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Monoclonal antibodies targeted against the immune checkpoint molecules CTLA-4 and PD-1 have recently obtained approval for the treatment of metastatic melanoma and advanced/refractory non small-cell lung cancers. Therefore, their use will not be limited anymore to selected hospitals involved in clinical trials. Indeed, they will be routinely prescribed in many cancer centers across the world. Besides their efficacy profile, these immune targeted agents also generate immune-related adverse events (irAEs). This new family of dysimmune toxicities remains largely unknown to the broad oncology community. Although severe irAEs remain rare (~10% of cases under monotherapy), they can become life-threatening if not anticipated and managed appropriately. Over the last 5 years, Gustave Roussy has accumulated a significant experience in the prescription of immune checkpoint blockade (ICB) antibodies and the management of their toxicities. Together with the collaboration of Gustave Roussy's network of organ specialists with expertise in irAEs, we propose here some practical guidelines for the oncologist to help in the clinical care of patients under ICB immunotherapy. [ABSTRACT FROM AUTHOR]

As a complex system governing and interconnecting numerous functions within the human body, the immune system is unsurprisingly susceptible to the impact of toxic chemicals. Toxicants can influence the immune system through a multitude of mechanisms, resulting in immunosuppression, hypersensitivity, increased risk of autoimmune diseases and cancer development. At present, the regulatory assessment of the immunotoxicity of chemicals relies heavily on rodent models and a limited number of Organisation for Economic Co-operation and Development (OECD) test guidelines, which only capture a fraction of potential toxic properties. Due to this limitation, various authorities, including the World Health Organization and the European Food Safety Authority have highlighted the need for the development of novel approaches without the use of animals for immunotoxicity testing of chemicals. In this paper, we present a concise overview of ongoing efforts dedicated to developing and standardizing methodologies for a comprehensive characterization of the immunotoxic effects of chemicals, which are performed under the EU-funded Partnership for the Assessment of Risk from Chemicals (PARC). [ABSTRACT FROM AUTHOR]

Perfluorinated compounds (PFCs) are a novel type of environmental pollutant with a specific structure. PFCs have become a global concern due to their environmental persistence and biotoxicity properties. In this paper, we review the hazardous effects, detection technologies, and treatment methods of PFCs. We present the current status of PFCs pollution in water, the atmosphere, soil, and organisms. Moreover, we show that PFCs have toxic effects, such as hepatotoxicity, neurotoxicity, immunotoxicity, endocrine disruption, and reproductive and developmental toxicity. Six sample pretreatment techniques and four assays for PFCs are listed in this paper. This review focuses on the analysis of the treatment methods for PFCs, such as physical adsorption, microbial degradation, photochemical oxidation, electrochemical oxidation, acoustic oxidation, Fenton oxidation, and so on. We systematically analyze the treatment effects, removal mechanisms, and future directions of various technologies to provide support and suggestions for PFCs pollution control technologies. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]

Repair and reconstruction of large bone defect were often difficult, and bone substitute materials, including autogenous bone, allogenic bone and artificial bone, were common treatment strategies. The key to elucidate the clinical effect of these bone repair materials was to study their osteogenic capacity and immunotoxicological compatibility. In this paper, the mechanical properties, micro-CT imaging analysis, digital image analysis and histological slice analysis of the three bone grafts were investigated and compared after different time points of implantation in rat femur defect model. Autogenous bone and biphasic calcium phosphate particular artificial bone containing 61.4% HA and 38.6% β-tricalcium phosphate with 61.64% porosity and 0.8617 ± 0.0068 g/cm3 density (d  ≤ 2 mm) had similar and strong bone repair ability, but autogenous bone implant materials caused greater secondary damage to experimental animals; allogenic bone exhibited poor bone defect repair ability. At the early stage of implantation, the immunological indexes such as Immunoglobulin G, Immunoglobulin M concentration and CD4 cells' population of allogenic bone significantly increased in compared with those of autologous bone and artificial bone. Although the repair process of artificial bone was relatively inefficient than autologous bone graft, the low immunotoxicological indexes and acceptable therapeutic effects endowed it as an excellent alternative material to solve the problems with insufficient source and secondary trauma of autogenous bone. [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]

Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are persistent organic pollutants in the environment and have serious health risks, including endocrine disrupting properties, immunotoxicity and developmental effects etc. The photochemical degradation has been proven to be a low-cost, efficient and sustainable technology for the removal of PFOX (X = A or S) in water. At present, most of the investigations have been conducted in ultrapure water and at concentrations much higher comparing to those detected in the real wastewaters. Furthermore, there are few studies about the toxicity of treated water. In this paper, the state of knowledge on the photocatalytic degradation of PFOX, including photo-oxidative and photo-reductive degradation, is reviewed comprehensively. Compared with photo-oxidation, photo-reduction appears to be more suitable for the PFOX removal since it is more favorable for the defluorination of PFOX and further complete mineralization. The effects of key parameters on the photocatalytic degradation and defluorination process of PFOX are commendably accessed, such as light wavelength, photocatalyst concentration, initial PFOX concentration, pH, reaction atmosphere, temperature, and coexisting organic or inorganic matters. The mechanisms of PFOX photodegradation process are also elucidated in detail. This paper will help to deeply understand PFOX decomposition process and put forward better perspectives in the future for researchers who work in this field. [ABSTRACT FROM AUTHOR]

2,2′,4,4′-Tetrabrominated biphenyl ether (BDE-47) is a polybrominated diphenyl ether (PBDE) homologue that is ubiquitous in biological samples and highly toxic to humans and other organisms. Prior research has confirmed that BDE-47 can induce oxidative damage in RAW264.7 cells, resulting in apoptosis and impaired immune function. The current study mainly focused on how Isoliquiritigenin (ISL) and Licochalcone B (LCB) might protect against BDE-47's immunotoxic effects on RAW264.7 cells. The results show that ISL and LCB could increase phagocytosis, increase the production of MHC-II, and decrease the production of inflammatory factors (TNF-α, IL-6, and IL-1β) and co-stimulatory factors (CD40, CD80, and CD86), alleviating the immune function impairment caused by BDE-47. Secondly, both ISL and LCB could reduce the expressions of the proteins Bax and Caspase-3, promote the expression of the protein Bcl-2, and reduce the apoptotic rate, alleviating the apoptosis initiated by BDE-47. Additionally, ISL and LCB could increase the levels of antioxidant substances (SOD, CAT, and GSH) and decrease the production of reactive oxygen species (ROS), thereby counteracting the oxidative stress induced by BDE-47. Ultimately, ISL and LCB suppress the NF-κB pathway by down-regulating IKBKB and up-regulating IκB-Alpha in addition to activating the Nrf2 pathway and promoting the production of HO-1 and NQO1. To summarize, BDE-47 causes oxidative damage that can be mitigated by ISL and LCB through the activation of the Nrf2 pathway and inhibition of the NF-κB pathway, which in turn prevents immune function impairment and apoptosis. These findings enrich the current understanding of the toxicological molecular mechanism of BDE-47 and the detoxification mechanism of licorice. [ABSTRACT FROM AUTHOR]

Flow cytometry is a unique technology useful in the examination of effects of immunotoxic agents on target cells of the immune system. The purpose of this workshop was to provide an overview of the use of flow cytometry in new and established models of immunotoxicity, with emphasis on the potential applications, assay validation, and potential pitfalls. This overview begins with a discussion of methods useful in the assessment of Ca2+ -dependent mechanisms of lymphoid cell activation in surface marker-defined human B cells, T cells, and monocytes. A discussion of the use of flow cytometry in analysis of apoptosis is also presented in this paper. The second paper presents data on the development and use of flow cytometry as an alternative to a Cr51 release assay for an assessment of cytotoxic T cell activation. The use of surface markers for characterizing and distinguishing the effects of chemical irritants from sensitizers is next presented, followed by an overview of the use of fluorescent probes to assess cell thiol status and overall oxidant-induced injury to lymphoid cells. Finally, an interlaboratory study designed to compare and evaluate the use of flow cytometry procedures in rat splenic cell subtyping is presented. Overall, these studies demonstrate the utility of flow cytometry assays in immunotoxicologic research, but further efforts are needed in the validation of many of these assays for routine use in immunotoxicologic testing. [ABSTRACT FROM AUTHOR]

As a complex system governing and interconnecting numerous functions within the human body, the immune system is unsurprisingly susceptible to the impact of toxic chemicals. Toxicants can influence the immune system through a multitude of mechanisms, resulting in immunosuppression, hypersensitivity, increased risk of autoimmune diseases and cancer development. At present, the regulatory assessment of the immunotoxicity of chemicals relies heavily on rodent models and a limited number of Organisation for Economic Co-operation and Development (OECD) test guidelines, which only capture a fraction of potential toxic properties. Due to this limitation, various authorities, including the World Health Organization and the European Food Safety Authority have highlighted the need for the development of novel approaches without the use of animals for immunotoxicity testing of chemicals. In this paper, we present a concise overview of ongoing efforts dedicated to developing and standardizing methodologies for a comprehensive characterization of the immunotoxic effects of chemicals, which are performed under the EU-funded Partnership for the Assessment of Risk from Chemicals (PARC).

Although the adverse health effects of nanoparticles/materials have been proposed and are being clarified, their facilitating effects on preexisting pathological conditions have not been fully examined. In this paper, we provide insights into the immunotoxicity of nanoparticles/materials as an aggravating factor in hypersusceptible subjects, especially those with immune-related respiratory disorders using our in vivo experimental model. We first exhibit the effects of nanoparticles/materials on lung inflammation induced by bacterial endotoxin (lipopolysaccharide: LPS) in vivo as a disease model in innate immunity, and demonstrated that nanoparticles instilled through both an intratracheal tube and an inhalation system can exacerbate the lung inflammation. Secondly, we introduce the effects of nanoparticles/materials on allergic asthma in vivo as a disease model in adaptive immunity, and showed that repetitive pulmonary exposure to nanoparticles has aggravating effects on allergic airway inflammation, including adjuvant effects on Th2-milieu. Taken together, nanoparticle exposure may synergistically facilitate pathological inflammatory conditions in the lung via both innate and adaptive immunological abnormalities. [ABSTRACT FROM AUTHOR]

Cyanobacteria (blue-green algae) have been present on Earth for over 2 billion years, and can produce a variety of bioactive molecules, such as cyanotoxins. Microcystins (MCs), the most frequently detected cyanotoxins, pose a threat to the aquatic environment and to human health. The classic toxic mechanism of MCs is the inhibition of the protein phosphatases 1 and 2A (PP1 and PP2A). Immunity is known as one of the most important physiological functions in the neuroendocrine-immune network to prevent infections and maintain internal homoeostasis in fish. The present review aimed to summarize existing papers, elaborate on the MC-induced immunotoxicity in fish, and put forward some suggestions for future research. The immunomodulatory effects of MCs in fish depend on the exposure concentrations, doses, time, and routes of exposure. Previous field and laboratory studies provided strong evidence of the associations between MC-induced immunotoxicity and fish death. In our review, we summarized that the immunotoxicity of MCs is primarily characterized by the inhibition of PP1 and PP2A, oxidative stress, immune cell damage, and inflammation, as well as apoptosis. The advances in fish immunoreaction upon encountering MCs will benefit the monitoring and prediction of fish health, helping to achieve an ecotoxicological goal and to ensure the sustainability of species. Future studies concerning MC-induced immunotoxicity should focus on adaptive immunity, the hormesis phenomenon and the synergistic effects of aquatic microbial pathogens. [ABSTRACT FROM AUTHOR]

Since the early 2000s, studies of the evolution of venom within animals have rapidly expanded, offering new revelations on the origins and development of venom within various species. The venomous mammals represent excellent opportunities to study venom evolution due to the varying functional usages, the unusual distribution of venom across unrelated mammals and the diverse variety of delivery systems. A group of mammals that excellently represents a combination of these traits are the slow (Nycticebus spp.) and pygmy lorises (Xanthonycticebus spp.) of south-east Asia, which possess the only confirmed two-step venom system. These taxa also present one of the most intriguing mixes of toxic symptoms (cytotoxicity and immunotoxicity) and functional usages (intraspecific competition and ectoparasitic defence) seen in extant animals. We still lack many pieces of the puzzle in understanding how this venom system works, why it evolved what is involved in the venom system and what triggers the toxic components to work. Here, we review available data building upon a decade of research on this topic, focusing especially on why and how this venom system may have evolved. We discuss that research now suggests that venom in slow lorises has a sophisticated set of multiple uses in both intraspecific competition and the potential to disrupt the immune system of targets; we suggest that an exudate diet reveals several toxic plants consumed by slow and pygmy lorises that could be sequestered into their venom and which may help heal venomous bite wounds; we provide the most up-to-date visual model of the brachial gland exudate secretion protein (BGEsp); and we discuss research on a complement component 1r (C1R) protein in saliva that may solve the mystery of what activates the toxicity of slow and pygmy loris venom. We conclude that the slow and pygmy lorises possess amongst the most complex venom system in extant animals, and while we have still a lot more to understand about their venom system, we are close to a breakthrough, particularly with current technological advances. [ABSTRACT FROM AUTHOR]

It is assumed that mycotoxins have been present in feed and food since the beginning of eukaryotic fungi's life on Earth. With the recognition of the symptoms of the first intoxications, the so-called mycotoxicosis, there was a desire to find strategies in the fight against secondary metabolites of different types of fungi. The mycotoxins that most commonly contaminate feed are aflatoxin B1 (AFB1), deoxynivalenol (DON), zearalenone (ZEN) and fumonisin B1 (FB1). These mycotoxins can primarily cause hepatotoxicity, immunotoxicity, neurotoxicity and nephrotoxicity, and consequently cause adverse effects on animal health and performance. Today, in the 21st century, the need to find a multidisciplinary and integrated plan in the fight against mycotoxins has grown with the realization that mycotoxins cause large-scale damage in livestock. Physical, chemical, biological and nutritional strategies have been developed to combat mycotoxins in the feed industry. Meanwhile, the use of each of these strategies achieves benefits, but also has drawbacks, including being expensive or impractical to apply on a large scale. [ABSTRACT FROM AUTHOR]

The potential for chemicals to adversely affect human immunologic health has traditionally been evaluated in rodents, under laboratory conditions. These laboratory studies have generated valuable hazard identification and immunotoxicologic mechanism data; however, genetically diverse populations exposed in the wild may better reflect both human exposure conditions and may provide insight into potential immunotoxic effects in humans. In addition, comparative studies of species occupying reference and impacted sites provide important information on the effects of environmental pollution on the immunologic health of wildlife populations. In this symposium overview, Peter Hodson describes physiological changes in fish collected above or below the outflows of paper mills discharging effluent from the bleaching process (BKME). Effects attributable to BKME were identified, as were physiological changes attributable to other environmental factors. In this context, he discussed the problems of identifying true cause and effect relationships in field studies. Mohamed Faisal described changes in immune function of fish collected from areas with high levels of polyaromatic hydrocarbon contamination. His studies identified a contaminant-related decreases in the ability of anterior kidney leukocytes to bind to and kill tumor cell line targets, as well as changes in lymphocyte proliferation in response to mitogens. Altered proliferative responses of fish from the contaminated site were partially reversed by maintaining fish in water from the reference site. Peter Ross described studies in which harbor seals were fed herring obtained from relatively clean (Atlantic Ocean) and contaminated (Baltic Sea) waters. Decreased natural killer cell activity and lymphoproliferative responses to T and B cell mitogens, as well as depressed antibody and delayed hypersensitivity responses to injected antigens, were identified in seals fed contaminated herring. In laboratory studies, it was determined that rats fed freeze-dried Baltic Sea herring had higher virus titers after challenge with rat cytomegalovirus (RCMV) than rats fed Atlantic Ocean herring; perinatal exposure of rats to oil extracted from Baltic herring also reduced the response to challenge with RCMV. Keith Grassman reported an association between exposure to polyhalogenated aryl hydrocarbons and decreased T cell immunity in the offspring of fish-eating birds (herring gulls and Capsian terns) at highly contaminated sites in the Great Lakes. The greatest suppression of skin test responses to phytohemagglutinin injection (an indicator of T cell immunity) was consistently found at sites with the highest contaminant concentrations. Judith Zelikoff addressed the applicability of immunotoxicity studies developed in laboratory-reared fish for detecting altered immune function in wild populations. She presented data from studies done in her laboratory with environmentally relevant concentrations of metals as examples. Although the necessity of proceeding with caution when extrapolating across species was emphasized, she concluded that published data, and results presented by the other Symposium participants, demonstrate that assays similar to those developed for use in laboratory rodents may be useful for detecting immune system defects in wildlife species directly exposed to toxicants present in the environment. [ABSTRACT FROM AUTHOR]

Dust, both industrial and household, contains particulates that can reach the most distal aspects of the lung. Silica and nickel compounds are two such particulates and have known profiles of poor health outcomes. While silica is well-characterized, nickel compounds still need to be fully understood for their potential to cause long-term immune responses in the lungs. To assess these hazards and decrease animal numbers used in testing, investigations that lead to verifiable in vitro methods are needed. To understand the implications of these two compounds reaching the distal aspect of the lungs, the alveoli, an architecturally relevant alveolar model consisting of epithelial cells, macrophages, and dendritic cells in a maintained submerged system, was utilized for high throughput testing. Exposures include crystalline silica (SiO2) and nickel oxide (NiO). The endpoints measured included mitochondrial reactive oxygen species and cytostructural changes assessed via confocal laser scanning microscopy; cell morphology evaluated via scanning electron microscopy; biochemical reactions assessed via protein arrays; transcriptome assessed via gene arrays, and cell surface activation markers evaluated via flow cytometry. The results showed that, compared to untreated cultures, NiO increased markers for dendritic cell activation, trafficking, and antigen presentation; oxidative stress and cytoskeletal changes, and gene and cytokine expression of neutrophil and other leukocyte chemoattractants. The chemokines and cytokines CCL3, CCL7, CXCL5, IL-6, and IL-8 were identified as potential biomarkers of respiratory sensitization. [ABSTRACT FROM AUTHOR]

Background: Exposure to perfluorinated alkylate substances (PFAS) is associated with harmful effects on human health, including developmental immunotoxicity. This outcome was chosen as the critical effect by the European Food Safety Authority (EFSA), which calculated a new joint reference dose for four PFAS using a Benchmark Dose (BMD) analysis of a study of 1-year old children. However, the U.S. Environmental Protection Agency (EPA) recently proposed much lower exposure limits. Methods: We explored the BMD methodology for summary and individual data and compared the results with and without grouping for two data sets available. We compared the performance of different dose-response models including a hockey-stick model and a piecewise linear model. We considered different ways of testing the assumption of equal weight-based toxicity of the four PFAS and evaluated more flexible models with exposure indices allowing for differences in toxicity. Results: Results relying on full and decile-based data were in good accordance. However, BMD results for the larger study were lower than observed by EFSA for the smaller study. EFSA derived a lower confidence limit for the BMD of 17.5 ng/mL for the sum of serum-PFAS concentration, while similar calculations in the larger cohort yielded values of about 1.5 ng/mL. As the assumption of equal weight-based toxicity of the four PFAS seems questionable, we confirmed dose-dependencies that allowed potency differences between PFAS. We also found that models linear in the parameters for the BMD analysis showed superior coverage probabilities. In particular, we found the piecewise linear model to be useful for Benchmark analysis. Conclusions: Both data sets considered could be analyzed on a decile basis without important bias or loss of power. The larger study showed substantially lower BMD results, both for individual PFAS and for joint exposures. Overall, EFSA's proposed tolerable exposure limit appears too high, while the EPA proposal is in better accordance with the results. [ABSTRACT FROM AUTHOR]

Micro- and nanoplastics (MNPs) are emerging pollutants with scarcely investigated effects on human innate immunity. If they follow a similar course of action as other, more thoroughly investigated particulates, MNPs may penetrate epithelial barriers, potentially triggering a cascade of signaling events leading to cell damage and inflammation. Inflammasomes are intracellular multiprotein complexes and stimulus-induced sensors critical for mounting inflammatory responses upon recognition of pathogen- or damage-associated molecular patterns. Among these, the NLRP3 inflammasome is the most studied in terms of activation via particulates. However, studies delineating the ability of MNPs to affect NLRP3 inflammasome activation are still rare. In this review, we address the issue of MNPs source and fate, highlight the main concepts of inflammasome activation via particulates, and explore recent advances in using inflammasome activation for assessment of MNP immunotoxicity. We also discuss the impact of co-exposure and MNP complex chemistry in potential inflammasome activation. Development of robust biological sensors is crucial in order to maximize global efforts to effectively address and mitigate risks that MNPs pose for human health. [ABSTRACT FROM AUTHOR]

As a new alternative to perfluorooctane sulfonic acid (PFOS), 6:2 fluorotelomer sulfonic acid (6:2 FTSA) has been widely produced and used in recent years, and its concentration and frequency of detection in the aquatic environment and aquatic organisms are increasing. However, studies of its toxicity in aquatic biological systems are alarmingly scarce, and the relevant toxicological information needs to be improved. In this study, we investigated AB wild-type zebrafish (Danio rerio) embryos subjected to acute 6:2 FTSA exposure for immunotoxicity using immunoassays and transcriptomics. Immune indexes showed significant decreases in SOD and LZM activities, but no significant change in NO content. Other indexes (TNOS, iNOS, ACP, AKP activities, and MDA, IL-1β, TNF-α, NF-κB, TLR4 content) all showed significant increases. These results indicated that 6:2 FTSA induced oxidative stress and inflammatory responses in zebrafish embryos and exhibited immunotoxicity. Consistently, transcriptomics showed that genes involved in the MAPK, TLR and NOD-like receptor signaling pathways (hsp70, hsp701, stat1b, irf3, cxcl8b, map3k8, il1b, tnfa and nfkb) were significantly upregulated after 6:2 FTSA exposure, suggesting that 6:2 FTSA might induce immunotoxicity in zebrafish embryos through the TLR/NOD-MAPK pathway. The results of this study indicate that the safety of 6:2 FTSA should be examined further. [ABSTRACT FROM AUTHOR]

Immunotoxicity, defined as adverse effects of xenobiotics on the immune system, is gaining increasing attention in the approval process of industrial chemicals and drugs. In-vivo and ex-vivo experiments have been the gold standard in immunotoxicity assessment so far, so the development of in-vitro and in-silico alternatives is an important issue. In this paper we describe a widely applicable, easy-to use computational approach which can serve as an initial immunotoxicity screen of new chemical entities. Molecular fingerprints describing chemical structure were used as parameters in a machine-learning approach based on the Naïve-Bayes learning algorithm. The model was trained using blood-cell growth inhibition data from the NCI database and validated externally with several in-house and literature-derived data sets tested in cytotoxicity assays on different types on immune cells. Both cross-validations and external validations resulted in areas under the receiver operator curves (ROC/AUC) of 75% or higher. The classification of the validation data sets occurred with excellent specificities and fair to excellent selectivities, depending on the data set. This means that the probability of actual immunotoxicity is very high for compounds classified as immunotoxic, while the fraction of false negative predictions might vary. Thus, in a multistep immunotoxicity screening scheme, the classification as immunotoxic can be accepted without additional confirmation, while compounds classified as not immunotoxic will have to be subjected to further investigation. [ABSTRACT FROM AUTHOR]

Zinc oxide (ZnO) nanoparticles (NPs) have potential applications in cosmetics, food packaging and biomedicine but concerns regarding their safety need to be addressed. In the present study, the immunotoxic potential of ZnO NPs was evaluated in different ages of BALB/c mice after sub-acute exposure. The cytokine release, immunophenotyping, distribution of ZnO NPs and ultrastructural changes were assessed. A significant (p < 0.05) change in the CD4- and CD8-cells, levels of IL-6, IFN-γ and TNF-α and reactive oxygen species were observed in aged mice. In juvenile mice, increase in reactive oxygen species and IL-6 and TNF-α levels was observed with no significant changes in adult mice. A significant (p < 0.05) increase in the expression levels of mitogen activated protein kinase (MAPK) cascade proteins such as phospho-ERK1/2, phospho-JNK and phospho-p38 were also induced in aged mice. Collectively, our results indicate that the aged mice are more susceptible to ZnO NP induced immunotoxicity. [ABSTRACT FROM AUTHOR]

Ochratoxin A (OTA), a toxin produced by Aspergillus ochraceus and Penicillium verrucosum, is one of the most abundant food-contaminating mycotoxins worldwide. OTA mainly exerts nephrotoxicity, immunotoxicity, mutagenicity, carcinogenicity, teratogenicity, and neurotoxicity. This paper describes a simple and sensitive aptamer/single-walled carbon nanohorn (SWCNH)-based assay for OTA detection. SWCNHs can protect DNA from DNase I cleavage. However, aptamers can be detached from the surface of SWCNHs through specific target binding, exposing them to enzymatic cleavage and releases the target for a new cycle. Cycling of targets leads to significant signal amplification and low limit of detection (LOD), resulting in a nearly 20-fold reduction in LOD for OTA assay compared with non-target recycling under the same experimental parameters. This technique responded specifically to OTA without interference from other analogues (Ochratoxin B, Ochratoxin C, warfarin, and N -acetyl- l -phenylalanine). Moreover, the application of this technique in real sample has been verified using red wine samples spiked with a series of OTA concentrations. This aptasensor offers a great practical importance in food safety and can be widely extended for detection of other toxins by replacing the sequence of the recognition aptamer. [ABSTRACT FROM AUTHOR]

This paper evaluates the coexistence risks of triphenyltin (TPT) and norfloxacin (NOR) to aquatic organisms in the aquatic environment. Carp (Cyprinus carpio) was used as the test organism, the control and exposure groups (1 μg/L TPT), 1 mg/L (NOR), 1 μg/LTPT+1 mg/LNOR (TPT_NOR)) were set up according to the environmental concentration in the severely polluted area for 42 days. The single/combined toxic effects of TPT and NOR on aquatic organisms were evaluated by analyzing carp brain transcriptome sequencing, gut microbiota structure, and detection of biochemical indicators and RT-qPCR. Our results show that TPT and NOR induce lipid metabolism disorder in carp brain tissue, affecting the metabolism of cytochrome P450 to exogenous substances, and NOR also induces immunosuppression in carp. Long-term exposure to TPT combined with NOR amplifies the monotoxicity of TPT or NOR on lipid metabolism and immunosuppression in carp, induces immune dysfunction in brain tissue and changes in gut microbiota structure. However, TPT_NOR has no obvious neurotoxicity on the brain, but it can inhibit the level of intestinal MDA. This highlights that co-exposure of TPT and NOR amplifies metabolic disorders and immunosuppressive functions in carp. [Display omitted] • TPT induces disorder of lipid metabolism in carp. • NOR induces lipid accumulation in carp and leads to immune dysfunction. • TPT combined with NOR amplifies the immunotoxicity and metabolic toxicity to carp. [ABSTRACT FROM AUTHOR]

Bisphenol A (BPA) is not a natural substance but is produced artificially during the manufacturing of various plastics. Exposure to (BPA) is a pervasive and growing concern. BPA has recently been classified as a substance of great concern by the European Union (EU). BPA is suspected to be associated with several chronic human health effects. In this study, the estimated total BPA exposure levels were based on biomonitoring of the general population, and exposure levels ranged from a mean of 0.031 to 0.042 µg/kg body weight (bw)/day, reaching up to 0.104 µg/kg bw/day in the high-exposure population. When comparing the exposure levels of BPA to some toxicological effects, such as immunotoxicity and thyroid function, a sufficient exposure margin was not secured in the high-exposure group. Food is considered the main source of exposure for the general population, but other sources of exposure may exist in the high-exposure group. As humans are primarily exposed to BPA through food, water, house dust, skin contact, and air, integrated risk management is required to reduce BPA exposure. In addition, it is considered necessary to develop a new methodology for human health evaluation in response to low-dose exposure to BPA. [ABSTRACT FROM AUTHOR]

Aflatoxin B1 (AFB1), ochratoxin A (OTA), and deoxynivalenol (DON) are the three mycotoxins that have received the most scholarly attention and have been tested most routinely in clinics. These mycotoxins not only suppress immune responses but also induce inflammation and even increase susceptibility to pathogens. Here, we comprehensively reviewed the determining factors for the bidirectional immunotoxicity of the three mycotoxins, their effects on pathogens, and their action mechanisms. The determining factors include mycotoxin exposure doses and times, as well as species, sex, and some immunologic stimulants. Moreover, mycotoxin exposure can affect the infection severity of some pathogens, including bacteria, viruses, and parasites. Their specific action mechanisms include three aspects: (1) mycotoxin exposure directly promotes the proliferation of pathogenic microorganisms; (2) mycotoxins produce toxicity, destroy the integrity of the mucosal barrier, and promote inflammatory response, thereby improving the susceptibility of the host; (3) mycotoxins reduce the activity of some specific immune cells and induce immune suppression, resulting in reduced host resistance. The present review will provide a scientific basis for the control of these three mycotoxins and also provide a reference for research on the causes of increased subclinical infections. [ABSTRACT FROM AUTHOR]

Background: Per- and polyfluoroalkyl substances (PFAS) are of public health concern, because of their ubiquitous and extremely persistent occurrence, and depending on their structure, their bio-accumulative, mobile and toxic properties. Human health effects associated with exposure to PFAS include adverse effects on the immune system. In 2020, EFSA (the European Food Safety Authority) defined adverse effects on the immune system as the most critical effect for human health risk assessment, based on reduced antibody responses to childhood vaccines and similar effects observed in experimental animal studies. Likewise, the U.S. EPA (Environmental Protection Agency) considers PFAS-induced immunotoxicity, especially in children, as the critical effect for risk assessment. However, the mechanisms by which antibody concentrations are impacted are not completely understood. Furthermore, other targets of the immune system functions have been reported in the literature. Objective: The aim of this review is to explore PFAS-associated immune-related effects. This includes, relevant mechanisms that may underlie the observed effects on the immune system, immunosuppression as well as immunoenhancement, such as i) modulation of cell signalling and nuclear receptors, such as NF-κB and PPARs; ii) alteration of calcium signalling and homoeostasis in immune cells; iii) modulation of immune cell populations; iv) oxidative stress and v) impact on fatty acid metabolism & secondary effects on the immune system. Methods: A literature research was conducted using three databases (Web of Science, PubMed, and Scopus), which were searched in July 2021 for relevant studies published in the time frame from 2018 to 2021. In total, 487 publications were identified as potentially eligible and following expert-based judgement, articles relevant for mechanisms of PFAS induced immunotoxicity are discussed. Conclusions: Taken together, we show that there is substantial evidence from both in vitro and in vivo experimental as well as epidemiological studies, supporting that various PFAS, not only PFOA and PFOS, affect multiple aspects of the immune system. Timing of exposure is critical, because the developing immune system is especially vulnerable to toxic insults, resulting in a higher risk of particularly adverse immune effects but also other organs later in life. [ABSTRACT FROM AUTHOR]

Hydrogen sulphide (H2S) is a gas that affects mucosal functions in mammals. However, its detrimental effects are less understood in fish despite being known to cause mass mortality. Here we used explant models to demonstrate the transcriptional responses of Atlantic salmon (Salmo salar) mucosa to the sulphide donor sodium hydrosulphide (NaHS). The study focused on two groups of genes: those encoding for sulphide detoxification and those for mucins. Moreover, we performed pharmacological studies by exposing the organ explants to mucus-interfering compounds and consequently exposed them to a sulphide donor. Exposure to NaHS significantly affected the expression of sulphide:quinone oxidoreductase (sqor1, sqor2) and mucinencoding genes (muc5ac, muc5b). The general profile indicated that NaHS upregulated the expression of sulphide detoxification genes while a significant downregulation was observed with mucins. These expression profiles were seen in both organ explant models. Pharmacological stimulation and inhibition of mucus production used acetylcholine (ACh) and niflumic acid (NFA), respectively. This led to a significant regulation of the two groups of marker genes in the gills and olfactory rosette explants. Treatment of the mucosal organ explants with the mucus-interfering compounds showed that low dose NFA triggered more substantial changes while a dose-dependent response could not be established with ACh. Pharmacological interference demonstrated that mucins played a crucial role in mucosal protection against H2S toxicity. These results offer insights into how a sulphide donor interfered with mucosal responses of Atlantic salmon and are expected to contribute to our understanding of the least explored H2S-fish interactions--particularly at the mucosa. [ABSTRACT FROM AUTHOR]

Micro- and nanoplastics (MNP) are ubiquitously present in the environment due to their high persistence and bioaccumulative properties. Humans get exposed to MNP via various routes and consequently, they will encounter dendritic cells (DC) which are antigen-presenting cells involved in regulating immune responses. The consequences of DC exposure to MNP are an important, yet understudied, cause of concern. Therefore, this study aimed to assess the uptake and effect of MNP in vitro by exposing human monocyte-derived dendritic cells (MoDC) to virgin and environmentally weathered polystyrene (PS) particles of different sizes (0.2, 1, and 10 µm), at different concentrations ranging from 1 to 100 µg/ml. The effects of these particles were examined by measuring co-stimulatory surface marker (i.e. CD83 and CD86) expression. In addition, T-cell proliferation was measured via a mixed-leukocyte reaction (MLR) assay. The results showed that MoDC were capable of absorbing PS particles, and this was facilitated by pre-incubation in heat-inactivated (HI) plasma. Furthermore, depending on their size, weathered PS particles in particular caused increased expression of CD83 and CD86 on MoDC. Lastly, weathered 0.2 µm PS particles were able to functionally activate MoDC, leading to an increase in T-cell activation. These in vitro data suggest that, depending on their size, weathered PS particles might act as an immunostimulating adjuvant, possibly leading to T-cell sensitization. [ABSTRACT FROM AUTHOR]

Regulators and risk managers in general need to decide whether an allergenic food or ingredient is of such public health importance that it needs to be actively managed. There is therefore a need to scale the relative allergenicity of foods and ingredients according to the hazards they pose. Objective criteria increase transparency and trust in this decision-making process and its conclusions. This paper proposes a framework that allows categorisation and prioritisation of allergenic foods according to their public health importance. The challenge is to find a basis on which the allergenicity of foods can best be described and a method to combine the relevant measures of allergenicity into a scoring system that prioritises allergenic foods on the basis of their public health relevance. The framework is designed in accordance with the generic risk analysis principles used in food safety and can be used by regulators to decide whether or not a specific allergenic food or ingredient is of sufficient public health importance that it warrants regulation (i.e. mandatory labelling) when used in the production of food products. [ABSTRACT FROM AUTHOR]

The preweaning piglet has been found to be a valuable research model for testing ingredients used in infant formula. As part of the safety assessment, the neonates' immune system is an important component that has to be evaluated. In this study three concurrent strategies were developed to assess immune system status. The methods included (1) immunophenotying to assess circulating innate immune cell populations, (2) monitoring of circulating cytokines, particularly in response to a positive control agent, and (3) monitoring of localized gastrointestinal tissue cytokines using immunohistochemistry (IHC), particularly in response to a positive control agent. All assays were validated using white papers and regulatory guidance within a GLP environment. To validate the assays precision, accuracy and sample stability were evaluated as needed using a fit for purpose approach. In addition animals were treated with proinflammtory substances to detect a positive versus negative signal. In conclusion, these three methods were confirmed to be robust assays to evaluate the immune system and GIT-specific immune responses of preweaning piglets. [ABSTRACT FROM AUTHOR]

In the field of science, technology and medicine, carbon-based nanomaterials and nanoparticles (CNMs) are becoming attractive nanomaterials that are increasingly used. However, it is important to acknowledge the risk of nanotoxicity that comes with the widespread use of CNMs. CNMs can enter the body via inhalation, ingestion, intravenously or by any other route, spread through the bloodstream and penetrate tissues where (in both compartments) they interact with components of the immune system. Like invading pathogens, CNMs can be recognized by large numbers of receptors that are present on the surface of innate immune cells, notably monocytes and macrophages. Depending on the physicochemical properties of CNMs, i.e., shape, size, or adsorbed contamination, phagocytes try to engulf and process CNMs, which might induce pro/anti-inflammatory response or lead to modulation and disruption of basic immune activity. This review focuses on existing data on the immunotoxic potential of CNMs, particularly in professional phagocytes, as they play a central role in processing and eliminating foreign particles. The results of immunotoxic studies are also described in the context of the entry routes, impacts of contamination and means of possible elimination. Mechanisms of proinflammatory effect depending on endocytosis and intracellular distribution of CNMs are highlighted as well. [ABSTRACT FROM AUTHOR]

Immune response is modulated by different substances that are present in the environment. Nevertheless, some of these may cause an immunotoxic effect. In this paper, the effect of organophosphorus pesticides (frequent substances spilled in aquatic ecosystems) on the immune system of fishes and in immunotoxicology is reviewed. Furthermore, some cellular and molecular mechanisms that might be involved in immunoregulation mechanisms of organophosphorus pesticides are discussed. [ABSTRACT FROM AUTHOR]

The use of nanomaterials has been increasing in recent times, and they are widely used in industries such as cosmetics, drugs, food, water treatment, and agriculture. The rapid development of new nanomaterials demands a set of approaches to evaluate the potential toxicity and risks related to them. In this regard, nanosafety has been using and adapting already existing methods (toxicological approach), but the unique characteristics of nanomaterials demand new approaches (nanotoxicology) to fully understand the potential toxicity, immunotoxicity, and (epi)genotoxicity. In addition, new technologies, such as organs-on-chips and sophisticated sensors, are under development and/or adaptation. All the information generated is used to develop new in silico approaches trying to predict the potential effects of newly developed materials. The overall evaluation of nanomaterials from their production to their final disposal chain is completed using the life cycle assessment (LCA), which is becoming an important element of nanosafety considering sustainability and environmental impact. In this review, we give an overview of all these elements of nanosafety. [ABSTRACT FROM AUTHOR]

Alongside physiochemical properties (PCP), it has been suggested that the protein corona of nanoparticles (NPs) plays a crucial role in the response of immune cells to NPs. However, due to the great variety of NPs, target cells, and exposure protocols, there is still no clear relationship between PCP, protein corona composition, and the immunotoxicity of NPs. In this study, we correlated PCP and the protein corona composition of NPs to the THP-1 macrophage response, focusing on selected toxicological endpoints: cell viability, reactive oxygen species (ROS), and cytokine secretion. We analyzed seven commonly used engineered NPs (SiO2, silver, and TiO2) and magnetic NPs. We show that with the exception of silver NPs, all of the tested TiO2 types and SiO2 exhibited moderate toxicities and a transient inflammatory response that was observed as an increase in ROS, IL-8, and/or IL-1β cytokine secretion. We observed a strong correlation between the size of the NPs in media and IL-1β secretion. The induction of IL-1β secretion was completely blunted in NLR family pyrin domain containing 3 (NLRP3) knockout THP-1 cells, indicating activation of the inflammasome. The correlations analysis also implicated the association of specific NP corona proteins with the induction of cytokine secretion. This study provides new insights toward a better understanding of the relationships between PCP, protein corona, and the inflammatory response of macrophages for different engineered NPs, to which we are exposed on a daily basis. [ABSTRACT FROM AUTHOR]

Allergens can elicit immunotoxic effects in humans. It is often lifethreatening and severe that influences the prevalence and course of allergic diseases like asthma, allergic rhinitis, atopic dermatitis, and contact dermatitis. Genetic as well as environmental factors may contribute to allergy and related physiological responses. The pathogenesis of asthma and allergy involves the interaction of genetic markers and environmental factors. Various toxic compounds like metals, foods, even certain kinds of drugs can elicit immunotoxicity. Asthma is subjected to inflammation of the airways; of which genes and environment both are responsible in an interactive way. The innate immunity genes particularly CD 14 and Toll like receptors TLR4 and TLR 2 play an important role on susceptibility to asthma and allergy. The genes interrelated to asthma have been found through Single Nucleotide Polymorphism (SNP) studies. There are other risk factors associated with allergic diseases which require long-term, effective therapeutic approaches as a treatment regimen. The present study is an attempt to highlight the immunological reactions of certain compounds and gene-environment interplay in developing the pathological symptoms associated with asthma. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Immunosuppressive drugs are associated with an increased risk of infections and in some cases neoplasia, particularly non-melanoma skin cancers. This paper describes the development of a model to test the effects of immunosuppressive drugs on local invasion and metastases of a squamous cell carcinoma in syngeneic, immunocompetent mice. Methods: SCC VII cells were labeled with 655 quantum dots (QDs), injected intramuscularly into C3H HEN mice and traffic and progressive growth in the draining popliteal lymph node were evaluated. Results: SCC VII cells express RAE-1, an NKG2D ligand, and were sensitive to natural killer (NK) cells in vitro. QDs were stable in SCC VII cells and showed no evidence of toxicity to the cells. In vivo, confocal microscopy showed that QD-labeled SCC VII cells could migrate to the draining node and microfluorimetry showed progressive traffic of QDs to the node. There was no evidence of systemic toxicity of QDs. Primary immunosuppression in SCID and SCID-beige mice and treatment of normal mice with immunosuppressive agents (anti-asialoGM1 and cyclophosphamide) can enhance traffic of QDs and/or metastases to the draining lymph node. In contrast, cyclosporine had no effect on traffic or metastases. Conclusion: This model of local invasion and metastases may be useful in immunotoxicology for identifying and characterizing the hazard posed by selective immunosuppressive drugs. [Copyright &y& Elsevier]

Abstract: Transgenic plants offer a promising system for large-scale production of therapeutic proteins such as monoclonal antibodies (mAbs). This paper describes a membrane-based process suitable for purification of a humanized mAb expressed in tobacco. Most monoclonal antibody purification schemes rely on the use of Protein A as the affinity ligand for antibody capture. The main objective of our work was to develop non-Protein A-based purification methods to avoid some of the problems and limitations associated with this ligand, e.g. cost, immunotoxicity, and antibody aggregation during elution. Ion exchange membrane chromatography (IEMC) was used for primary capture and preliminary purification of the mAb from tobacco juice. Hydrophobic interaction membrane chromatography (HIMC) was then used for high-resolution purification, followed by ultrafiltration for polishing, desalting and buffer exchange. Using this scheme, both high mAb purity (single peak in size exclusion chromatogram, i.e., ca. 100% purity) and high recovery (77% of mAb spiked into the tobacco extract) were achieved. Membrane chromatography is generally considered unsuitable for resolving bound proteins by gradient elution and is therefore commonly used in the bind and elute mode with a single-step change of mobile phase. We show that the gradient elution process in the HIMC step can be optimized to increase the resolution and thereby obtain product of high purity. [Copyright &y& Elsevier]

There is mounting evidence that earthworms could be used as a sentinel species for soil ecotoxicity evaluation. In this aspect, phagocytosis by coelomocytes was shown to be a sensitive biomarker of exposure to xenobiotics. In this paper, we introduce a simple method for ultrasound extrusion of earthworm coelomocytes that generates a high cell yield, does not interfere with phagocytic competence, and requires a minimum of manipulations. Coelomocytes were extruded from the earthworm Eisenia fetida using this new ultrasound method and compared with ethanol and electrical extrusion. The ultrasonic extrusion showed the highest cell recovery with 3.17±0.8×106 cells per earthworm compared with 2.22±0.8×106 cells per earthworm for electrical extrusion and 1.57±0.07×106 cells per earthworm for ethanol extrusion. No significant differences in the cell viability were observed using propidium iodide and flow cytometry with viability for extrusion with ethanol of 63.8±12.7%, electrical 76.8±7.5%, and ultrasound 68.2±7.8%. To compare the potential effect of extrusion on cell quality, the cells extruded using the three methods were subjected to an 18-h in vitro exposure to methylmercury chloride (MeHgCl; CH3HgCl) with concentrations ranging from 10-9 to 10-4 M. The half-maximal effective concentration (EC50) for inhibition of phagocytosis occurred between 10–7 and 10–6 M. We found no significant differences among the extrusion methods for the phagocytic potential of the coelomocytes. This method does not harm the worms and can certainly improve collection of coelomocytes from earthworms and therefore contribute to the development of bioassays using invertebrates. [Copyright &y& Elsevier]

Aims  The risk and incidence of cardiovascular (CV) immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs) in cancer patients remain unknown. Methods and results We systematically reviewed all randomized clinical trials (RCTs) including at least one ICI-containing arm and available CV adverse event (CVAE) data in cancer patients in the ClinicalTrials.gov registry, Medline, and the Cochrane CENTRAL Register of Controlled Trials, up to 31 August 2020 (CRD42020165672). The primary outcome was the summary risk of 16 different CVAEs associated with ICI exposure vs. controls (placebo and non-placebo) in RCTs. CVAEs with an increased risk associated with ICI exposure were considered as CV irAEs. Summary incidences of CV irAEs identified in our primary outcome analyses were computed using all RCTs including at least one ICI-containing arm. We used a random-effects meta-analysis to obtain Peto odds ratios (ORs) with 95% confidence intervals (CIs) and logit transformation and inverse variance weighting to compute summary incidences. Sixty-three unique RCTs with at least one ICI-containing arm (32 518 patients) were retrieved, among which 48 (29 592 patients) had a control arm. Among the 16 CVAEs studied, ICI use was associated with an increased risk of 6 CV irAEs including myocarditis, pericardial diseases, heart failure, dyslipidemia, myocardial infarction, and cerebral arterial ischaemia with higher risks for myocarditis (Peto OR: 4.42, 95% CI: 1.56–12.50, P  < 0.01; I 2 = 0%, P  = 0.93) and dyslipidemia (Peto OR: 3.68, 95% CI: 1.89–7.19, P  < 0.01; I 2 = 0%, P  = 0.66). The incidence of these CVAEs ranged from 3.2 (95% CI 2.0–5.1) to 19.3 (6.7–54.1) per 1000 patients, in studies with a median follow-up ranging from 3.2 to 32.8 months. Conclusion In RCTs, ICI use was associated with six CV irAEs, not confined to myocarditis and pericarditis. [ABSTRACT FROM AUTHOR]

In development of peptide therapeutics, rodents are commonly-used preclinical models when screening compounds for efficacy endpoints in the early stages of discovery projects. During the screening process, some peptides administered subcutaneously to rodents caused injection site reactions manifesting as localized swelling. Screening by postmortem evaluations of injection site swelling as a marker for local subcutaneous histamine release, were conducted in rats to select drug candidates without this adverse effect. Histological analysis of skin samples revealed that the injection site reactions were concurrent with mast cell degranulation, resulting in histamine release. Mast cell activation can be mediated by MRGPRX2, a GPCR that induces a pseudo-allergenic immune response. The present study demonstrates that a commercially-available cell-based MRGPRX2 assay reliably identifies compounds that induce histamine release or localized edema in ex vivo human and rodent skin samples. In vitro screening was subsequently implemented using the MRGPRX2 assay as a substitute for postmortem injection site evaluation, thus achieving a significant reduction in animal use. Thus, in cases where injection site reactions are encountered during in vivo screening, to enable faster screening during the early drug discovery process, an MRGPRX2 in vitro assay can be used as an efficient, more ethical tool with human translational value for the development of safer pharmacotherapies for patients. [ABSTRACT FROM AUTHOR]

Environmental exposure to a number of xenobiofics, including pesticides, can have serious effects on the immune system of children, thus rendering them susceptible to infections or other disease states. To study this problem, a recycling chromatographic system for assessing cytokine profiles in humans has been developed and used for the measurement of immune system function in children with documented exposure to residential pesticides. The system is capable of measuring 30 different analytes in a single sample thus enabling the same time examination of representative markers of immune differentiation and function. In the present study, a cohort of 25 exposed children were examined and shown to exhibit a number of features; all subjects demonstrated some abnormalities in cytokines associated with hematopoiesis. Additionally, elevations in pro-inflammatory cytokines and neuropeptides indicated a state of generalized and neurogenic inflammation. Further analysis indicated that a depression of the cellular arm of the immune system that correlated with clinical indicators of lowered host resistance to infection could also be detected in a subgroup of the exposed subjects. Ali exposed children demonstrated evidence of hyperstimulation of the humoral immune system as indicated by elevated IL-5 concentrations and clinical allergy. The degree of immune dysregulation in the exposed children was found to be quite marked when compared to similar studies performed on age-matched controls. [ABSTRACT FROM AUTHOR]

Glycyrrhiza glabra root (licorice) is a widely used herb for its beneficial effects on health. This study explored the protective effects of licorice extract against oxidative stress and testicular dysfunction caused by methotrexate (MTX). Mice were allocated into (i) negative control group that received saline; (ii) licorice extract group, orally administered with 200 mg/kg body weight (bw) licorice extract for 12 days; (iii) positive MTX-intoxicated group, injected with a single intraperitoneal dose of MTX (20 mg/kg bw) on day 7; and (iv) a protective group that received licorice extract for 12 days and then MTX on day 7 as in groups 2 and 3. Total proteins, albumin, globulins, malondialdehyde, glutathione peroxidase, reduced glutathione, IL-1, and IL-6 were measured in blood and testis samples collected from all groups. Testicular oxidative stress, serum reproductive hormones, and spermogram were examined. The expression of steroidogenesis-associated genes (translocator protein; and P450scc) was examined by quantitative real-time PCR. Bcl-2-associated X protein and cyclogenase-2 genes were examined by immunohistochemical analysis. The bioactive contents of licorice extract were confirmed by gas chromatography-mass spectrometry analysis. Pretreatment with licorice extract ameliorated the toxic effects of MTX on total proteins, albumin, and globulins and oxidative stress biomarkers and reversed the effect of MTX on examined serum and tissue antioxidants. Besides, MTX down-regulated mRNA expression of translocator protein and P450scc genes. Licorice extract averted the decrease in serum testosterone and the increase in IL-1β and IL-6 levels induced by MTX. Moreover, MTX increased sperm abnormalities and percentage of dead sperms and reduced sperm motility. These changes were absent in the licorice preadministered group. Licorice prevented the increase in immunoreactivity of testis for Bcl-2-associated X protein and cyclogenase-2 that were overexpressed in MTX-injected mice. Licorice extracts positively regulated the expression of steroidogenesis genes suppressed by MTX, increased antioxidant enzymes (glutathione peroxidase, reduced glutathione, and catalase) and reduced biomarker of oxidative stress (testicular malondialdehyde) and inflammatory cytokines (IL-1 and -6). Moreover, reduction in testicular tissue immunoreactivity to Bcl-2-associated X protein and cyclogenase-2. In conclusion, licorice extract mitigated the toxic effects of MTX-induced testicular dysfunction at biochemical, molecular, and cellular levels. [ABSTRACT FROM AUTHOR]

Cyhalofop-butyl is a kind of aromatic phenoxypropionic acid herbicide widely used in agriculture. However, studies on its immunotoxicity to aquatic organisms have not been reported. In this study paper, morphological, immunological, cytological, biochemical and molecular biology methods were used to study the effects of cyhalofop-butyl on the developmental toxicity and immunotoxicity in zebrafish. After cyhalofop-butyl exposed, the results showed that the zebrafish embryos had shorter length, yolk sac edema, significantly reduced number of immune cells, inflammatory response and immunocytes apoptosis. In addition, we found that the expression of immune-related genes and pro-apoptotic genes were up-regulated, and the JAK-STAT signaling pathway mediated the immunotoxicity induced by cyhalofop-butyl. Therefore, our results indicate that cyhalofop-butyl has developmental toxicity and immunotoxicity to zebrafish, and this study offer new contents for the effects of cyhalofop-butyl exposure on aquatic organisms. Image 1 • Cyhalofop-butyl induces developmental toxicity and immunotoxicity to zebrafish. • Cyhalofop-butyl induces oxidative stress and apoptosis of immune cells in zebrafish. • Jak-STAT signaling pathway is involved in cyhalofop-butyl-induced immunotoxicity in zebrafish. [ABSTRACT FROM AUTHOR]

A wide variety of environmental contaminants has been shown to disrupt immune functions of fish and may compromise their defense capability against pathogens. Immunotoxic effects, however, are rarely considered in ecotoxicological testing strategies. The aim of this study was to systematically evaluate the suitability of an in vitro immuno-assay using selected fish immune parameters to screen for chemicals with known immunotoxic potential and to differentiate them from non-immunotoxicants. Non-stimulated and lipopolysaccharide-stimulated head kidney leukocytes of rainbow trout (Oncorhynchus mykiss) were exposed for 3 h or 19 h to chemicals with different modes of action. As immune parameters, phagocytosis activity, oxidative burst activity and cytokine transcription (IL-1β, TNFα, IL-10) were examined, accompanied by in silico modelling. The immunotoxicants dexamethasone, benzo(a)pyrene, ethinylestradiol and bisphenol A significantly altered the immune parameters at non-cytotoxic concentrations whereas diclofenac had only weak effects. However, the two baseline chemicals with no known immunotoxic potential, butanol and ethylene glycol, caused significant effects, too. From our results it appears that the in vitro fish leukocyte assay as performed in the present study has only a limited capacity for discriminating between immunotoxicants and non-immunotoxicants. [ABSTRACT FROM AUTHOR]

Nickel (Ni) is a widely distributed metal in the environment and an important pollutant because of its many industrial applications. With increasing incidences of Ni contamination, Ni toxicity has become a global public health concern and recent evidence suggests that Ni adversely affects the immune system. Hence, this paper reviews the literature on immune-related effects of Ni exposure, the immunotoxicological effects of Ni, and the underlying mechanism of Ni immunotoxicity. The main focus was on the effect of Ni on the development of organs of immune system, lymphocyte subpopulations, cytokines, immunoglobulins, natural killer (NK) cells, and macrophages. Moreover, Ni toxicity also induces inflammation and several studies demonstrated that Ni could induce immunotoxicity. Excessive Ni exposure can inhibit the development of immune organs by excessively inducing apoptosis and inhibiting proliferation. Furthermore, Ni can decrease T and B lymphocytes, the specific mechanism of which requires further research. The effects of Ni on immunoglobulin A (IgA), IgG, and IgM remain unknown and while Ni inhibited IgA, IgG, and IgM levels in an animal experiment, the opposite result was found in research on humans. Ni inhibits the production of cytokines in non-inflammatory responses. Cytokine levels increased in Ni-induced inflammation responses, and Ni activates inflammation through toll like (TL)4-mediated nuclear factor-κB (NF-κB) and signal transduction cascades mitogen-activated protein kinase (MAPK) pathways. Ni has been indicated to inactivate NK cells and macrophages both in vitro and in vivo. Identifying the mechanisms underlying the Ni-induced immunotoxicity may help to explain the growing risk of infections and cancers in human populations that have been exposed to Ni for a long time. Such knowledge may also help to prevent and treat Ni-related carcinogenicity and toxicology. Image 1 • Ni inhibits immune organ development. • Ni inhibits cytokines and immunoglobulins production. • Ni impair NK cells and macrophages activity. • Ni induces allergic contact dermatitis. [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]

The mammalian immune system is a highly complex, interactive network of cells that facilitates innate and adaptive immune responses. The neonatal immune system may be more susceptible to chemical perturbations than that of the adult. The effects of immunotoxicants during development may not be fully detected in toxicity studies performed on adult animals. Studies characterizing the ontogeny of the immune system in developing animals have shown that there are different critical windows of susceptibility to immunotoxicants. Developmental differences are evident among species compared to humans. Functional immune assays, such as the T-cell antibody dependent response assay, in rat models have been validated for use in the assessment of immunotoxicity with other assays. Recently, published studies have explored the feasibility of using additional techniques, such as in vitro studies using human whole blood cells or cell lines, mostly lacking either sensitivity or proper validation for regulatory purposes. However, some techniques may be developed further to enable translation of animal toxicity findings to human risk assessment of potential immunotoxicants. This paper summarizes the information on the developing immune system in humans versus rats and how the currently available assays might be used to contribute to the safety assessment of food contact substances. [ABSTRACT FROM AUTHOR]

Plastic represents 60-80% of litter in the ocean. Degradation of plastic to small fragments leads to the formation of microplastics (MPs <5 mm) and nanoplastics (NPs <1 µm). One of the most widely used and representative plastics found in the ocean is polystyrene (PS). Among marine organisms, the immune system of bivalves is recognized as suitable to assess nanomaterial toxicity. Hemocyte subpopulations [R1 (large granular cells), R2 (small semi-granular cells) and R3 (small agranular or hyaline cells)] of Mytilus galloprovincialis are specialized in particular tasks and functions. The authors propose to examine the effects of different sizes (50 nm, 100 nm and 1 μm) PS NPs on the different immune cells of mussels when they were exposed to (1 and 10 mg·L−1) of PS NPs. The most noteworthy results found in this work are: (i) 1 µm PS NPs provoked higher immunological responses with respect to 50 and 100 nm PS NPs, possibly related to the higher stability in size and shape in hemolymph serum, (ii) the R1 subpopulation was the most affected with respect to R2 and R3 concerning immunological responses and (iii) an increase in the release of toxic radicals, apoptotic signals, tracking of lysosomes and a decrease in phagocytic activity was found in R1. [ABSTRACT FROM AUTHOR]