jnci/djq093.

  24. 24.

    Ostrosky-Wegman P, Gonsebatt ME, Montero R, Vega L, Barba H, Espinosa J, Palao A, Cortinas C, Garcia-Vargas G, Del Razo LM, Cebrian M: Lymphocyte proliferation kinetics and genotoxic findings in a pilot study on individuals chronically exposed to arsenic in Mexico. Mutat Res. 1991, 250: 477-482. 10.1016/0027-5107(91)90204-2.

  25. 25.

    Gonsebatt ME, Vega L, Montero R, Garcia-Vargas G, Del Razo LM, Albores A, Cebrian ME, Ostrosky-Wegman P: Lymphocyte replicating ability in individuals exposed to arsenic via drinking water. Mutat Res. 1994, 313: 293-299. 10.1016/0165-1161(94)90059-0.

  26. 26.

    Biswas R, Ghosh P, Banerjee N, Das JK, Sau T, Banerjee A, Roy S, Ganguly S, Chatterjee M, Mukherjee A, Giri AK: Analysis of T-cell proliferation and cytokine secretion in the individuals exposed to arsenic. Hum Exp Toxicol. 2008, 27: 381-386. 10.1177/0960327108094607.

  27. 27.

    Escobar J, Varela-Nallar L, Coddou C, Nelson P, Maisey K, Valdes D, Aspee A, Espinosa V, Rozas C, Montoya M, Mandiola C, Rodríguez FE, Acuña-Castillo C, Escobar A, Fernández R, Diaz H, Sandoval M, Imarai M, Rios M: Oxidative damage in lymphocytes of copper smelter workers correlated to higher levels of excreted arsenic. Mediators Inflamm. 2010, 2010: 403830-

  28. 28.

    Maiti S, Chattopadhyay S, Deb B, Samanta T, Maji G, Pan B, Ghosh A, Ghosh D: Antioxidant and metabolic impairment result in DNA damage in arsenic-exposed individuals with severe dermatological manifestations in Eastern India. Environ Toxicol. 2012, 27: 342-350. 10.1002/tox.20647.

  29. 29.

    Banerjee N, Banerjee S, Sen R, Bandyopadhyay A, Sarma N, Majumder P, Das JK, Chatterjee M, Kabir SN, Giri AK: Chronic arsenic exposure impairs macrophage functions in the exposed individuals. J Clin Immunol. 2009, 29: 582-594. 10.1007/s10875-009-9304-x.

  30. 30.

    Hernandez-Castro B, Doniz-Padilla LM, Salgado-Bustamante M, Rocha D, Ortiz-Perez MD, Jimenez-Capdeville ME, Portales-Perez DP, Quintanar-Stephano A, Gonzalez-Amaro R: Effect of arsenic on regulatory T cells. J Clin Immunol. 2009, 29: 461-469. 10.1007/s10875-009-9280-1.

  31. 31.

    Miyara M, Sakaguchi S: Natural regulatory T cells: mechanisms of suppression. Trends Mol Med. 2007, 13: 108-116. 10.1016/j.molmed.2007.01.003.

  32. 32.

    Ehrenstein MR, Evans JG, Singh A, Moore S, Warnes G, Isenberg DA, Mauri C: Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFalpha therapy. J Exp Med. 2004, 200: 277-285. 10.1084/jem.20040165.

  33. 33.

    Bencko V, Wagner V, Wagnerova M, Batora J: Immunological profiles in workers of a power plant burning coal rich in arsenic content. J Hyg Epidemiol Microbiol Immunol. 1988, 32: 137-146.

  34. 34.

    Islam LN, Nabi AH, Rahman MM, Zahid MS: Association of respiratory complications and elevated serum immunoglobulins with drinking water arsenic toxicity in human. J Environ Sci Health A Tox Hazard Subst Environ Eng. 2007, 42: 1807-1814. 10.1080/10934520701566777.

  35. 35.

    Smith AH, Marshall G, Yuan Y, Liaw J, Ferreccio C, Steinmaus C: Evidence from Chile that arsenic in drinking water may increase mortality from pulmonary tuberculosis. Am J Epidemiol. 2011, 173: 414-420. 10.1093/aje/kwq383.

  36. 36.

    Von Ehrenstein OS, Mazumder DN, Yuan Y, Samanta S, Balmes J, Sil A, Ghosh N, Hira-Smith M, Haque R, Purushothamam R, Lahiri S, Das S, Smith AH: Decrements in lung function related to arsenic in drinking water in West Bengal, India. Am J Epidemiol. 2005, 162: 533-541. 10.1093/aje/kwi236.

  37. 37.

    Tsai SM, Wang TN, Ko YC: Mortality for certain diseases in areas with high levels of arsenic in drinking water. Arch Environ Health. 1999, 54: 186-193. 10.1080/00039899909602258.

  38. 38.

    De BK, Majumdar D, Sen S, Guru S, Kundu S: Pulmonary involvement in chronic arsenic poisoning from drinking contaminated ground-water. J Assoc Physicians India. 2004, 52: 395-400.

  39. 39.

    Mazumder DN, Haque R, Ghosh N, De BK, Santra A, Chakraborti D, Smith AH: Arsenic in drinking water and the prevalence of respiratory effects in West Bengal, India. Int J Epidemiol. 2000, 29: 1047-1052. 10.1093/ije/29.6.1047.

  40. 40.

    Milton AH, Rahman M: Respiratory effects and arsenic contaminated well water in Bangladesh. Int J Environ Health Res. 2002, 12: 175-179. 10.1080/09603120220129346.

  41. 41.

    Milton AH, Hasan Z, Rahman A, Rahman M: Non-cancer effects of chronic arsenicosis in Bangladesh: preliminary results. J Environ Sci Health A Tox Hazard Subst Environ Eng. 2003, 38: 301-305. 10.1081/ESE-120016896.

  42. 42.

    Mazumder DN, Steinmaus C, Bhattacharya P, Von Ehrenstein OS, Ghosh N, Gotway M, Sil A, Balmes JR, Haque R, Hira-Smith MM, Smith AH: Bronchiectasis in persons with skin lesions resulting from arsenic in drinking water. Epidemiology. 2005, 16: 760-765. 10.1097/01.ede.0000181637.10978.e6.

  43. 43.

    Smith AH, Marshall G, Yuan Y, Ferreccio C, Liaw J, Von Ehrenstein O, Steinmaus C, Bates MN, Selvin S: Increased mortality from lung cancer and bronchiectasis in young adults after exposure to arsenic in utero and in early childhood. Environ Health Perspect. 2006, 114: 1293-1296. 10.1289/ehp.8832.

  44. 44.

    Ilowite J, Spiegler P, Chawla S: Bronchiectasis: new findings in the pathogenesis and treatment of this disease. Curr Opin Infect Dis. 2008, 21: 163-167. 10.1097/QCO.0b013e3282f4f237.

  45. 45.

    King P, Holdsworth S, Freezer N, Holmes P: Bronchiectasis. Intern Med J. 2006, 36: 729-737. 10.1111/j.1445-5994.2006.01219.x.

  46. 46.

    Yuan Y, Marshall G, Ferreccio C, Steinmaus C, Liaw J, Bates M, Smith AH: Kidney cancer mortality: fifty-year latency patterns related to arsenic exposure. Epidemiology. 2010, 21: 103-108. 10.1097/EDE.0b013e3181c21e46.

  47. 47.

    Marshall G, Ferreccio C, Yuan Y, Bates MN, Steinmaus C, Selvin S, Liaw J, Smith AH: Fifty-year study of lung and bladder cancer mortality in Chile related to arsenic in drinking water. J Natl Cancer Inst. 2007, 99: 920-928. 10.1093/jnci/djm004.

  48. 48.

    Rahman M, Vahter M, Sohel N, Yunus M, Wahed MA, Streatfield PK, Ekstrom EC, Persson LA: Arsenic exposure and age and sex-specific risk for skin lesions: a population-based case-referent study in Bangladesh. Environ Health Perspect. 2006, 114: 1847-1852.

  49. 49.

    Lindberg AL, Ekstrom EC, Nermell B, Rahman M, Lonnerdal B, Persson LA, Vahter M: Gender and age differences in the metabolism of inorganic arsenic in a highly exposed population in Bangladesh. Environ Res. 2008, 106: 110-120. 10.1016/j.envres.2007.08.011.

  50. 50.

    Hegedus CM, Skibola CF, Warner M, Skibola DR, Alexander D, Lim S, Dangleben NL, Zhang L, Clark M, Pfeiffer RM, Steinmaus C, Smith AH, Smith MT, Moore LE: Decreased urinary beta-defensin-1 expression as a biomarker of response to arsenic. Toxicol Sci. 2008, 106: 74-82. 10.1093/toxsci/kfn104.

  51. 51.

    Goldman MJ, Anderson GM, Stolzenberg ED, Kari UP, Zasloff M, Wilson JM: Human beta-defensin-1 is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis. Cell. 1997, 88: 553-560. 10.1016/S0092-8674(00)81895-4.

  52. 52.

    Weinberg A, Krisanaprakornkit S, Dale BA: Epithelial antimicrobial peptides: review and significance for oral applications. Crit Rev Oral Biol Med. 1998, 9: 399-414. 10.1177/10454411980090040201.

  53. 53.

    Moser C, Weiner DJ, Lysenko E, Bals R, Weiser JN, Wilson JM: beta-Defensin 1 contributes to pulmonary innate immunity in mice. Infect Immun. 2002, 70: 3068-3072. 10.1128/IAI.70.6.3068-3072.2002.

  54. 54.

    Ichikawa T, Nihei N, Kuramochi H, Kawana Y, Killary AM, Shimazaki J, Oshimura M, Kugoh H, Isaacs JT, Barrett JC, Rinker Schaeffer CW: Metastasis suppressor genes for prostate cancer. Prostate Suppl. 1996, 6: 31-35.

  55. 55.

    Knuutila S, Aalto Y, Autio K, Bjorkqvist AM, El-Rifai W, Hemmer S, Huhta T, Kettunen E, Kiuru-Kuhlefelt S, Larramendy ML, Lushnikova T, Monni O, Pere H, Tapper J, Tarkkanen M, Varis A, Wasenius VM, Wolf M, Zhu Y: DNA copy number losses in human neoplasms. Am J Pathol. 1999, 155: 683-694. 10.1016/S0002-9440(10)65166-8.

  56. 56.

    Perinchery G, Bukurov N, Nakajima K, Chang J, Hooda M, Oh BR, Dahiya R: Loss of two new loci on chromosome 8 (8p23 and 8q12-13) in human prostate cancer. Int J Oncol. 1999, 14: 495-500.

  57. 57.

    Young AN, Amin MB, Moreno CS, Lim SD, Cohen C, Petros JA, Marshall FF, Neish AS: Expression profiling of renal epithelial neoplasms: a method for tumor classification and discovery of diagnostic molecular markers. Am J Pathol. 2001, 158: 1639-1651. 10.1016/S0002-9440(10)64120-X.

  58. 58.

    Donald CD, Sun CQ, Lim SD, Macoska J, Cohen C, Amin MB, Young AN, Ganz TA, Marshall FF, Petros JA: Cancer-specific loss of beta-defensin 1 in renal and prostatic carcinomas. Lab Invest. 2003, 83: 501-505. 10.1097/01.LAB.0000063929.61760.F6.

  59. 59.

    Wenghoefer M, Pantelis A, Dommisch H, Reich R, Martini M, Allam JP, Novak N, Berge S, Jepsen S, Winter J: Decreased gene expression of human beta-defensin-1 in the development of squamous cell carcinoma of the oral cavity. Int J Oral Maxillofac Surg. 2008, 37: 660-663. 10.1016/j.ijom.2008.02.003.

  60. 60.

    Joly S, Compton LM, Pujol C, Kurago ZB, Guthmiller JM: Loss of human beta-defensin 1, 2, and 3 expression in oral squamous cell carcinoma. Oral Microbiol Immunol. 2009, 24: 353-360. 10.1111/j.1399-302X.2009.00512.x.

  61. 61.

    Sun CQ, Arnold R, Fernandez-Golarz C, Parrish AB, Almekinder T, He J, Ho SM, Svoboda P, Pohl J, Marshall FF, Petros JA: Human beta-defensin-1, a potential chromosome 8p tumor suppressor: control of transcription and induction of apoptosis in renal cell carcinoma. Cancer Res. 2006, 66: 8542-8549. 10.1158/0008-5472.CAN-06-0294.

  62. 62.

    Bullard RS, Gibson W, Bose SK, Belgrave JK, Eaddy AC, Wright CJ, Hazen-Martin DJ, Lage JM, Keane TE, Ganz TA, Donald CD: Functional analysis of the host defense peptide Human Beta Defensin-1: new insight into its potential role in cancer. Mol Immunol. 2008, 45: 839-848. 10.1016/j.molimm.2006.11.026.

  63. 63.

    Vahter M: Effects of arsenic on maternal and fetal health. Annu Rev Nutr. 2009, 29: 381-399. 10.1146/annurev-nutr-080508-141102.

  64. 64.

    de la Fuente H, Portales-Perez D, Baranda L, Diaz-Barriga F, Saavedra-Alanis V, Layseca E, Gonzalez-Amaro R: Effect of arsenic, cadmium and lead on the induction of apoptosis of normal human mononuclear cells. Clin Exp Immunol. 2002, 129: 69-77. 10.1046/j.1365-2249.2002.01885.x.

  65. 65.

    Rocha-Amador DO, Calderon J, Carrizales L, Costilla-Salazar R, Perez-Maldonado IN: Apoptosis of peripheral blood mononuclear cells in children exposed to arsenic and fluoride. Environ Toxicol Pharmacol. 2011, 32: 399-405. 10.1016/j.etap.2011.08.004.

  66. 66.

    Thompson CB: Apoptosis in the pathogenesis and treatment of disease. Science. 1995, 267: 1456-1462. 10.1126/science.7878464.

  67. 67.

    Soto-Pena GA, Luna AL, Acosta-Saavedra L, Conde P, Lopez-Carrillo L, Cebrian ME, Bastida M, Calderon-Aranda ES, Vega L: Assessment of lymphocyte subpopulations and cytokine secretion in children exposed to arsenic. Faseb J. 2006, 20: 779-781.

  68. 68.

    Schofer H, Roder C: Hautarzt. Kaposi sarcoma in Caucasian women. Clinical, chemical laboratory and endocrinologic studies in 8 women with HIV-associated or classical Kaposi sarcoma. 1995, 46: 632-637.

  69. 69.

    Wikby A, Maxson P, Olsson J, Johansson B, Ferguson FG: Changes in CD8 and CD4 lymphocyte subsets, T cell proliferation responses and non-survival in the very old: the Swedish longitudinal OCTO-immune study. Mech Ageing Dev. 1998, 102: 187-198. 10.1016/S0047-6374(97)00151-6.

  70. 70.

    Hernberg M, Turunen JP, Von Boguslawsky K, Muhonen T, Pyrhonen S: Prognostic value of biomarkers in malignant melanoma. Melanoma Res. 1998, 8: 283-291. 10.1097/00008390-199806000-00013.

  71. 71.

    Zhan Y, Xu Y, Lew AM: The regulation of the development and function of dendritic cell subsets by GM-CSF: more than a hematopoietic growth factor. Mol Immunol. 2012, 52: 30-37. 10.1016/j.molimm.2012.04.009.

  72. 72.

    Luna AL, Acosta-Saavedra LC, Lopez-Carrillo L, Conde P, Vera E, De Vizcaya-Ruiz A, Bastida M, Cebrian ME, Calderon-Aranda ES: Arsenic alters monocyte superoxide anion and nitric oxide production in environmentally exposed children. Toxicol Appl Pharmacol. 2010, 245: 244-251. 10.1016/j.taap.2010.03.006.

  73. 73.

    Pineda-Zavaleta AP, Garcia-Vargas G, Borja-Aburto VH, Acosta-Saavedra LC, Calderon-Aranda ES, Cebrian ME, Gomez-Munoz A, Vera Aguilar E: Nitric oxide and superoxide anion production in monocytes from children exposed to arsenic and lead in region Lagunera, Mexico. Toxicol Appl Pharmacol. 2004, 198: 283-290. 10.1016/j.taap.2003.10.034.

  74. 74.

    Concha G, Vogler G, Lezcano D, Nermell B, Vahter M: Exposure to inorganic arsenic metabolites during early human development. Toxicol Sci. 1998, 44: 185-190. 10.1093/toxsci/44.2.185.

  75. 75.

    Rahman A, Vahter M, Ekstrom EC, Rahman M, Golam Mustafa AH, Wahed MA\, Yunus M, Persson LA: Association of arsenic exposure during pregnancy with fetal loss and infant death: a cohort study in Bangladesh. Am J Epidemiol. 2007, 165: 1389-1396. 10.1093/aje/kwm025.

  76. 76.

    Rahman A, Persson LA, Nermell B, El Arifeen S, Ekstrom EC, Smith AH, Vahter M: Arsenic exposure and risk of spontaneous abortion, stillbirth, and infant mortality. Epidemiology. 2010, 21: 797-804. 10.1097/EDE.0b013e3181f56a0d.

  77. 77.

    Raqib R, Ahmed S, Sultana R, Wagatsuma Y, Mondal D, Hoque AM, Nermell B, Yunus M, Roy S, Persson LA, Arifeen SE, Moore S, Vahter M: Effects of in utero arsenic exposure on child immunity and morbidity in rural Bangladesh. Toxicol Lett. 2009, 185: 197-202. 10.1016/j.toxlet.2009.01.001.

  78. 78.

    Rahman A, Vahter M, Ekstrom EC, Persson LA: Arsenic exposure in pregnancy increases the risk of lower respiratory tract infection and diarrhea during infancy in Bangladesh. Environ Health Perspect. 2011, 119: 719-724.

  79. 79.

    Ahmed S, Raqib R, Vahter M, Ekstrom EC, Moore S, Ameer SS, Gardner RM, Rekha RS, Mahabbat-e Khoda S: Arsenic-associated oxidative stress, inflammation, and immune disruption in human placenta and cord blood. Environ Health Perspect. 2011, 119: 258-264.

  80. 80.

    Ahmed S, Ahsan KB, Kippler M, Mily A, Wagatsuma Y, Hoque AM, Ngom PT, El Arifeen S, Raqib R, Vahter M: In utero arsenic exposure is associated with impaired thymic function in newborns possibly via oxidative stress and apoptosis. Toxicol Sci. 2012, 129: 305-314. 10.1093/toxsci/kfs202.

  81. 81.

    Andrew AS, Bernardo V, Warnke LA, Davey JC, Hampton T, Mason RA, Thorpe JE, Ihnat MA, Hamilton JW: Exposure to arsenic at levels found inU.S. drinking water modifies expression in the mouse lung. Toxicol Sci. 2007, 100: 75-87. 10.1093/toxsci/kfm200.

  82. 82.

    Kozul CD, Hampton TH, Davey JC, Gosse JA, Nomikos AP, Eisenhauer PL, Weiss DJ, Thorpe JE, Ihnat MA, Hamilton JW: Chronic exposure to arsenic in the drinking water alters the expression of immune response genes in mouse lung. Environ Health Perspect. 2009, 117: 1108-1115. 10.1289/ehp.0800199.

  83. 83.

    Mattingly CJ, Hampton TH, Brothers KM, Griffin NE, Planchart A: Perturbation of defense pathways by low-dose arsenic exposure in zebrafish embryos. Environ Health Perspect. 2009, 117: 981-987.

  84. 84.

    Hermann AC, Kim CH: Effects of arsenic on zebrafish innate immune system. Mar Biotechnol (NY). 2005, 7: 494-505. 10.1007/s10126-004-4109-7.

  85. 85.

    Nayak AS, Lage CR, Kim CH: Effects of low concentrations of arsenic on the innate immune system of the zebrafish (Danio rerio). Toxicol Sci. 2007, 98: 118-124. 10.1093/toxsci/kfm072.

  86. 86.

    Xia Y, Hao G, Yang Y: [Study on reproductive and immune toxicity of male rats exposed to As2O3]. Wei Sheng Yan Jiu. 2009, 38: 720-722.

  87. 87.

    Flora SJ, Kumar P: Biochemical and immunotoxicological alterations following repeated gallium arsenide exposure and their recoveries by meso-2,3-dimercaptosuccinic acid and 2,3-dimercaptopropane 1-sulfonate administration in rats. Environ Toxicol Pharmacol. 1996, 2: 315-320. 10.1016/S1382-6689(96)00063-4.

  88. 88.

    Schulz H, Nagymajtenyi L, Institoris L, Papp A, Siroki O: A study on behavioral, neurotoxicological, and immunotoxicological effects of subchronic arsenic treatment in rats. J Toxicol Environ Health A. 2002, 65: 1181-1193. 10.1080/152873902760125390.

  89. 89.

    Sikorski EE, Burns LA, Stern ML, Luster MI, Munson AE: Splenic cell targets in gallium arsenide-induced suppression of the primary antibody response. Toxicol Appl Pharmacol. 1991, 110: 129-142. 10.1016/0041-008X(91)90296-Q.

  90. 90.

    Ghosh D, Bhattacharya S, Mazumder S: Perturbations in the catfish immune responses by arsenic: organ and cell specific effects. Comp Biochem Physiol C Toxicol Pharmacol. 2006, 143: 455-463. 10.1016/j.cbpc.2006.04.010.

  91. 91.

    Aggarwal M, Naraharisetti SB, Dandapat S, Degen GH, Malik JK: Perturbations in immune responses induced by concurrent subchronic exposure to arsenic and endosulfan. Toxicology. 2008, 251: 51-60. 10.1016/j.tox.2008.07.050.

  92. 92.

    Soto-Pena GA, Vega L: Arsenic interferes with the signaling transduction pathway of T cell receptor activation by increasing basal and induced phosphorylation of Lck and Fyn in spleen cells. Toxicol Appl Pharmacol. 2008, 230: 216-226. 10.1016/j.taap.2008.02.029.

  93. 93.

    Ghosh D, Datta S, Bhattacharya S, Mazumder S: Long-term exposure to arsenic affects head kidney and impairs humoral immune responses of Clarias batrachus. Aquat Toxicol. 2007, 81: 79-89. 10.1016/j.aquatox.2006.11.004.

  94. 94.

    Sikorski EE, McCay JA, White KL, Bradley SG, Munson AE: Immunotoxicity of the semiconductor gallium arsenide in female B6C3F1 mice. Fundam Appl Toxicol. 1989, 13: 843-858. 10.1016/0272-0590(89)90338-2.

  95. 95.

    Burchiel SW, Mitchell LA, Lauer FT, Sun X, McDonald JD, Hudson LG, Liu KJ: Immunotoxicity and biodistribution analysis of arsenic trioxide in C57Bl/6 mice following a 2-week inhalation exposure. Toxicol Appl Pharmacol. 2009, 241: 253-259. 10.1016/j.taap.2009.09.019.

  96. 96.

    Blakley BR, Sisodia CS, Mukkur TK: The effect of methylmercury, tetraethyl lead, and sodium arsenite on the humoral immune response in mice. Toxicol Appl Pharmacol. 1980, 52: 245-254. 10.1016/0041-008X(80)90111-8.

  97. 97.

    Nain S, Smits JE: Pathological, immunological and biochemical markers of subchronic arsenic toxicity in rats. Environ Toxicol. 2010, 4: 244-254.

  98. 98.

    Burns LA, Munson AE: Reversal of gallium arsenide-induced suppression of the antibody-forming cell response by vehicle supernatants. II. Nature and identification of reversing factors. J Pharmacol Exp Ther. 1993, 265: 150-158.

  99. 99.

    Patterson R, Vega L, Trouba K, Bortner C, Germolec D: Arsenic-induced alterations in the contact hypersensitivity response in Balb/c mice. Toxicol Appl Pharmacol. 2004, 198: 434-443. 10.1016/j.taap.2003.10.012.

  100. 100.

    Savabieasfahani M, Lochmiller RL, Rafferty DP, Sinclair JA: Sensitivity of wild cotton rats (Sigmodon hispidus) to the immunotoxic effects of low-level arsenic exposure. Arch Environ Contam Toxicol. 1998, 34: 289-296. 10.1007/s002449900320.

  101. 101.

    Arkusz J, Stanczyk M, Lewiniska D, Stepnik M: Modulation of murine peritoneal macrophage function by chronic exposure to arsenate in drinking water. Immunopharmacol Immunotoxicol. 2005, 27: 315-330. 10.1081/IPH-200067947.

  102. 102.

    Chakraborty S, Ray M, Ray S: Evaluation of phagocytic activity and nitric oxide generation by molluscan haemocytes as biomarkers of inorganic arsenic exposure. Biomarkers. 2009, 14: 539-546. 10.3109/13547500903240473.

  103. 103.

    Sengupta M, Bishayi B: Effect of lead and arsenic on murine macrophage response. Drug Chem Toxicol. 2002, 25: 459-472. 10.1081/DCT-120014796.

  104. 104.

    Lantz RC, Parliman G, Chen GJ, Carter DE: Effect of arsenic exposure on alveolar macrophage function. I. Effect of soluble as(III) and as(V). Environ Res. 1994, 67: 183-195. 10.1006/enrs.1994.1073.

  105. 105.

    Bishayi B, Sengupta M: Intracellular survival of Staphylococcus aureus due to alteration of cellular activity in arsenic and lead intoxicated mature Swiss albino mice. Toxicology. 2003, 184: 31-39. 10.1016/S0300-483X(02)00549-8.

  106. 106.

    Sikorski EE, Burns LA, McCoy KL, Stern M, Munson AE: Suppression of splenic accessory cell function in mice exposed to gallium arsenide. Toxicol Appl Pharmacol. 1991, 110: 143-156. 10.1016/0041-008X(91)90297-R.

  107. 107.

    Yan S, Zhang QY, Zhou B, Xue L, Chen H, Wang Y, Zheng SS: Arsenic trioxide attenuated the rejection of major histocompatibility complex fully-mismatched cardiac allografts in mice. Transplant Proc. 2009, 41: 1855-1858. 10.1016/j.transproceed.2009.02.073.

  108. 108.

    Kavian N, Marut W, Servettaz A, Laude H, Nicco C, Chereau C, Weill B, Batteux F: Arsenic trioxide prevents murine sclerodermatous graft-versus-host disease. J Immunol. 2012, 188: 5142-5149. 10.4049/jimmunol.1103538.

  109. 109.

    Escudero-Lourdes C, Martinez FD, Calvillo RQ, Medina de la Garza CE: Effect of oral chronic intoxication with sodium arsenite on murine giardiasis. Proc West Pharmacol Soc. 2005, 48: 92-99.

  110. 110.

    Kozul CD, Ely KH, Enelow RI, Hamilton JW: Low-dose arsenic compromises the immune response to influenza A infection in vivo. Environ Health Perspect. 2009, 117: 1441-1447.

  111. 111.

    Lin-fu Z, Kai-sheng Y, Zhi-min Z: Role of low dosage arsenic trioxide on pulmonary dendritic cells in asthmatic mice. Chin J Integr Med. 2003, 9: 281-284. 10.1007/BF02838615.

  112. 112.

    Zhang L, Li K, Bing Ma L, Gong SB, Wang GY, Liu Y, Ji XY, Xu L, Liu SK, Chen P, Ouyang RY, Xiang XD: Effects and mechanism of arsenic trioxide on reversing the asthma pathologies including Th17-IL-17 axis in a mouse model. Iran J Allergy Asthma Immunol. 2012, 11: 133-145.

  113. 113.

    Martin-Chouly C, Morzadec C, Bonvalet M, Galibert MD, Fardel O, Vernhet L: Inorganic arsenic alters expression of immune and stress response genes in activated primary human T lymphocytes. Mol Immunol. 2011, 48: 956-965. 10.1016/j.molimm.2011.01.005.

  114. 114.

    Morzadec C, Bouezzedine F, Macoch M, Fardel O, Vernhet L: Inorganic arsenic impairs proliferation and cytokine expression in human primary T lymphocytes. Toxicology. 2012, 300: 46-56. 10.1016/j.tox.2012.05.025.

  115. 115.

    Conde P, Acosta-Saavedra LC, Goytia-Acevedo RC, Calderon-Aranda ES: Sodium arsenite-induced inhibition of cell proliferation is related to inhibition of IL-2 mRNA expression in mouse activated T cells. Arch Toxicol. 2007, 81: 251-259. 10.1007/s00204-006-0152-7.

  116. 116.

    Cho Y, Ahn KH, Back MJ, Choi JM, Ji JE, Won JH, Fu Z, Jang JM, Kim DK: Age-related effects of sodium arsenite on splenocyte proliferation and Th1/Th2 cytokine production. Arch Pharm Res. 2012, 35: 375-382. 10.1007/s12272-012-0219-3.

  117. 117.

    Das S, Pan D, Bera AK, Rana T, Bhattacharya D, Bandyapadyay S, De S, Sreevatsava V, Bhattacharya S, Das SK, Bandyopadhayay S: Sodium arsenite mediated immuno-disruption through alteration of transcription profile of cytokines in chicken splenocytes under in vitro system. Mol Biol Rep. 2011, 38: 171-176. 10.1007/s11033-010-0091-5.

  118. 118.

    Frouin H, Fortier M, Fournier M: Toxic effects of various pollutants in 11B7501 lymphoma B cell line from harbour seal (Phoca vitulina). Toxicology. 2010, 270: 66-76. 10.1016/j.tox.2010.01.014.

  119. 119.

    McCabe M, Maguire D, Nowak M: The effects of arsenic compounds on human and bovine lymphocyte mitogenesis in vitro. Environ Res. 1983, 31: 323-331. 10.1016/0013-9351(83)90010-5.

  120. 120.

    Morzadec C, Macoch M, Robineau M, Sparfel L, Fardel O, Vernhet L: Inorganic arsenic represses interleukin-17A expression in human activated Th17 lymphocytes. Toxicol Appl Pharmacol. 2012, 262: 217-222. 10.1016/j.taap.2012.05.004.

  121. 121.

    Macoch M, Morzadec C, Fardel O, Vernhet L: Inorganic arsenic impairs differentiation and functions of human dendritic cells. Toxicol Appl Pharmacol. 2013, 266: 204-213. 10.1016/j.taap.2012.11.008.

  122. 122.

    Tenorio EP, Saavedra R: Differential effect of sodium arsenite during the activation of human CD4+ and CD8+ T lymphocytes. Int Immunopharmacol. 2005, 5: 1853-1869. 10.1016/j.intimp.2005.06.006.

  123. 123.

    Binet F, Antoine F, Girard D: Interaction between arsenic trioxide and human primary cells: emphasis on human cells of myeloid origin. Inflamm Allergy Drug Targets. 2009, 8: 21-27. 10.2174/187152809787582516.

  124. 124.

    Bustamante J, Dock L, Vahter M, Fowler B, Orrenius S: The semiconductor elements arsenic and indium induce apoptosis in rat thymocytes. Toxicology. 1997, 118: 129-136. 10.1016/S0300-483X(96)03607-4.

  125. 125.

    Harrison MT, McCoy KL: Immunosuppression by arsenic: a comparison of cathepsin L inhibition and apoptosis. Int Immunopharmacol. 2001, 1: 647-656. 10.1016/S1567-5769(00)00048-5.

  126. 126.

    Lemarie A, Morzadec C, Merino D, Micheau O, Fardel O, Vernhet L: Arsenic trioxide induces apoptosis of human monocytes during macrophagic differentiation through nuclear factor-kappaB-related survival pathway down-regulation. J Pharmacol Exp Ther. 2006, 316: 304-314.

  127. 127.

    Gonzalez-Rangel Y, Portales-Perez DP, Galicia-Cruz O, Escudero-Lourdes C: Chronic exposure to arsenic sensitizes CD3+ and CD56+ human cells to sodium arsenite-mediated apoptosis. Proc West Pharmacol Soc. 2005, 48: 89-91.

  128. 128.

    Yoshida T, Shimamura T, Shigeta S: Enhancement of the immune response in vitro by arsenic. Int J Immunopharmacol. 1987, 9: 411-415. 10.1016/0192-0561(87)90068-3.

  129. 129.

    Li Q, Lauer FT, Liu KJ, Hudson LG, Burchiel SW: Low-dose synergistic immunosuppression of T-dependent antibody responses by polycyclic aromatic hydrocarbons and arsenic in C57BL/6J murine spleen cells. Toxicol Appl Pharmacol. 2010, 245: 344-351. 10.1016/j.taap.2010.03.020.

  130. 130.

    Lemarie A, Morzadec C, Bourdonnay E, Fardel O, Vernhet L: Human macrophages constitute targets for immunotoxic inorganic arsenic. J Immunol. 2006, 177: 3019-3027.

  131. 131.

    Sakurai T, Ohta T, Tomita N, Kojima C, Hariya Y, Mizukami A, Fujiwara K: Evaluation of immunotoxic and immunodisruptive effects of inorganic arsenite on human monocytes/macrophages. Int Immunopharmacol. 2006, 6: 304-315. 10.1016/j.intimp.2005.06.012.

  132. 132.

    Wang L, Weng CY, Wang YJ, Wu MJ: Lipoic acid ameliorates arsenic trioxide-induced HO-1 expression and oxidative stress in THP-1 monocytes and macrophages. Chem Biol Interact. 2011, 190: 129-138. 10.1016/j.cbi.2011.02.001.

  133. 133.

    Bourdonnay E, Morzadec C, Fardel O, Vernhet L: Redox-sensitive regulation of gene expression in human primary macrophages exposed to inorganic arsenic. J Cell Biochem. 2009, 107: 537-547. 10.1002/jcb.22155.

  134. 134.

    Bourdonnay E, Morzadec C, Sparfel L, Galibert MD, Jouneau S, Martin-Chouly C, Fardel O, Vernhet L: Global effects of inorganic arsenic on gene expression profile in human macrophages. Mol Immunol. 2009, 46: 649-656. 10.1016/j.molimm.2008.08.268.

  135. 135.

    Bomberger JM, Coutermarsh BA, Barnaby RL, Stanton BA: Arsenic promotes ubiquitinylation and lysosomal degradation of cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels in human airway epithelial cells. J Biol Chem. 2012, 287: 17130-17139. 10.1074/jbc.M111.338855.

  136. 136.

    Shaw JR, Bomberger JM, VanderHeide J, LaCasse T, Stanton S, Coutermarsh B, Barnaby R, Stanton BA: Arsenic inhibits SGK1 activation of CFTR Cl- channels in the gill of killifish, Fundulus heteroclitus. Aquat Toxicol. 2010, 98: 157-164. 10.1016/j.aquatox.2010.02.001.

  137. 137.

    Olsen CE, Liguori AE, Zong Y, Lantz RC, Burgess JL, Boitano S: Arsenic upregulates MMP-9 and inhibits wound repair in human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2008, 295: L293-302. 10.1152/ajplung.00134.2007.

  138. 138.

    Sherwood CL, Lantz RC, Burgess JL, Boitano S: Arsenic Alters ATP-Dependent Ca2+ Signaling in Human Airway Epithelial Cell Wound Response. Toxicol Sci. 2011, 121: 191-206. 10.1093/toxsci/kfr044.

  139. 139.

    Josyula AB, Poplin GS, Kurzius-Spencer M, McClellen HE, Kopplin MJ, Sturup S, Clark Lantz R, Burgess JL: Environmental arsenic exposure and sputum metalloproteinase concentrations. Environ Res. 2006, 102: 283-290. 10.1016/j.envres.2006.01.003.

  140. 140.

    Lantz RC, Hays AM: Role of oxidative stress in arsenic-induced toxicity. Drug Metab Rev. 2006, 38: 791-804. 10.1080/03602530600980108.

  141. 141.

    Lantz RC, Lynch BJ, Boitano S, Poplin GS, Littau S, Tsaprailis G, Burgess JL: Pulmonary biomarkers based on alterations in protein expression after exposure to arsenic. Environ Health Perspect. 2007, 115: 586-591. 10.1289/ehp.9611.

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Acknowledgments

We thank Elizabeth Trenkwalder and Dr. Fenna Sillé for assistance with PubMed literature searches and final preparation of the manuscript for submission, respectively. This work was supported by the National Institute of Environmental Health Sciences [P42 ES004705 to MTS] and the National Science Foundation [NSF 04–615 to NLD].

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Affiliations

  1. Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA 94720, USA

    • Nygerma L Dangleben
    •  & Martyn T Smith

  2. Department of Epidemiology, School of Public Health, University of Alabama, Birmingham, AL 35294, USA

    • Christine F Skibola

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Correspondence to Martyn T Smith.

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The authors declare that they have no competing interests.

Authors’ contributions

NLD, CFS and MTS conceived of the study; NLD reviewed the literature and wrote and edited the manuscript; CFS and MTS critically reviewed the manuscript. All authors read and approved the final manuscript.

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Dangleben, N.L., Skibola, C.F. & Smith, M.T. Arsenic immunotoxicity: a review. Environ Health 12, 73 (2013) doi:10.1186/1476-069X-12-73

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Keywords

  • Arsenic
  • Immune system
  • Immunotoxicity
  • Immunocompromised
  • Immunosuppression

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