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Shortly after its discovery in 1960, aflatoxin – a group of fungal toxins or mycotoxins produced by the fungi Aspergillus flavus and A. parasiticus in food crops such as maize, peanuts and tree nuts – was found to cause liver cancer in humans and multiple animal species. Hence, regulations on maximum allowable aflatoxin levels in food worldwide have focused on protecting humans from aflatoxin's carcinogenic effects. However, aflatoxin may also have non-carcinogenic health effects (e.g., immunotoxicity) that are particularly relevant today. Our current review highlights the growing evidence that aflatoxin exposure adversely affects immunity. Here, we comprehensively evaluated human and mammalian animal studies that link aflatoxin exposure with adverse effects on the immune system. We organized the review by organism as well as by the effects on adaptive and innate immune functions. There is abundant evidence that aflatoxin exhibits immunotoxicity, and therefore may compromise the ability of both humans and animals to resist infections. However, the reported effects of aflatoxin on certain specific immune biomarkers are inconsistent in the existing literature. The extent of the immunotoxic effects of aflatoxin must be clarified, so that the contribution of such immunotoxicity to the overall burden of aflatoxin-related diseases can be established. [ABSTRACT FROM AUTHOR]

AbstractSilica nanoparticles are increasingly considered for drug delivery applications. These applications require an understanding of their biocompatibility, including their interactions with the immune system. However, systematic studies for silica nanoparticle immunological safety profiles are lacking. To fill this gap, we conducted an in vitro study investigating various aspects of silica nanoparticles’ interactions with blood and immune cells. Four types of silica nanoparticles with variations in size and porosity were studied. These included nonporous Stöber silica nanoparticles with average diameters of approximately 50 and 100 nm (SNP50 and SNP100), mesoporous silica nanoparticles of approximately 100 nm (Meso100), and hollow mesoporous silica nanoparticles of approximately 100 nm (HMSNP100) in diameter, respectively. The hematological compatibility was assessed using hemolysis, complement activation, platelet aggregation, and plasma coagulation assays. The effects of nanoparticles on immune cell function were studied using in vitro phagocytosis, chemotaxis, natural killer cell cytotoxicity, leukocyte proliferation, human lymphocyte activation, colony-forming unit granulocyte-macrophage, and leukocyte procoagulant activity assays. The in vitro findings suggest that at high concentrations, corresponding to the in vivo human dose of 40 mg/kg, silica nanoparticles demonstrated an array of immunotoxic effects that depended on their physicochemical properties. However, all types of silica nanoparticles studied were not immunotoxic at concentrations corresponding to lower doses (≤ 8 mg/kg) comparable to that of nanocarriers in other nanomedicines currently used in the clinic. These findings are promising for using silica nanoparticles for the systemic delivery of bioactive and imaging agents. [ABSTRACT FROM AUTHOR]

The European Union (EU) Chemicals Strategy for Sustainability regards chemicals that affect the immune system among the most harmful ones. The Extended One-Generation Reproductive Toxicity study (EOGRTS; Organisation for Economic Co-Operation and Development (OECD) Test Guideline (TG) 443), addresses, among others, potential effects of chemicals on development. In specific cases, the EOGRTS is performed with addition of a so-called cohort 3, that addresses potential effects on the developing immune system, by means of a central assay measuring the T-cell dependent antibody response (TDAR). This assay is based on an interplay of antigen presentation, T-cell help and antibody production by B-cells, and together comprises a functional immune response. In the context of the EOGRTS review project of the European Chemicals Agency (ECHA), we evaluated 15 available TDARs for compliance with conduct and reporting requirements. Collectively, the majority of the TDAR studies were considered to be adequately conducted. We however observed: (i) the protocols differed by the antigen used (sheep red blood cells (SRBC) or KLH), the route of administration (intravenous, intraperitoneal, or subcutaneous), prime or prime/boost immunizations, and whether IgG was measured. (ii) There was major variation in the effects of the positive control for immunosuppression, cyclophosphamide. (iii) Proficiency was not always shown. (iv) Statistical analysis was not always done or reported. (v) Results of effects on lymphocyte populations or other immunotoxicity observations obtained in cohort 1 (or 2) of the EOGRTS were not always discussed together with results of the TDAR. Taken together, next to an improved quality of reporting, this may suggest a need to better define the conduct of the TDAR in OECD TG 443 and OECD Guidance Document (GD) 151, at least for certain aspects. [ABSTRACT FROM AUTHOR]

Exposure to microplastics may be associated with damage of immune system. Polypropylene microplastics (PP-MPs) with a wide range of beneficial applications have not been extensively studied with respect to the immune system. The aim of this investigation is to examine the influence of two different sizes of PP-MPs (5.2 and 23.9 μm diameter) on immune system components in ICR mice. PP-MPs were administered orally to female and male mice at 0 (corn oil vehicle), 500, 1000, or 2000 mg/kg/d for single and daily for 4-week repeated toxicity test, respectively. No significant differences were observed in number of thymic CD4+, CD8+, CD4+CD8+ T lymphocytes, splenic helper T cells, cytotoxic T cells, and B cells. The ratio of interferon-γ to interleukin-4 in culture supernatants from activated splenocytes ex vivo (48 hr) was lower in females which were repeatedly administered with PP-MPs compared to vehicle irrespective of PP-MPs size and dose. In contrast, the opposite trend was observed in males. Production of tumor necrosis factor-α was upregulated in females that were repeatedly exposed to PP-MPs. The serum IgG2a/IgG1 ratio was lowered in female receiving large-size PP-MPs. Data suggest that immune disturbances resulting in predominant type-2 helper T cell reactivity may occur in mice, especially in females, when repeatedly exposed to PP-MPs. Further investigations with longer exposure periods are necessary to determine the immunotoxicities attributed to PP-MPs. [ABSTRACT FROM AUTHOR]

The growing application of silver nanoparticles (AgNPs) in consumer, healthcare, and industrial products has raised concern over potential health implications due to increasing exposure. The evaluation of the immune response to nanomaterials is one of the key criteria to assess their biocompatibility. There are well-recognized sex-based differences in innate and adaptive immune responses. However, there is limited information available using human models. The aim was to investigate the potential sex-based differences in immune functions after exposure to AgNPs using human peripheral blood mononuclear cells (PBMCs) and plasma from healthy donors. These functions include inflammasome activation, cytokine expression, leukocyte proliferation, chemotaxis, plasma coagulation, and complement activation. AgNPs were characterized by dynamic light scattering and transmission electron microscopy. Inflammasome activation by AgNPs was measured after 6- and 24-hours incubations. AgNPs-induced inflammasome activation was significantly higher in the females, especially for the 6-hour exposure. No sex-based differences were observed for Ag ions controls. Younger donors exhibited significantly more inflammasome activation than older donors after 24-hours exposure. IL-10 was significantly suppressed in males and females after exposure. AgNPs suppressed leukocyte proliferation similarly in males and females. No chemoattractant effects, no alterations in plasma coagulation, or activation of the complement were observed after AgNPs exposure. In conclusion, the results highlight that there are distinct sex-based differences in inflammasome activation after exposure to AgNPs in human PBMCs. The results highlight the importance of considering sex-based differences in inflammasome activation induced by exposure to AgNPs in any future biocompatibility assessment for products containing AgNPs. [ABSTRACT FROM AUTHOR]

Nanocrystal drug formulation involves several critical manufacturing procedures that result in complex structures to improve drug solubility, dissolution, bioavailability, and consequently the efficacy of poorly soluble Biopharmaceutics Classification System (BCS) II and IV drugs. Nanocrystal formulation of an already approved oral drug may need additional immunotoxic assessment due to changes in the physical properties of the active pharmaceutical ingredient (API). In this study, we selected Zileuton, an FDA-approved drug that belongs to BCS-II for nanocrystal formulation. To evaluate the efficacy and mucosal immune profile of the nanocrystal drug, 10-week-old rats were dosed using capsules containing either API alone or nanocrystal formulated Zileuton (NDZ), or with a physical mixture (PM) using flexible oral gavage syringes. Control groups consisted of untreated, or placebo treated animals. Test formulations were administrated to rats at a dose of 30 mg/kg body weight (bw) once a day for 15 days. The rats treated with NDZ or PM had approximately 4.0 times lower (7.5 mg/kg bw) API when compared to the micron sized API treated rats. At the end of treatment, mucosal (intestinal tissue) and circulating cytokines were measured. The immunological response revealed that NDZ decreased several proinflammatory cytokines in the ileal mucosa (Interleukin-18, Tumor necrosis Factor-α and RANTES [regulated upon activation, normal T cell expressed and secreted]). A similar pattern in the cytokine profile was also observed for the micron sized API and PM treated rats. The cytokine production revealed that there was a significant increase in the production of IL-1β and IL-10 in the females in all experimental groups. Additionally, NDZ showed an immunosuppressive effect on proinflammatory cytokines both locally and systemically, which was similar to the response in micron sized API treated rats. These findings indicate that NDZ significantly decreased several proinflammatory cytokines and it displays less immunotoxicity, probably due to the nanocrystal formulation. Thus, the nanocrystal formulation is more suitable for oral drug delivery, as it exhibited better efficacy, safety, and reduced toxicity. [ABSTRACT FROM AUTHOR]

Immunotoxic effects of sodium benzoate (SB, E211), sodium nitrate (SNa, E251), and sodium nitrite (SNi, E250), a few of the most common food preservatives, on the model organism Galleria mellonella L. (Lepidoptera: Pyralidae) larvae were investigated in this study. The last instar larvae were used for all experimental analyses. For this purpose, median lethal doses of SB, SNa, and SNi were applied to the larvae by the force-feeding method. We found that force-feeding G. mellonella larvae with SB, SNa, and SNi significantly reduced the larval total hemocyte counts, prohemocyte, and granulocyte ratios but increased plasmatocyte, spherulocyte, and oenocyte ratios, as well as the hemocyte mitotic indices and micronucleus frequency. The spreading ability of hemocytes and hemocyte-mediated immune responses were lower in the SB, SNa-, and SNi-treated larval groups compared to controls. Apoptotic indices were higher in all larval groups treated with food preservatives, but increments in necrotic indices were only significantly higher in SNi-treated larvae compared to controls. Our research shows that SB, SNa, and SNi have immunotoxic and cytotoxic potential on G. mellonella larvae. Thus, we suggest that G. mellonella larvae can be used as preliminary in vivo models to screen the immunotoxic effects of food preservative agents. [ABSTRACT FROM AUTHOR]

The toxicity of engineered nanomaterials (ENMs) in vivo and in vitro has formed the basis of most studies. However, the toxicity of ENMs, particularly on the immune system, i.e. immunotoxicity, and their role in manipulating it, are less known. This review addresses the initiation or exacerbation as well as the attenuation of allergic asthma by a variety of ENMs and how they may be used in drug delivery to enhance the treatment of asthma. This review also highlights a few research gaps in the study of the immunotoxicity of ENMs, for example, the potential drawbacks of assays used in immunotoxicity assays; the potential role of hormesis during dosing of ENMs; and the variables that result in discrepancies among different studies, such as the physicochemical properties of ENMs, differences in asthmatic animal models, and different routes of administration. Abbreviations: AHR: airway hyperresponsiveness; ALI: air-lung epithelium interface; BDP: beclometasone dipropionate; CB: carbon black; CNTs: carbon nanotubes; CpG: cytosine linked through a phosphodiester to guanine; EGFR: epidermal growth factor receptor; ENMs: engineered nanomaterials; GLA: gut--lung axis; Ig: immunoglobulin; IL: interleukin; LC: liquid crystalline; LLNA: local lymph node assay; LPS: lipopolysaccharide; MWCNTs: multi-walled CNTs; NPs: nanoparticles; OVA: ovalbumin; PAMAM: polyamidoamine; PFC: plaque-forming cell; PM: particulate matter; ROS: reactive oxygen species; SBS: salbutamol sulfate; SWCNTs: single-walled CNTs; TDI: toluene diisocyanate; VEGF: vascular endothelial growth factor [ABSTRACT FROM AUTHOR]

Immunotoxicity is the critical endpoint used by some regulatory agencies to establish toxicity values for perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). However, the hypothesis that exposure to certain per- and polyfluoroalkyl substances (PFAS) causes immune dysregulation is subject to much debate. An independent, international expert panel was engaged utilizing methods to reduce bias and "groupthink". The panel concluded there is moderate evidence that PFOS and PFOA are immunotoxic, based primarily on evidence from animal data. However, species concordance and human relevance cannot be well established due to data limitations. The panel recommended additional testing that includes longer-term exposures, evaluates both genders, includes other species of animals, tests lower dose levels, assesses more complete measures of immune responses, and elucidates the mechanism of action. Panel members agreed that the Faroe Islands cohort data should not be used as the primary basis for deriving PFAS risk assessment values. The panel agreed that vaccine antibody titer is not useful as a stand-alone metric for risk assessment. Instead, PFOA and PFOS toxicity values should rely on multiple high-quality studies, which are currently not available for immune suppression. The panel concluded that the available PFAS immune epidemiology studies suffer from weaknesses in study design that preclude their use, whereas available animal toxicity studies provide comprehensive dataset to derive points of departure (PODs) for non-immune endpoints. The panel recommends accounting for potential PFAS immunotoxicity by applying a database uncertainty factor to POD values derived from animal studies for other more robustly supported critical effects. [ABSTRACT FROM AUTHOR]

Epidemiological studies suggest suppression of the lymphocytes function through cholinergic stimulation due to organophosphorus pesticide exposure. The study aimed to assess the alteration in the levels of immune cell phenotypes among farm women (FW) and farm children (FC) who were occupationally exposed to pesticides and age/gender-matched control subjects belonging to Rangareddy district (Telangana, India). A total of 129 FW, 129 FC and 268 age/gender-matched controls were recruited. Blood samples were collected from the selected subjects to estimate the levels of nine organophosphorus pesticide residues and CD (CD3+, CD4+, CD8+, CD16+ and CD19+) cell markers using LC-MS/MS and flow cytometry, respectively. Independent t-test analysis was conducted to compare the immune cell phenotypes between exposed and control groups. Spearman's rank correlation test was further carried out to identify any possible correlation between the pesticide residues and CD markers. The mean percentage for CD4+, CD8+ and CD16+ was found to be significantly low, while for CD19 + itwas significantly high in the FW as compared to the CW group (p < 0.01). Further, the residues of chlorpyrifos and monocrotophos among FW were found to be significantly correlating with the mean percentages of CD19+ and CD8+ markers, respectively. The cell marker subsets of CD4+ and CD8+ were significantly low in FC children 9–12 years and 13–15 years age groups, respectively (p < 0.05). Also, these levels were significantly correlating with the residues of malathion and monocrotophos. The present study could indicate an alteration in the lymphocytes' subpopulations, which may thereby infer the toxicity in the first phase assessment of immunotoxicity. Therefore, further studies may be conducted to understand the suspected pesticides' mechanism along with various other factors in causing immune suppression coupled with nutritional and other related disorders. [ABSTRACT FROM AUTHOR]

People are exposed to pesticides through food, drinking water, and the environment. These compounds are associated with several disorders, such as inflammatory diseases, rheumatoid arthritis, cancer, and a condition related to metabolic syndrome. The immunotoxicants or immunotoxic compounds can cause a wide variety of effects on immune function, altering humoral immunity and cell-mediated immunity, resulting in adverse effects to the body. Here, immune system disorders are highlighted because they are closely linked to multiple organs, including the nervous, endocrine, reproductive, cardiovascular, and respiratory systems, leading to transient or permanent changes. Therefore, this study reviewed the mechanisms involved in the immunotoxicity of fungicides, herbicides, and insecticides in cells, animals, and humans in the past 11 years. According to the studies analyzed, the pesticides interfere with innate and adaptive immune functions, but the effects observed mainly on cellular and humoral immunity were highlighted. These compounds affected specific immune cells, causing apoptosis, changes in factor nuclear kappa B (NF-κB) expression, pro-inflammatory factors interleukin 6 (IL-6), interleukin 8 (IL-8), interferon-gamma (IFN-γ), chemokines (CXCL-c1c), and anti-inflammatory factor, such as interleukin 10 (IL-10). To verify the threats of these compounds, new evaluations with immunotoxicological biomarkers are necessary. Pesticides interfere with the innate and adaptive immune response. Cells, animals and human studies demonstrate the immunotoxicity of pesticides in the cellular and humoral immune response. Fungicides, herbicides, and insecticides alter the immune system by various mechanisms, such as pro-inflammatory and anti-inflammatory factors. [ABSTRACT FROM AUTHOR]

Cadmium (Cd) is an immunotoxic metal frequently found in the environment. The in vitro study undertaken here evaluated the immunotoxic effects of Cd in isolated human peripheral blood monocytes (hPBM). The results of the studies of exposures to varying doses of Cd (0, 0.1, 1, 10, and 100 µM, as cadmium dichloride [CdCl2]) for 3, 6, 12, 24, 48, and 72 hr showed the test agent was cytotoxic to the cells in time- and concentration-related manners. Thereafter, using only those doses found to not cause extreme cell lethality a 48-hr period, the impact of 0.1 or 1 µM CdCl2 on the cells was evaluated. Functionally, CdCl2 treatment led to time- and concentration-related decreases in hPBM phagocytic activities as well as in the ability of the cells to form/release cytokines (including tumor necrosis factor [TNF]-α and interleukin [IL]-6 and −8). The CdCl2 also led to significantly decreased ATP production (in part, via inhibition of mitochondrial complexes I and III) as well as in mitochondrial membrane potentials (MMP) and oxygen consumption rates (OCR; associated with parallel increases in cell lactate production) in the cells. In addition, CdCl2 treatment resulted in significant increases in mitochondrial membrane fluidity (MMF) and cell unsaturated fatty acid content. Based on the results here, one might conclude that some of the effects that arose during the CdCl2-induced dysfunction of the isolated hPBM (i.e. changes phagocytic activity, cytokine formation/secretion) could have evolved secondary to CdCl2-induced disruptions of hPBM cell bioenergetics – an effect that itself was a culmination of an overall toxicity from CdCl2 upon the mitochondria within these cells. [ABSTRACT FROM AUTHOR]

Diazinon is an organophosphorus pesticide, which may have potential toxic effects on the liver and immune system; however, the underlying mechanisms remain mostly unidentified. This work is aimed at evaluating the oxidative stress and cell cycle alterations elicited by low-dose diazinon in a rat liver cell line (BRL-3A) and spleen mononuclear cells (SMC) from Wistar rats. Diazinon (10–50 μM) caused early reactive oxygen species (ROS) generation (from 4 h) as well as increased O2•- level (from 0.5 h), which led to subsequent lipid peroxidation at 24 h, in BRL-3A cells. In SMC, diazinon (20 μM) produced similar increases in ROS levels, at 4 and 24 h, with the highest O2•- level being found at 4 h. Low-dose diazinon induced G1-phase arrest and cell death in hepatic cells and SMC. Therefore, diazinon could affect the liver and the immunological system through the premature oxidative stress induction. Abbreviations: O2•-: superoxide anion radical; ROS: reactive oxygen species; SMC: spleen mononuclear cells; TBARS: thiobarbituric acid reactive substances [ABSTRACT FROM AUTHOR]

Allergic disease represents one of the most prominent global public health crises of the 21st century. Although many different substances are known to produce hypersensitivity responses, metals constitute one of the major classes of allergens responsible for a disproportionately large segment of the total burden of disease associated with allergy. Some of the most prevalent forms of metal allergy – including allergic contact dermatitis – are well-recognized; however, to our knowledge, a comprehensive review of the many unique disease variants implicated in human cases of metal allergy is not available within the current scientific literature. Consequently, the main goal in composing this review was to (1) generate an up-to-date reference document containing this information to assist in the efforts of lab researchers, clinicians, regulatory toxicologists, industrial hygienists, and other scientists concerned with metal allergy and (2) identify knowledge gaps related to disease. Accordingly, an extensive review of the scientific literature was performed – from which, hundreds of publications describing cases of metal-specific allergic responses in human patients were identified, collected, and analyzed. The information obtained from these articles was then used to compile an exhaustive list of distinctive dermal/ocular, respiratory, gastrointestinal, and systemic hypersensitivity responses associated with metal allergy. Each of these disease variants is discussed briefly within this review, wherein specific metals implicated in each response type are identified, underlying immunological mechanisms are summarized, and major clinical presentations of each reaction are described. Abbreviations: ACD: allergic contact dermatitis, AHR: airway hyperreactivity, ASIA: autoimmune/ autoinflammatory syndrome induced by adjuvants, BAL: bronchoalveolar lavage, CBD: chronic beryllium disease, CTCL: cutaneous T-cell lymphoma, CTL: cytotoxic T-Lymphocyte, DRESS: drug reaction with eosinophilia and systemic symptoms, GERD: gastro-esophageal reflux disease, GI: gastrointestinal, GIP: giant cell interstitial pneumonia, GM-CSF: granulocyte macrophage-colony stimulating factor, HMLD: hard metal lung disease, HMW: high molecular weight, IBS: irritable bowel syndrome, Ig: immunoglobulin, IL: interleukin, LMW: low molecular weight, PAP: pulmonary alveolar proteinosis, PPE: personal protective equipment, PRR: pathogen recognition receptor, SLE: systemic lupus erythematosus, SNAS: systemic nickel allergy syndrome, Th: helper T-cell, UC: ulcerative colitis, UV: ultraviolet. [ABSTRACT FROM AUTHOR]

The current study has focused on the effects of enniatin B (ENN B, a major mycotoxin produced by Fusarium fungi) on early embryonic development. In in vitro analysis, mouse blastocysts were incubated in medium with ENN B (0–40 μM) or 0.5% DMSO (control group) for 24 hours. In an animal study, blastocysts were collected from mice which were intravenously injected with ENN B (1, 3, 5, and 7mg/kg body weight/day) for 4 days in order to analyze apoptosis and necrosis via Annexin V/PI staining assay; and proliferation using dual differential staining. Exposure to low ENN B concentration (10 μM in vitro and 3 mg/kg/day in vivo) promoted Reactive Oxygen Species (ROS) generation and apoptosis in the Inner Cell Mass (ICM), the mass of cells inside the blastocyst, impairing post-implantation development alone. On the other hand, exposure to a higher ENN B concentration (40 μM in vitro and 7 mg/kg/day in vivo) induced ROS generation and decreased in intracellular ATP which encouraged necrotic processes in both trophectoderm (TE) and ICM of blastocysts leading to impaired implantation and post-implantation development. Moreover, 5 and 7 mg/kg/day ENN B intraperitoneal injection to female mice for 4 days has caused downregulation of CXCL1, IL-1β and IL-8 expressions and increased ROS generation in the liver of newborn mice. Over all, ENN B can induce apoptosis and/or necrosis depending on the treatment dosage in mouse blastocysts. ENN B-induced necrosis in blastocysts may exert long-term harmful effects on next-generation newborns. [ABSTRACT FROM AUTHOR]

There is a global research interest in metal nanoparticles (MNPs) due to their diverse applications, rapidly increasing use, and increased presence in the aquatic environment. Currently, most MNPs in the environment are at levels unlikely to cause overt toxicity. Sub-lethal effects that MNPs may induce, notable immunotoxicity, could however have significant health implications. Thus, deciphering the immunological interactions of MNPs with aquatic organisms constitutes a much-needed area of research. In this article, we critically assess the evidence for immunotoxic effects of MNPs in bivalves and fish, as key wildlife sentinels with widely differing ecological niches that are used as models in ecotoxicology. The first part of this review details the properties, fate, and fundamental physicochemical behavior of MNPs in the aquatic ecosystem. We then consider the toxicokinetics of MNP uptake, accumulation, and deposition in fish and bivalves. The main body of the review then focuses on immune reactions in response to MNPs exposure in bivalves and fish illustrating their immunotoxic potential. Finally, we identify major knowledge gaps in our current understanding of the implications of MNPs exposure for immunological functions and the associated health consequences for bivalves and fish, as well as the general lessons learned on the immunotoxic properties of the emerging class of nanoparticulate contaminants in fish and bivalves. [ABSTRACT FROM AUTHOR]

The prevalence of unconventional oil and gas (UOG) operations raises concerns regarding the potential for adverse health outcomes following exposure to water tainted by mixtures of UOG associated chemicals. The potential effects that exposure to complex chemical mixtures has on the immune system have yet to be fully evaluated. In this study, effects on the immune system of adult mice exposed to a mixture of 23 chemicals that have been associated with water near active UOG operations were investigated. Female and male mice were exposed to the mixture via their drinking water for at least 8 weeks. At the end of the exposure, cellularity of primary and secondary immune organs, as well as an immune system function, were assessed using three different models of disease, i.e. house dust mite (HDM)-induced allergic airway disease, influenza A virus infection, and experimental autoimmune encephalomyelitis (EAE). The results indicated exposures resulted in different impacts on T-cell populations in each disease model. Furthermore, the consequences of exposure differed between female and male mice. Notably, exposure to the chemical mixture significantly increased EAE disease severity in females, but not in male, mice. These findings indicated that direct exposure to this mixture leads to multiple alterations in T-cell subsets and that these alterations differ between sexes. This suggested to us that direct exposure to UOG-associated chemicals may alter the adult immune system, leading to dysregulation in immune cellularity and function. [ABSTRACT FROM AUTHOR]

Sulfolane is a solvent used in the petrochemical industry and a groundwater contaminant in areas near refineries. The current studies were conducted to assess the impact of oral exposure to sulfolane on the immune system using two models: (1) a perinatal drinking water exposure to 0, 30, 100, 300, or 1000 mg/L from gestation day (GD) 6 until ∼13 weeks-of-age in Harlan Sprague Dawley rats; and, (2) a 90-day gavage exposure of adult female B6C3F1/N mice to 0, 1, 10, 30, 100, or 300 mg/kg/day. Immune parameters evaluated included measurement of antibody production against sheep red blood cells (SRBC) and keyhole limpet hemocyanin (KLH), ex vivo measurements of natural killer (NK) cell activity, cytotoxic T-cell (CTL) activity, and T-cell proliferation, as well as measures of splenic immune cell populations, hematological parameters, and histopathology of immune tissues. A decrease in ex vivo NK cell activity was observed in cells from female – but not male – F1 rats following developmental exposure. In adult female mice, splenic NK cell number was lower than the vehicle controls at doses ≥ 100 mg/kg; however, ex vivo NK cell activity was not affected by sulfolane treatment. In female mice, a decrease in the number of large unstained cells at doses ≥ 30 mg/kg was observed. In F1 rats, effects on white blood cells (WBC) were limited to a decreasing trend in leukocytes in females; no effects were observed in males. Under the conditions of this study, a no-observed-effect level (NOEL) of 3 mg/kg/day was identified based on reduced NK cell activity in female F1 rats. Overall, these findings suggest that oral exposure to sulfolane in rodents had minimal effects on the immune system. [ABSTRACT FROM AUTHOR]

A subacute toxicity test of 52.077 and 104.154 mg/L glyphosate-based herbicide (GBH) on common carp for 7 days was conducted. The results of qPCR reveled that GBH treatment generally promoted the HSP70, HSC70, and HSP90 levels in fish liver, kidney, spleen, and intestine, suggesting that the induction of HSPs might be associated with the toxicity of GBH. Further research revealed that GBH exposure remarkably promoted the expressions of IL-1β, IL-6, IL-8, IFN-γ, and TNF-α at mRNA level and altered the mRNA and protein levels of IL-10 and TGF-β, and generally inhibited T-AOC activity, but increased the MDA level, suggesting that GBH has immunotoxicity and causes oxidative stress on common carp. [ABSTRACT FROM AUTHOR]

Metal oxide nanoparticles are widely used in both consumer products and medical applications, but the knowledge regarding exposure-related health effects is limited. However, it is challenging to investigate nanoparticle interaction processes with biological systems. The overall aim of this project was to improve the possibility to predict exposure-related health effects of metal oxide nanoparticles through interdisciplinary collaboration by combining workflows from the pharmaceutical industry, nanomaterial sciences, and occupational medicine. Specific aims were to investigate nanoparticle-protein interactions and possible adverse immune reactions. Four different metal oxide nanoparticles; CeOx nanocrystals with 5% or 14% Gd, Co3O4, and Fe2O3, were characterized by dynamic light scattering and high-resolution transmission electron microscopy. Nanoparticle-binding proteins were identified and screened for HLA-binding peptides in silico. Monocyte interaction with nanoparticle–protein complexes was assessed in vitro. Herein, for the first time, immunogenic properties of nanoparticle-binding proteins have been characterized. The present study indicates that especially Co3O4-protein complexes can induce both 'danger signals', verified by the production of inflammatory cytokines and simultaneously bind autologous proteins, which can be presented as immunogenic epitopes by MHC class II. The clinical relevance of these findings should be further evaluated to investigate the role of metal oxide nanoparticles in the development of autoimmune disease. The general workflow identified experimental difficulties, such as nanoparticle aggregate formation and a lack of protein-free buffers suitable for particle characterization, protein analyses, as well as for cell studies. This confirms the importance of future interdisciplinary collaborations. [ABSTRACT FROM AUTHOR]

Endocrine-disrupting chemicals (EDCs) refer to a group of chemicals that cause adverse effects in human health, impairing hormone production and regulation, resulting in alteration of homeostasis, reproductive, and developmental, and immune system impairments. The immunotoxicity of EDCs involves many mechanisms altering gene expression that depend on the activation of nuclear receptors such as the aryl hydrocarbon receptor (AHR), the estrogen receptor (ER), and the peroxisome proliferator-activated receptor (PPAR), which also results in skin and intestinal disorders, microbiota alterations and inflammatory diseases. This systematic review aims to review different mechanisms of immunotoxicity and immunomodulation of T cells, focusing on T regulatory (Treg) and Th17 subsets, B cells, and dendritic cells (DCs) caused by specific EDCs such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), bisphenols (BPs) and polyfluoroalkyl substances (PFASs). To achieve this objective, a systematic study was conducted searching various databases including PubMed and Scopus to find in-vitro, in-vivo, and biomonitoring studies that examine EDC-dependent mechanisms of immunotoxicity. While doing the systematic review, we found species- and cell-specific outcomes and a translational gap between in-vitro and in-vivo experiments. Finally, an adverse outcome pathway (AOP) framework is proposed, which explains mechanistically toxicity endpoints emerging from different EDCs having similar key events and can help to improve our understanding of EDCs mechanisms of immunotoxicity. In conclusion, this review provides insights into the mechanisms of immunotoxicity mediated by EDCs and will help to improve human health risk assessment. Overview of the mechanisms of immunotoxicity of EDCs for T, B, and Dendritic cells and the main outcomes of exposure that result in immunotoxicity: imbalance of Treg/Th17 lymphocyte populations; a decrease of antibodies production; an increase of DCs maturation. [ABSTRACT FROM AUTHOR]

The potential public health risk through utilizing of zinc oxide nanoparticles (ZnO NPs) in food constitutes the major obstacle to the expansion of nanoparticle (NP) in food industry. Liver histology, bone marrow and liver genotoxicity, immunity, and oxidant status were investigated upon long-term ZnO NPs feed supplementation. One hundred and sixty male IR (Indian River) chicks were randomly allocated to one of the four dietary treatments: control, ZnO NPs at 10, 20, or 40 mg/kg for 42 days. This study revealed non-significant hepatic histopathological alterations and DNA damage and the treatment had no influence on body and organ weights, liver enzymes, lipid peroxidation (MDA), IgG, IgM, and interferon gamma (IFN-γ). This study suggests that low-dose (< 40 mg/kg diet) long-term ZnO NPs supplementation to broiler chicks has no observed potential adverse effects on normal histology of the liver, blood physiology, immune system, and DNA damage of liver and bone marrows, which are critical features for validating ZnO NPs for use in food. Further studies are required to evaluate the probable withdrawal period of ZnO NPs before approval as a dietary supplement in broiler or livestock diets. [ABSTRACT FROM AUTHOR]

Bisphenols are common chemicals found in plastics and epoxy resins. Over the past decades, many studies have shown that bisphenol A (BPA) is a potential endocrine-disrupting chemical that may cause multisystem toxicity. However, the relative safety of BPA analogues is a controversial subject. Herein, we conducted a review of the reproductive toxicity, neurotoxicity, immunotoxicity, metabolic toxicity and gut microbiome toxicity of the BPA analogues in various species, including Caenorhabditis elegans, zebrafish, turtles, sheep, rodents, and humans. In addition, the mechanisms of action were discussed with focus on bisphenol S and bisphenol F. It was found that these BPA analogues exert their toxic effects on different organs and systems through various mechanisms including epigenetic modifications and effects on cell signaling pathways, microbiome, and metabolome in different species. More research is needed to study the relative toxicity of the lesser-known BPA analogues compared to BPA, both systemically and organ specifically, and to better define the underlying mechanisms of action, in particular, the potentials of disrupting microbiome and metabolism. [ABSTRACT FROM AUTHOR]

Aflatoxin M1 (AFM1) is a 4-hydroxylated metabolite of aflatoxin B1 (AFB1). It induces various toxicological effects including immunotoxicity. In the present study, we investigated the effects of AFM1 on immune system and its modulation by MicroRNA (miR)-155. AFM1 was administered intraperitoneally at doses of 25 and 50 µg/kg for 28 days to Balb/c mice and different immune system parameters were analyzed. The levels of miR-155 and targeted proteins were evaluated in isolated T cells from spleens of mice. Spleen weight was reduced in mice exposed to AFM1 compared to negative control. Proliferation of splenocytes in response to phytohemagglutinin-A was reduced in mice exposed to AFM1. IFN-γ was decreased in mice exposed to AFM1, whereas IL-10 was increased. Concentration of IL-4 did not change different in mice exposed to AFM1 compared to negative control. Exposure to AFM1 reduced the expression of miR-155. Significant upregulation of phosphatidylinositol-3, 4, 5-trisphosphate 5-phosphatase 1 (Ship1) and suppressor of cytokine signaling 1 (Socs1) was observed in isolated T cells from spleens of mice treated with AFM1, but the transcription factor Maf (c-MAF) was not affected. These results suggest that miR-155 and targeted proteins might be involved in the immunotoxicity observed in mice exposed to AFM1. The Immunotoxic effects of AFM1 on T cell functions. Exposure to AFM1 reduced the expression of miR-155. Significant upregulation of Ship1 and Socs1 was observed in isolated T cells from spleens of mice treated with AFM1, but the c-MAF was not affected. Since Ship1 is a functional target of miR-155 that modulates production of IFN-γ, miR-155 may play a role in AFM1-induced Th1 response suppression (DTH) through targeting of this protein (↑ increase; ↓ decrease). AFM1 inhibited cell-mediated immunity. Exposure of mice to AFM1 resulted in a significant decrease in expression of miR-155. Exposure of mice to AFM1 resulted in up-regulation of Ship1 and Socs1. [ABSTRACT FROM AUTHOR]

Fumonisin B1 (FB1) is a natural contaminant of agricultural commodities that has displayed a myriad of toxicities in animals. Moreover, it is known to be a hepatorenal carcinogen in rodents and may be associated with oesophageal and hepatocellular carcinomas in humans. The most well elucidated mode of FB1-mediated toxicity is its disruption of sphingolipid metabolism; however, enhanced oxidative stress, endoplasmic reticulum stress, autophagy, and alterations in immune response may also play a role in its toxicity and carcinogenicity. Alterations to the host epigenome may impact on the toxic and carcinogenic response to FB1. Seeing that the contamination of FB1 in food poses a considerable risk to human and animal health, a great deal of research has focused on new methods to prevent and attenuate FB1-induced toxic consequences. The focus of the present review is on the molecular and epigenetic interactions of FB1 as well as recent research involving FB1 detoxification. [ABSTRACT FROM AUTHOR]

Aflatoxin M1 (AFM1) is a 4-hydroxylated metabolite of aflatoxin B1 (AFB1). It induces various toxicological effects including immunotoxicity. In the present study, we investigated the effects of AFM1 on immune system and its modulation by MicroRNA (miR)-155. AFM1 was administered intraperitoneally at doses of 25 and 50 µg/kg for 28 days to Balb/c mice and different immune system parameters were analyzed. The levels of miR-155 and targeted proteins were evaluated in isolated T cells from spleens of mice. Spleen weight was reduced in mice exposed to AFM1 compared to negative control. Proliferation of splenocytes in response to phytohemagglutinin-A was reduced in mice exposed to AFM1. IFN-γ was decreased in mice exposed to AFM1, whereas IL-10 was increased. Concentration of IL-4 did not change different in mice exposed to AFM1 compared to negative control. Exposure to AFM1 reduced the expression of miR-155. Significant upregulation of phosphatidylinositol-3, 4, 5-trisphosphate 5-phosphatase 1 (Ship1) and suppressor of cytokine signaling 1 (Socs1) was observed in isolated T cells from spleens of mice treated with AFM1, but the transcription factor Maf (c-MAF) was not affected. These results suggest that miR-155 and targeted proteins might be involved in the immunotoxicity observed in mice exposed to AFM1. The Immunotoxic effects of AFM1 on T cell functions. Exposure to AFM1 reduced the expression of miR-155. Significant upregulation of Ship1 and Socs1 was observed in isolated T cells from spleens of mice treated with AFM1, but the c-MAF was not affected. Since Ship1 is a functional target of miR-155 that modulates production of IFN-γ, miR-155 may play a role in AFM1-induced Th1 response suppression (DTH) through targeting of this protein (↑ increase; ↓ decrease). AFM1 inhibited cell-mediated immunity. Exposure of mice to AFM1 resulted in a significant decrease in expression of miR-155. Exposure of mice to AFM1 resulted in up-regulation of Ship1 and Socs1. [ABSTRACT FROM AUTHOR]

Oral mucositis (OM) is a severe side effect in patients undergoing anticancer therapies, which negatively impacts on their quality of life often leading to either the interruption of the therapy. Photobiomodulation (PBM) is emerging as an effective strategy allowing a faster wound healing. This pilot study aims at verifying whether PBM modulates the inflammatory response in patients and its effect on the oral microbiome composition. Buccal swabs were collected from four patients affected by OM, both on ulcerated and clinically healthy areas, before and on the last day of PBM therapy, as well as on the first day after treatment discontinuation. The concentration of 38 cytokines and the composition of oral microbiome were measured. Most of the pro-inflammatory cytokines were reduced, whereas anti-inflammatory cytokines resulted up-regulated by PBM. In addition, PBM influenced the composition of oral microbiome, by decreasing the amount of pathogenic species and promoting the growth of commensal bacteria. These changes were even more evident when separately analysing patients who clinically responded to PBM and the only patient who did not respond. PBM reduces inflammatory burden in patients affected by OM and positively influences the composition of the oral microbiome. [ABSTRACT FROM AUTHOR]

Zinc ferrate nanoparticles (ZnFe2O4 NPs) have attracted enormous interest as potential nanomaterials. The purpose of this study was to examine the in vitro macrophages toxicity, in vivo safety, and immunogenicity. Three kinds of ZnFe2O4 NPs with different shapes (round, litchi, and raspberry), nano-sizes, and pores were successfully prepared. In vitro experiments showed that ZnFe2O4 NPs caused no cytotoxicity against the RAW 264.7 cells up to administered dose of 200 μg/mL, enhanced proinflammatory cytokine TNF-α, and costimulatory marker CD86 expression in the RAW 264.7 cells. Interestingly, ZnFe2O4 NPs reduced ROS expression, which was inconsistent with common metal oxide NPs such as iron oxide (Fe3O4) NPs and zinc oxide (ZnO) NPs. ZnFe2O4 NPs improved the RAW 264.7 cells phagocytosed more neutral red. There was no obvious difference in body weight, the number of immune cells, organ index, and expression of inflammatory factors in serum of rats administrated intravenously and subcutaneously on day 21 after treatment by ZnFe2O4 NPs in comparison with the blank control. These results demonstrated that ZnFe2O4 NPs slightly enhanced the function of the RAW 264.7 cells in vitro but caused no obvious toxicity to macrophages as well as rat blood cells, and low immunogenicity in rats, suggesting that ZnFe2O4 NPs as a biocompatible nanomaterials achieved potential for bioapplication in the future. [ABSTRACT FROM AUTHOR]

Resveratrol is a naturally occurring polyphenol that is being investigated to treat and prevent various diseases, both experimentally and in the clinic. Despite increased use and interest in resveratrol due to its immunomodulatory properties, there is a lack of studies evaluating potential toxicities, particularly immunotoxicity, associated with resveratrol use. A previous 2-week study found decreasing thymus weight in male B6C3F1/N mice with increasing exposure to trans-resveratrol. This study is a follow-up on those findings by evaluating immune function. Male adult B6C3F1/N mice were given trans-resveratrol (0, 156, 312, 625, 1250, 2500 mg/kg/day) via oral gavage for 28 days and functional immune tests and histopathology were evaluated. There were no treatment-related effects on body weight during the study. Humoral, cell-mediated, and innate immune function were not altered after 28 days of trans-resveratrol treatment. There were also no changes in organ weight or microscopic alterations in immune organs. Overall, under the conditions of this study, there was no evidence of immunotoxicity or improvements in immune function associated with oral exposure to trans-resveratrol in male mice. Importantly, the immunomodulatory benefits of resveratrol may require a prerequisite level of inflammatory activity and may not be observable in healthy individuals. [ABSTRACT FROM AUTHOR]

Various types of transgenic mice carrying either class I or II human leukocyte antigen (HLA) molecules are readily available, and reports describing their use in a variety of studies have been published for more than 30 years. Examples of their use include the discovery of HLA-specific antigens against viral infection as well as the reproduction of HLA-mediated autoimmune diseases for the development of therapeutic strategies. Recently, HLA transgenic mice have been used to reproduce HLA-mediated idiosyncratic drug toxicity (IDT), a rare and unpredictable adverse drug reaction that can result in death. For example, abacavir-induced IDT has successfully been reproduced in HLA-B*57:01 transgenic mice. Several reports using HLA transgenic mice for IDT have proven the utility of this concept for the evaluation of IDT using various HLA allele combinations and drugs. It has become apparent that such models may be a valuable tool to investigate the mechanisms underlying HLA-mediated IDT. This review summarizes the latest findings in the area of HLA transgenic mouse models and discusses the current challenges that must be overcome to maximize the potential of this unique animal model. [ABSTRACT FROM AUTHOR]

Prenatal particle exposure has been shown to increase allergic responses in offspring. Carbon nanotubes (CNTs) possess immunomodulatory properties, but it is unknown whether maternal exposure to CNTs interferes with offspring immune development. Here, C57Bl/6J female mice were intratracheally instilled with 67 of μg multiwalled CNTs on the day prior to mating. After weaning, tolerance and allergy responses were assessed in the offspring. Offspring of CNT-exposed (CNT offspring) and of sham-exposed dams (CTRL offspring) were intranasally exposed to ovalbumin (OVA) once weekly for 5 weeks to induce airway mucosal tolerance. Subsequent OVA sensitization and aerosol inhalation caused low or no OVA-specific IgE production and no inflammation. However, the CNT offspring presented with significantly lower OVA-specific IgG1 levels than CTRL offspring. In other groups of 5-week-old offspring, low-dose sensitization with OVA and subsequent OVA aerosol inhalation led to significantly lower OVA-specific IgG1 production in CNT compared to CTRL offspring. OVA-specific IgE and airway inflammation were non-significantly reduced in CNT offspring. The immunomodulatory effects of pre-gestational exposure to multiwalled CNTs were unexpected, but very consistent. The observations of suppressed antigen-specific IgG1 production may be of importance for infection or vaccination responses and warrant further investigation. [ABSTRACT FROM AUTHOR]

Engineered nanomaterials (ENM) are being used in a wide range of consumer products and pharmaceuticals; hence, there is an increasing risk for human exposure and potential adverse outcomes. The immune system, vital in host defense and protection against environmental agents, is typically initiated and executed by innate effector immune cells including macrophages and neutrophils. Previous literature has reported the immune system as a major target of ENM toxicity; however, there is inconsistency regarding the immunotoxicity of ENM. This could be attributed to differences in ENM physicochemical properties, cellular models examined, biocorona formation, etc. Thus, the current study examined the toxicity and immunomodulatory effects of silver nanoparticles (AgNP), one of the most utilized ENM in consumer and medical products, in two key innate immune cell models, e.g. RAW 264.7 cells (macrophages) and differentiated MPRO 2.1 cells (promyelocytes/neutrophils). The results showed that despite a generation of reactive oxygen species, exposure to 20 nm citrate-coated AgNP was not associated with major oxidative damage, inflammatory responses, nor cytotoxicity. Nevertheless, and most importantly, pre-exposure to the AgNP for 24 h enhanced RAW 264.7 cell phagocytic ability as well as the release of inflammatory cytokine interleukin-6 in response to lipopolysaccharide (LPS). In MPRO 2.1 cells, AgNP pre-exposure also resulted in enhanced phagocytic ability; however, these cells manifest reduced cell degranulation (elastase release) and oxidative burst in response to phorbol myristate acetate (PMA). Taken together, these findings indicated to us that exposure to AgNP, despite not being directly (cyto)toxic to these cells, had the potential to alter immune cell responses. The findings underscore the import of assessing immune cell function post-exposure to ENM beyond the standard endpoints such as oxidative stress and cytotoxicity. In addition, these findings further illustrate the importance of understanding the underlying molecular mechanisms of ENM-cellular interactions, particularly in the immune system. [ABSTRACT FROM AUTHOR]

This study was performed to determine the median lethal concentration (96-h LC50) of penoxsulam (PNX) in Nile tilapia, Oreochromis niloticus, fingerlings and to investigate the protective effect of vitamin E (Vit E) against biochemical and immunological alterations induced by two sublethal concentrations of PNX (1/10 and 1/20 of 96-h LC50). The 96-h LC50 of PNX was found to be 3.1 mg l−1. Fish was exposed to sublethal concentrations of PNX for 45 days. The fish exposed to Vit E + PNX were fed a Vit E-supplemented diet (700 mg kg–1 diet) daily for 10 days, then exposed to the same concentrations of PNX and fed a Vit E-supplemented diet for 45 days. The results showed that PNX exposure caused significant concentration-dependent increases in serum alanine transaminase, aspartate transaminase, creatinine, malondialdehyde and nitric oxide and significant decreases in serum total protein, albumin, reduced glutathione, glutathione peroxidase, superoxide dismutase and lysozyme activity. Furthermore, PNX significantly upregulated the expression of immune-related genes in the head kidney in a concentration-dependent manner when compared with the control group. However, Vit E supplementation in the diet alleviated PNX-induced toxic effects. These results concluded that Vit E could be effective in the protection of fish against PNX toxicity. [ABSTRACT FROM AUTHOR]

Silver nanoparticles (AgNPs) are now being of a great interest by ecotoxicological researchers. Their potential hazards to humans and other non-target organisms had led to crucial concerns. In this research, white radish leaf extract was used for the green synthesis of AgNPs. UV–Vis spectroscopy, transmission electron microscopy (TEM) and X-ray diffraction (XRD) have been utilised to characterise the biosynthesised AgNPs. Furthermore, the present study aimed to investigate the ecotoxicological effects of 1 mM biosynthesised AgNPs on the land snail, Theba pisana after two weeks of exposure and one week recovery with respect to oxidative stress parameters; lipid peroxidation (LPO), reduced glutathione (GSH), catalase (CAT) and glutathione-S-transferase (GST), cytogenetic parameters; DNA content and micronucleus test, as well as immunological parameters; cell death, phagocytosis, lysosomal membrane stability (LMS), lectins, superoxide anion (O2−) generation, phenoloxidase (PO), peroxidase (POD) and haemocyanin (Hc) were examined. AgNPs have been biosynthesised successfully; the UV–vis spectrum exhibited a single and broad absorption band located between 375 and 415 nm, TEM image shows AgNPs formed were nearly spherical in shape with a mean size of 2.18–19.87 nm and the crystalline nature of nanoparticles was confirmed by XRD. After two weeks exposure, the result showed that AgNPs significantly increased LPO level as well as CAT and GST activities, cell death, cell abnormalities and Hc level, whereas, significant decline was found in DNA and GSH contents, phagocytic activity, LMS, lectins, O2− generation, POD and PO activities compared to the controls. After a week of recovery, most of the tested biomarkers in AgNP-exposed snails did not completely return to the control levels. The multiple measured parameters could be effectively used as sensitive biomarkers in the risk assessment of contaminants in the terrestrial ecosystem. [ABSTRACT FROM AUTHOR]

Modified nanoparticles (NPs) can interact with the immune system by causing its activation to fight tumors or for vaccination. During this activation, dendritic cells (DCs) are effective in generating robust immune response. However, the effect of nanomaterials on dendritic cell (DC) maturation, and the associated adjuvant effect, should be assessed as a novel biocompatibility criteria for biomaterials since immune consequences may constitute potential complications in nanomedicine. Among emerging biomaterials, poly(lactic-co-glycolic acid) NPs (PLGA NPs) are widely explored for various applications in which the degree of desired adjuvant effect may vary. As contradictory results are reported regarding their effects on DCs, we aimed at clarifying this point with particular emphasis on the relative impact of particle surface properties. To that end, NP uptake and effects on the viability, phenotype, and secretory activity of DC primary cultures. Intracellular signaling pathways were explored and evaluated. Immature human and murine DCs were exposed to cationic, neutral, or anionic PLGA NPs. Particle uptake was assessed by both confocal microscopy and flow cytometry. Cell viability was then evaluated prior to the study of maturation by examination of both surface marker expression and cytokine release. Our results demonstrate that PLGA NPs are rapidly engulfed by DCs and do not exert cytotoxic effects. However, upon exposure to PLGA NPs, DCs showed phenotypes and cytokine secretion profiles consistent with maturation which resulted, at least in part, from the transient intracellular activation of mitogen-activated protein kinases (MAPKs). Interestingly, NP-specific stimulation patterns were observed since NP surface properties had a sensible influence on the various parameters measured. [ABSTRACT FROM AUTHOR]

Aim: Aluminum (Al) is a ubiquitous element extensively utilized in many products like food additives, pharmaceuticals, and vaccines, but its hematotoxic and immunotoxic effects are not entirely clarified. The present study explored the developmental hematotoxic and immunotoxic properties of aluminum sulfate (AS) in rats' offspring. Methods: Forty female offspring (10 rats each) were given three incremental AS doses plus a control group, from conception through lactation and after weaning until reached eight weeks old (near adults). Spleen relative weights along with total and differential blood counts were evaluated. Spectroscopic Al levels in spleen and brain were analyzed. Three immunoglobulins (IgG, IgM, and IgE) and two cytokines, interferon-γ and tumor necrosis factor-α, were measured through the ELISA technique. Results: The results revealed a significant relative increase in splenic weights mostly observed in the highest AS dose treated group. Reduction in the total leukocytic count was noticed in the three AS treated groups with relative lymphocytosis. Additionally, a significant decline in RBCs counts and hemoglobin concentrations were recorded. Tumor necrosis factor-α was significantly elevated in the three Al treated groups, while, interferon- γ showed a non-significant reduction compared to the control group. A significant increment in IgG and decline in IgE concentrations with no change in IgM level among groups were observed. Conclusion: Perinatal AS exposure caused mostly non-linear dose-dependent hematotoxicity and immunological impairment especially for the acquired immunity either cellular or humoral. Further studies can examine the immunotoxic effect of Al on male offspring during different stages of immune development. [ABSTRACT FROM AUTHOR]

Imidacloprid (IMI), a neonicotinoid insecticide, is widely used to control pests in agriculture. We investigated the changes in antioxidant enzyme activities, lipid peroxidation levels, biochemical effects, genotoxic effect, and immunotoxic effect of sublethal doses (0.25, 0.50, 0.75, and 1.00 µg) of IMI at different time periods (24, 48, 72, and 96 h) on a model organism, Galleria mellonella L. The results indicated that there were dose-dependent increases in both antioxidant enzyme activities (SOD and CAT) and MDA levels. Protein content was not affected by IMI at 24th and 48th, whereas it was decreased by the highest dose of IMI (1.00 µg) at 72nd and 96th h. Lipid and carbohydrate contents were reduced with increasing doses of IMI. Micronucleus frequency significantly increased in all IMI doses. All IMI doses caused a significant decrease in THC at 24th, 48th, and 72nd h. Our results can help to illustrate the effects of IMI in target organisms and indirectly may aid to discover potential risk of it on nontarget organisms. Future studies, at molecular levels, will be helpful in understanding the mechanism of action of IMI on these biomarkers. [ABSTRACT FROM AUTHOR]

The immunotoxic potential of drug candidates is assessed through the examination of results from a variety of studies and endpoints. While the functional assessment of CD8+ cytotoxic T-lymphocytes (CTL) is well-characterized in the clinic, the lack of a robust macaque CTL functional assay has been an important hurdle in evaluating and accurately quantifying cell-mediated CD8+ T-cell effector responses in the nonclinical setting. This paper describes the development of an assay to measure CTL activity in peripheral blood mononuclear cells (PBMC) isolated from Cynomolgus macaques. A human EGFR/CD3 Bispecific T-cell Engager (BiTE®) was used to mount a robust CD8+ T-cell response in the presence of target-expressing cells. Upon target engagement, degranulation of CD107a and production of interferon (IFN)-γ both reliably indicated a robust functional response in CD8+ T-cells. The BiTE®-mediated stimulation method proved to be favorable when compared to other methods of stimulation in the absence of target cells. These studies demonstrated acceptable longitudinal variability of the functional assay and sensitivity to dexamethasone-mediated immunosuppression. Taken together, the results indicated an assay leveraging CD3-bispecific antibodies and target-expressing cells can provide a robust approach to the in vitro or ex vivo assessment of CTL function in Cynomolgus macaques. Because the impairment of CTL activity by immunomodulators is recognized to be an important contributor to decreased antiviral defense and increased carcinogenicity risk, we believe that this novel assay to be a valuable addition to the immunotoxicology assessment of therapeutic drug candidates. [ABSTRACT FROM AUTHOR]

Skin sensitization is an important occupational health problem and immunotoxicity endpoint. Considering animal welfare and time and cost savings, many alternative approaches, such as those conducted in vitro, in silico, and in chemo, have been proposed and applied to predict skin sensitization of compounds. Toxicologically, sensitizers can elicit excess toxicity at greater levels than non-sensitizers due to their capacity to react with proteins/peptides. Based on this understanding, calculated toxicity enhancements (Te) of 65 organic compounds from three in vitro bioassays, i.e. 48-hr ciliate (Tetrahymena pyriformis) growth inhibition, and both 96-hr fathead minnow and 48-hr Daphnia magna acute lethal toxicities, were employed to qualitatively and quantitatively predict skin sensitization potencies of the test agents. The sensitivity, specificity, and accuracy reaching 80% strongly suggested toxicity enhancement was an excellent parameter for predicting skin sensitization. Linear regressions of skin sensitization against toxicity enhancement were fitted for each bioassay, and they were improved after the sensitizers were categorized into different reaction mechanistic domains, which, in decreasing order of contribution from Te to sensitization, were SNAr > SN1 > MA. These results indicated that toxicity bioassays are useful tools and that Te could be a useful parameter that might be applied to predict skin sensitization. [ABSTRACT FROM AUTHOR]

The nerve agent VX is one of the most deadly threat agents available in weapons stockpiles for intentional release. While mostly considered a percutaneous toxicant, it can be fatal when aerosolized. The objective of this study was to investigate toxic responses in the lung up to two weeks following a single 10-minute exposure to inhaled VX. Anesthetized rats were exposed singly and only once to VX. The nebulization rate in this system was 0.2-0.3 ml per minute with the delivery of a consistent particle size of 2.1 µm. Following exposure, all rats were removed from the ventilator and allowed to recover in the glovebox for 10-15 minutes. Results showed that inhaled VX altered several respiratory parameters and caused increased lung resistance up to 6 h post-exposure (PE). There was a trending increase in SOD and xanthine oxidoreductase (XOR) activities, both of which are indicative of oxidative stress. Based on increased lung tissue p38 signaling, MAP kinase expression was activated after VX exposure. IL-6 expression was also increased at 6 h post-inhalation for the 31.6 mg/m3 exposed group. Innate survival response mechanisms in rats may be present due to increased lung tissue mRNA AChE expression 6 h after exposure. Immunohistochemistry showed reduced staining for surfactant D and increased expression of iNOS, indicating that the activation of •NO precursor pathways. Bronchoalveloar lavage fluid (BALF) results from 1 h to 2 weeks PE show that inflammatory cells are highly active as evidenced by the increased production of cytokines and chemokines. This is the first study linking VX-induced lung injury to a possible innate survival amplification of AChE and possibly compromised immune function. These results could supplement medical treatment strategies with regard to therapeutic approaches against VX inhalational challenge. [ABSTRACT FROM AUTHOR]

Recently, magnetic nanoparticles (MNP) have been used in several medical applications. High accumulations of MNP can be found in spleen and liver after different injection routes. Immunotoxicities produced by MNP in spleen, a lymphoid organ, need more investigations. This study investigated biodistribution, histological and immune responses to MNP in spleen after intra-testicular injection. Echinacea purpurea (EP) extract has immune stimulation and anti-oxidant properties. Investigation was done on the role of EP reduction of immunotoxicities produced by MNP in the spleen. After intra-testicular injection, MNP reached spleen parenchyma through blood circulation. Long term EP administration induced mild iron accumulation resulting from red blood cell (RBC) lysis. The opposite was observed when MNP treatment during EP administration significantly reduced lysed RBC iron in the spleen as well as MNP iron. It is possible the chelating properties of EP molecules possibly explained the presence of inert iron complexes from RBC in the spleen after EP administration only. The presence of MNP induced severe splenic cell degeneration and hemorrhage. The treatment with MNP combined with EP administration reduced these abnormalities. Additionally, anti-oxidant properties of EP and presence of MNP iron in the spleen had a role in activating macrophages to recycle all splenic iron. However, F4/80+, immunoglobulin A (IgA)+ and Ulex europaeus agglutinin I (UEAI)+ expressions significantly decreased when MNP were injected without EP. Otherwise, long term EP treatment maintained normal function of these cells. [ABSTRACT FROM AUTHOR]

Polycyclic aromatic hydrocarbons are pollutants which are persistent in nature. The aryl hydrocarbon receptor is a ligand-activated cytosolic transcription factor activated by xenobiotics. The objective was to isolate and identify AHR mRNA transcript in immune organs of developing chicks and to interpret the correlation between AHR induction and dose of PAHs. Specific pathogen free embryonated eggs on day nine were inoculated with solutions of pyrene, phenanthrene, and fluoranthene dissolved in tricaprylin (vehicle) through the allantoic route at three dose levels: 0.2 mg/kg, 2 mg/kg, and 20 mg/kg. A 650 base pair product was observed by RNA extraction and reverse transcription PCR from thymus, bursa of Fabricius and spleen on 21st day. When AHR concentration was analyzed by ELISA in these organs, pyrene showed maximum potency in inducing AHR in thymus. Fluoranthene made highest concentration of AHR in bursa of Fabricius. None of these chemicals caused an increase in AHR concentration in spleen. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate in vitro effects of fenitrothion (FNT) on mouse splenic lymphocytes. Here, naïve mice had their spleens harvested and splenocytes isolated. After exposure to FNT for 48 hr: splenocyte viability was measured using a tetrazolium dye assay; cell phenotypes, i.e., B-cells (CD19+), T-cells (CD3+), and T-cell subsets (CD4+ and CD8+), were quantified by flow cytometry; and, production of cytokines/granzyme-B was assessed via enzyme-linked immunosorbent assay. The ability for FNT to induce oxidative stress in the cells was evaluated by measuring hydroxyl radical (·OH) and malondialdehyde (MDA) production and changes in glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activity. The results showed that FNT significantly inhibited splenocyte proliferation, and decreased production of interleukin (IL)-2, interferon gamma, IL-4, and granzyme B, but had no impact on IL-6 production. FNT also selectively decreased splenic T-cell levels but did not induce changes in CD19+ B-cells. Further, within the T-cell populations, percentages of CD3+, CD4+, and CD8+ T-cells (particularly CD8+ T-cells) were reduced. Lastly, FNT selectively increased MDA and ·OH production and inhibited SOD and GSH-Px activities in the splenic lymphocytes. These findings suggest that, due to oxidative damage, FNT selectively inhibits splenic T-lymphocyte survival and cytokine/granzyme production in vitro. [ABSTRACT FROM AUTHOR]

Sodium dichromate dihydrate (SDD), an inorganic compound containing hexavalent chromium (Cr(VI)), is a common environmental contaminant of groundwater sources due to widespread industrial use. There are indications in the literature that Cr(VI) may induce immunotoxic effects following dermal exposure, including acting as both an irritant and a sensitizer; however, the potential immunomodulatory effects of Cr(VI) following oral exposure are relatively unknown. Following the detection of Cr(VI) in drinking water sources, the National Toxicology Program (NTP) conducted extensive evaluations of the toxicity and carcinogenicity of SDD following drinking water exposure, including studies to assess the potential for Cr(VI) to modulate immune function. For the immunotoxicity assessments, female Fischer 344/N (F344/N) and Sprague Dawley (SD) rats and female B6C3F1mice were exposed to SDD in drinking water for 28 consecutive days and evaluated for alterations in cellular and humoral immune function as well as innate immunity. Rats were exposed to concentrations of 0, 14.3, 57.3, 172, or 516 ppm SDD while mice were exposed to concentrations of 0, 15.6, 31.3, 62.5, 125, or 250 ppm SDD. Final mean body weight and body weight gain were decreased relative to controls in 250 ppm B6C3F1mice and 516 ppm SD rats. Water consumption was significantly decreased in F344/N and SD rats exposed to 172 and 516 ppm SDD; this was attributed to poor palatability of the SDD drinking water solutions. Several red blood cell-specific parameters were significantly (5–7%) decreased in 250 ppm mice; however, these parameters were unaffected in rats. Sporadic increases in the spleen IgM antibody response to sheep red blood cells (SRBC) were observed, however, these increases were not dose-dependent and were not reproducible. No significant effects were observed in the other immunological parameters evaluated. Overall, exposure to Cr(VI) in drinking water had limited effects on the immune system in both rats and mice. [ABSTRACT FROM PUBLISHER]

Exposure to arsenic (As) is an ongoing, and in some places increasing, health problem. Still, however, the effects of As exposure on the immune system are not well understood. Dendritic cells (DC) are a critical immune cell that bridges the innate and adaptive immune systems. To determine the impact of inorganic (i)As exposure on DC, the effects of (geo)anthropogenically relevant levels of NaAsO2on the function of porcine monocyte-derived DC (MoDC) were evaluated in anin vitromodel. The results showed a low dose of iAs reduced the phagocytic capacity of MoDC. Furthermore, although surface expression of DC activation markers, such as major histocompatibility complex (MHC)-II, CD80/86, CD40 and CD25, were only slightly changed, MoDC T-cell proliferation-inducing capacity was remarkably diminished by iAs treatment. Additionally, iAs induced significant interleukin (IL)-6 secretion by MoDC after 12- or 24-h incubation, whereas IL-1β secretion was only significantly up-regulated after 12 h. The secretion patterns of IL-8, tumor necrosis factor α (TNFα and IL-10 by iAs-treated MoDC were almost similar to that by mock-treated MoDC. Considering the broad roles of DC in immunobiology, this finding deepens the understanding of molecular mechanisms/functional consequences underpinning the immunopathology, inflammation, and increases in infection arising from As exposure. [ABSTRACT FROM AUTHOR]

Environmentally induced perturbation of health parameters lead to morphological changes associated to the inflammatory response. Hematoxyline and eosin (H&E)-stained gill filaments sections were examined for such changes and inflammation intensity was scored according to a quantitative model in order to evaluate the health status ofin vivoexposed (for 3, 6, and 12 h) mussels to silver nanoparticles (Ag-NPs <50 nm and Ag-NPs <100 nm) prior and after the inhibition of two potential uptake pathways (clathrin- and caveolae-mediated endocytosis) with the aid of pharmaceutical inhibitors (amantadine and nystatin). The impacts of the nanoparticles (NPs) size, as well as their uptake routes within different time of exposure on the inflammatory response were assessed. The results showed that Ag-NPs clearly induced morphological changes associated to the inflammatory response in gill tissues (Mann–Whitneypvalues were <.05). It is also clear that the length of the exposure as well as the NP size highly impacted inflammation intensity (highest histopathological indices recorded with Ag-NPs <100 nm). Also, the routes of NPs entry noticed to be major factor underlying inflammatory response (significant inflammation intensity reported with Ag-NPs <50 nm after blockade of uptake routes;p <.05). Throughout, it was concluded that inflammation intensity was related to NPs size and exposure time. Overall, uptake routes are shown to be the major factor underlying nanotoxicity. [ABSTRACT FROM AUTHOR]

Context:Soluble CD40 ligand (sCD40l) can predict cardiovascular events (CVE) and mortality in haemodialysis (HD) patients (short-, medium-term follow-up studies). Objective:To evaluate the relationship between sCD40l and survival, CVE and mortality in HD patients on long-term follow-up. Methods:We registered 46 HD patients’ baseline characteristics, mortality and CVE for 108 months. Results: SCD40l correlated positively with C-reactive protein, was higher in survivors, but had no impact on survival and was not predictive for CVE or CV mortality. Conclusion:The levels of sCD40l have no influence on survival or CVE and mortality in HD patients in a long-term follow-up. [ABSTRACT FROM PUBLISHER]

Mercury (Hg) is toxic and hazardous metal that causes natural disasters in the earth's crust. Exposure to Hg occurs via various routes; like oral (fish), inhalation, dental amalgams, and skin from cosmetics. In this review, we have discussed the sources of Hg and its potential for causing toxicity in humans. In addition, we also review its bio-chemical cycling in the environment; its systemic, immunotoxic, genotoxic/carcinogenic, and teratogenic health effects; and the dietary influences; as well as the important considerations in risk assessment and management of Hg poisoning have been discussed in detail. Many harmful outcomes have been reported, which will provide more awareness. [ABSTRACT FROM PUBLISHER]

C60 fullerene (C60), or buckminsterfullerene, is a spherical arrangement of 60 carbon atoms, having a diameter of approximately 1 nm, and is produced naturally as a by-product of combustion. Due to its small size, C60 has attracted much attention for use in a variety of applications; however, insufficient information is available regarding its toxicological effects. The effects on respiratory toxicity and immunotoxicity of C60 aggregates (50 nm [nano-C60] and 1 μm [micro-C60] diameter) were examined in B6C3F1/N mice and Wistar Han rats after nose-only inhalation for 13 weeks. Exposure concentrations were selected to allow for data evaluations using both mass-based and particle surface area-based exposure metrics. Nano-C60 exposure levels selected were 0.5 and 2 mg/m3(0.033 and 0.112 m2/m3), while micro-C60 exposures were 2, 15 and 30 mg/m3(0.011, 0.084 and 0.167 m2/m3). There were no systemic effects on innate, cell-mediated, or humoral immune function. Pulmonary inflammatory responses (histiocytic infiltration, macrophage pigmentation, chronic inflammation) were concentration-dependent and corresponded to increases in monocyte chemoattractant protein (MCP)-1 (rats) and macrophage inflammatory protein (MIP)-1α (mice) in bronchoalveolar lavage (BAL) fluid. Lung overload may have contributed to the pulmonary inflammatory responses observed following nano-C60 exposure at 2 mg/m3and micro-C60 exposure at 30 mg/m3. Phenotype shifts in cells recovered from the BAL were also observed in all C60-exposed rats, regardless of the level of exposure. Overall, more severe pulmonary effects were observed for nano-C60 than for micro-C60 for mass-based exposure comparisons. However, for surface-area-based exposures, more severe pulmonary effects were observed for micro-C60 than for nano-C60, highlighting the importance of dosimetry when evaluating toxicity between nano- and microparticles. [ABSTRACT FROM PUBLISHER]

Amphenicols are effective, broad-spectrum antibiotics that function by inhibiting the peptidyl transferase activity of bacteria, while the drugs can also inhibit mitochondrial protein synthesis in eukaryotes through the same mechanism, which leads to multi-organ toxicity. Some side effects of each drug have been studied, while differences in the severity of the hemotoxicities and immunotoxicities of amphenicols have not been reported. Thus, it is important to identify, evaluate, and compare the potential hemotoxicities and immunotoxicities to guide their proper use in humans and animals, which will guarantee food safety and animal welfare. Ovalbumin-immunized Kunming mice were gavaged daily with amphenicols for seven days. Blood samples were collected for hematology analysis, and measuring anti-ovalbumin antibody levels and serum intereukin-2 concentrations. The bone marrow, spleen and thymus were collected for histopathology and apoptosis analyzes. Bone marrow nucleated cells (BMNCs) and splenocytes were harvested to determine their cell cycle stages and to analyze lymphocyte proliferation. The results demonstrated that amphenicols, especially florfenicol (FLO), induced cell cycle arrest and apoptosis of hematopoietic cells, and it changed the bone marrow hematopoietic microenvironment by decreasing the number of peripheral blood cells. Moreover, amphenicols, especially FLO, induced hypoplasia and atrophy of the spleen and thymus, induced cell cycle arrest, as well as splenocyte apoptosis, and decreased the proliferation and viability of lymphocytes and the humoral and cellular immunity of the treated mice. These results suggest that amphenicols induce hemotoxicity and immunotoxicity to some extent, and that FLO induces more severe toxicity than equal doses of chloramphenicol (CAP) and thiamphenicol (TAP). [ABSTRACT FROM AUTHOR]