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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]

Background: Bisphenol (BP‐)A is a chemical used in Europe to produce polycarbonate plastics and epoxy resin or as colour developer in thermal paper. Due to its toxicity, BPA presence was restricted by European regulations. Therefore, substitute chemicals are replacing BPA. Objective: To assess the allergenic sensitizing potential of 27 substitutes to BPA used in the industry. Methods: The expression of two costimulatory molecules and six cytokines were analysed by flow cytometry in mouse bone marrow‐derived dendritic cells (BMDCs) exposed to the chemicals. Results: All substances except one induced overexpression of at least one receptor and were thus identified as having allergenic sensitizing potential. Based on the BMDC model, they were classified as extreme (1 out of 27), strong (20 out of 27) and moderate (5 out of 27) sensitizers. BPA was classified as a moderate sensitizer and BPF was the only substitute classified as a non‐sensitizer. The more potent substitutes induced more than 2‐fold secretion of CCL3, CCL4 and/or CCL5 by dendritic cells. Conclusion: Most of the BPA substitutes tested in this study have an allergenic sensitizing potential; 24 of them being more potent than BPA itself. Only BPE, BPF and 2,4‐BPS appeared to be weaker sensitizers than BPA. [ABSTRACT FROM AUTHOR]

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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]

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]

The long-distance migration of polycyclic aromatic hydrocarbons (PAHs) promotes their release into the marine environment, posing a serious threat to marine life. Studies have shown that PAHs have significant immunotoxicity effects on bivalves, but the exact mechanism of immunotoxicity remains unclear. This paper aims to investigate the effects of exposure to 0.4, 2, and 10 μg/L of benzo(a)pyrene (B[a]P) on the immunity of Chlamys farreri under environmental conditions, as well as the potential molecular mechanism. Multiple biomarkers, including phagocytosis rate, metabolites, neurotoxicity, oxidative stress, DNA damage, and apoptosis, were adopted to assess these effects. After exposure to 0.4, 2, and 10 μg/L B[a]P, obvious concentration-dependent immunotoxicity was observed, indicated by a decrease in the hemocyte index (total hemocyte count, phagocytosis rate, antibacterial and bacteriolytic activity). Analysis of the detoxification metabolic system in C. farreri revealed that B[a]P produced B[a]P-7,8-diol-9,10-epoxide (BPDE) through metabolism, which led to an increase in the expression of protein tyrosine kinase (PTK). In addition, the increased content of neurotransmitters (including acetylcholine, γ -aminobutyric acid, enkephalin, norepinephrine, dopamine, and serotonin) and related receptors implied that B[a]P might affect immunity through neuroendocrine system. The changes in signal pathway factors involved in immune regulation indicated that B[a]P interfered with Ca2+ and cAMP signal transduction via the BPDE-PTK pathway or neuroendocrine pathway, resulting in immunosuppression. Additionally, B[a]P induced the increase in reactive oxygen species (ROS) content and DNA damage, as well as an upregulation of key genes in the mitochondrial pathway and death receptor pathway, leading to the increase of apoptosis rate. Taken together, this study comprehensively investigated the detoxification metabolic system, neuroendocrine system, and cell apoptosis to explore the toxic mechanism of bivalves under B[a]P stress. [ABSTRACT FROM AUTHOR]

The influence of temperature variation on the humoral immune response using the plaque-forming cell (PFC) assay in freshwater fish Channa punctatus (Bloch) was investigated. The fish was exposed to 1% concentration (v/v in water) of paper and pulp mill effluent under standard laboratory conditions in glass aquaria. Effect of effluent exposure on the organ weight and organ cellularity was also evaluated. In general, lower temperature in winter produced a subdued response in control as well as experimental group. At higher temperature of summer and rainy seasons, an elevated response was observed. It was revealed that though suppressive effect of effluent was evident during all the seasons, in summer, extent of suppression was greater as compared to winter. Paper and pulp mill effluent exposure resulted in a decrease in the splenic and pronephric (head kidney) cellularity, with more pronounced effect in the summer season. We also studied the effects of the length of exposure on various parameters. Fish were exposed for 15, 30, 60, and 90 days to effluent. Short-term exposure for 15 days induced an elevated PFC response, but change was not statistically significant. Conversely, the exposure for 30, 60, and 90 days significantly reduced (p < 0.05–0.001) the PFC response. Long-term exposure also caused significant reduction (p < 0.05–0.01) in the weights of lymphoid organs (spleen, head kidney, and total kidney). These results show a suppressive effect of chemical constituents of paper and pulp mill effluent on the immune functions. Furthermore, results demonstrated that though modulatory effect of the temperature on immune functions is recognized, it was not a major contributory factor to the elevated immunotoxicity of paper and pulp mill effluent in the seasons of high temperature. [ABSTRACT FROM AUTHOR]

The COVID‐19 pandemic is a highly dramatic concern for mankind. In Italy, the pandemic exerted its major impact throughout the period of February to June 2020. To date, the awkward amount of more than 134,000 deaths has been reported. Yet, post‐mortem autopsy was performed on a very modest number of patients who died from COVID‐19 infection, leading to a first confirmation of an immune‐thrombosis of the lungs as the major COVID‐19 pathogenesis, likewise for SARS. Since then (June–August 2020), no targeted early therapy considering this pathogenetic issue was approached. The patients treated with early anti‐inflammatory, anti‐platelet, anticoagulant and antibiotic therapy confirmed that COVID‐19 was an endothelial inflammation with immuno‐thrombosis. Patients not treated or scarcely treated with the most proper and appropriate therapy and in the earliest, increased the hospitalization rate in the intensive care units and also mortality, due to immune‐thrombosis from the pulmonary capillary district and alveoli. The disease causes widespread endothelial inflammation, which can induce damage to various organs and systems. Therapy must be targeted in this consideration, and in this review, we demonstrate how early anti‐inflammatory therapy may treat endothelia inflammation and immune‐thrombosis caused by COVID‐19, by using drugs we are going to recommend in this paper. [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]

Bisphenol A (BPA) is a known endocrine disruptor found in many consumer products that humans come into contact with on a daily basis. Due to increasing concerns about the safety of BPA and the introduction of new legislation restricting its use, industry has responded by adopting new, less studied BPA analogues that have similar polymer-forming properties. Some BPA analogues have already been shown to exhibit effects similar to BPA, for example, contributing to endocrine disruption through agonistic or antagonistic behaviour at various nuclear receptors such as estrogen (ER), androgen (AR), glucocorticoid (GR), aryl hydrocarbon (AhR), and pregnane X receptor (PXR). Since the European Food Safety Authority (EFSA) issued a draft re-evaluation of BPA and drastically reduced the temporary tolerable daily intake (t-TDI) of BPA from 4 mg/kg body weight/day to 0.2 ng/kg body weight/day due to increasing concern about the toxic properties of BPA, including its potential to disrupt immune system processes, we conducted a comprehensive review of the immunomodulatory activity of environmentally abundant BPA analogues. The results of the review suggest that BPA analogues may affect both the innate and acquired immune systems and can contribute to various immune-mediated conditions such as hypersensitivity reactions, allergies, and disruption of the human microbiome. [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]

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]

In November of 2021, the European Food Safety Authority (EFSA) released a draft scientific opinion on bisphenol A (BPA) exposure and health outcomes released to the public. EFSA concluded that the most sensitive outcome category to BPA exposure is the immune system. In this scientific opinion, EFSA utilized a weight of evidence approach to conclude that it is likely that BPA exposure promotes the development of TH17 cell-mediated atopic respiratory disease (eg, wheezing, rhinitis and asthma). Here, we present a dissenting analysis to that put forward in the draft EFSA scientific opinion and raise concerns about the studies and EFSA's interpretation of data that were used to arrive at their conclusion. [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]

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]

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]

Immunotoxicity has been an important topic in toxicology since inadvertent exposures to xenobiotics were found to alter immune functions in humans. While rodent toxicity tests can reveal some levels of immunotoxicity, alternative methods must be developed to identify the detailed mechanisms. In this study, a method of in vitro prediction of innate immune suppression by substances was developed using a genomics approach. The primary selection of immune suppressors was based on their ability to downregulate MCP-1, CCL3, TNF, IL-8, and IL-12p40 expression levels in lipopolysaccharide (LPS)-stimulated THP-1 cells. Among 11 substances classified as potent immune suppressors, six including dexamethasone, tacrolimus, tofacitinib, prednisolone, sodium lauryl sulfate, and benzoic acid were used to create a dataset by transcriptomics of chemical-treated THP-1 cells using bulk RNA sequencing. We selected genes that were significantly upregulated by suppressor treatment while filtering out genes also upregulated in LPS-treated THP-1 cells. We identified a 226-gene immunosuppressive gene set (ISG). Innate immune suppressor signature scores were calculated as the median expression of the ISG. In a validation dataset, the signature score predicted acyclovir, cyclosporine, and mercuric chloride as immune suppressors, while selecting genistein as a non-immune suppressor. Although more dataset integration is needed in the future, our results demonstrated the possibility and utility of a novel genomics-based approach, the transcriptome-based determination of innate immune suppressor (TDIS) assay, to evaluate innate immune suppression by different substances. This provides insight into the development of future alternative testing methods because it reflects a comprehensive genetic signature derived from multiple substances rather than one cytokine. [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]

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]

Various heteroatomic constituents are present in the composition of the petroleum, which have an important influence. Sulphur compounds are among the most important constituents of petroleum, and there are certain types of compounds in different types of petroleum. The presence of sulphur compounds in petroleum and its products often leads to harmful effects. The present work is aimed to predict the probable hepatotoxicity and four toxicological endpoints (carcinogenicity, immunotoxicity, mutagenicity and cytotoxicity) of twelve polycyclic aromatic sulphur heterocycles (benzothiophene derivatives) in petroleum by the ProTox-II software. [ABSTRACT FROM AUTHOR]

With a growing interest in the concept of a circular economy, the use of lignocellulosic residues, such as lignins and humins, as potential renewable feedstock for biorefining processes looks increasingly promising. Many challenges remain for the sustainable use of humins, starting from the need to provide reference data reflecting actual usable feedstocks of such materials. This paper offers the first study, from this perspective, of the potential environmental fate of those materials and components, all related to furanics, a family of compounds the toxicity of which is still a matter of debate. Conventional ecotoxicity and biodegradability tests required by European regulation on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) for the primary evaluation of environmental hazards were conducted in combination with fish immunomarker tests to study possible long‐term effects on aquatic ecosystems. These first results are promising as humins did not give rise to any immediate ecotoxicological concerns, and hence their use could be considered in environment‐friendly applications. © 2018 Society of Chemical Industry and John Wiley & Sons, Ltd [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]

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]

Polychlorinated biphenyls (PCBs), and similar environmental contaminants, have been linked to virus outbreaks and increased viral induced mortality since the 1970s. Yet the mechanisms behind this increased susceptibility remain elusive. It has recently been illustrated that the innate immune viral detection system is tightly regulated by small non‐coding RNAs, including microRNAs (miRNAs). For virus infections miRNA‐155 expression is an important host response against infection, and deregulation of this miRNA is closely associated with adverse outcomes. Thus, we designed a targeted in vitro study using primary chicken fibroblasts, first exposed to a mixture of PCBs (Arochlor‐1250) before being stimulated with a synthetic RNA virus (poly I:C), to determine if PCBs have the potential to deregulate miRNA‐155. In this paper, we provide the first data for the deregulation of miRNA‐155 when a host is exposed to a mixture of PCBs before a virus infection. Thus, we provide important evidence that PCBs can be involved in the deregulation of important miRNA pathways involved in the immune system; thereby demonstrating novel insights into the mechanism of PCB toxicity on the immune system. [ABSTRACT FROM AUTHOR]

Polyfluorinated alkylated substances are recognized as an important class of pollutants in marine environments. Bivalves are good model organisms for evaluating the toxicity of pollutants and monitoring marine environments. In the present study, immunotoxicity of perfluorooctanoic acid (PFOA) was investigated by measuring biomarkers of the immune profile of Ruditapes philippinarum. In bivalves, hemocytes are an important component of the immune system. Thus, hemocyte proliferation, phagocytosis, cell viability, and immune enzyme activities, which have been applied as marine pollution bioindicators, were identified and observed for changes after exposure to PFOA in R. philippinarum. Based on the integrated biomarker responses method, we selected five biomarkers to evaluate PFOA risk at the multibiomarker level. In addition, the histopathological alterations of hemocytes in bivalves were used as indexes of the response to environmental stress. The subcellular structure of the hemocytes in R. philippinarum changed significantly with PFOA exposure, including hemocyte and nucleus morphological changes, organelle dissolution, cytomembrane and karyotheca swelling, and cytoplasm vacuolization. The present study verifies PFOA immunotoxicity to R. philippinarum at different levels and the integrated assessment of stress levels caused by PFOA in marine environment. Our results will provide new insights into evaluating adverse effects of PFOA and monitoring marine ecosystem. Environ Toxicol Chem 2022;41:426–436. © 2021 SETAC [ABSTRACT FROM AUTHOR]

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]

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

Prebiotics are known as the ‘food’ for beneficial gut microbiota that are capable of promoting host health. Their effects depend on the product of gut fermentation or metabolites. This paper discusses the role of prebiotics on cytotoxicity, genotoxicity, and cell integrity. Metabolites produced from the fermentation of prebiotics can be used to understand gut diseases such as colorectal cancer. Fecal water fromin vivoorin vitrostudies can be used to understand the relationship between prebiotics and gut diseases because of its close contact with colon epithelium. Besides, fecal water has compounds that are capable of modifying colonocytes. [ABSTRACT FROM AUTHOR]

The adverse health effects of benzene occupational and circumstance pollution exposure are an increasing concern. It leads to damage to various human tissues including bone marrow and ovarian tissues and many vital physiological processes. Previous studies showed that kefir is a rich probiotic, having protective effect, thanks to its antioxidant, anti-inflammatory, and immunomodulatory capacity. The purpose of this study was to evaluate the potential efficacy of kefir to remediate benzene toxicity in rat. Thirty-two female rats were randomly allocated and administered orally with benzene and/or kefir during a period of 21 consecutive days. At the end of the experiment, hematological and bone marrow cell changes were estimated. The animals exposed to benzene exhibited anemia and a significant decrease in the levels of white blood cell. Moreover, benzene led to the activation of gene expression of the pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-6 (IL-6), a myelotoxicity in bone marrow cells. Our data showed that kefir treatment alleviated benzene-associated weight loss and increased the number of whole blood cells in peripheral blood and nucleated cells in the bone marrow. Furthermore, these physiological results were observed with animals showing high concentrations of lactic acid bacteria (LAB) determined from fecal samples, which are considered an indicator of kefir-associated microorganisms. Our study suggests that kefir is a potential nutritional supplement target to attenuate hematotoxicity induced by benzene. [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]

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]

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]

Increased expectations from a number of regulatory agencies, e.g., Environmental Protection Agency (EPA), Food and Drug Administration (FDA), European Medicines Agency (EMEA), and the Ministry of Health, Labour and Welfare (MHLW) of Japan, call for the evaluation of potential adverse effects on the immune system. As recently summarized in the ICH S8 guideline, the T-cell-dependent antibody response (TDAR) has been identified in a regulatory context as a main functional test of immunotoxicity. While the characterization of immunotoxic potential is pertinent to both the chemical and pharmaceutical industries, the use of immunotoxicology data for hazard identification and/or risk assessment in each case is different. Therefore, multiple approaches to immunotoxicity testing have evolved. The assays that evaluate TDAR function include both well-established tests, e.g., anti-sheep red blood cell plaque-forming cell (PFC) assay, and newer models, e.g., anti-keyhole limpet hemocyanin (KLH) antibody ELISA. These tests vary in the study design, antigen application and analytical methods. However, they all evaluate the same endpoint - a competent immune (e.g., antibody) response to an antigen. Numerous issues have been identified in the application of TDAR tests, including high animal to animal variability; differences in antigen source and potency; a lack of established "normal range" of the immune response and uncertainty about the degree of inhibition of the TDAR to be considered toxicologically important. As such, the need for a forum to discuss these issues was recognized by the immunotoxicology community, and was addressed at the 2006 Society of Toxicology (SOT) Workshop. A series of papers will summarize that forum with the ultimate objectives being to build a consensus among immunotoxicologists on the implications of these factors on using TDAR results in hazard identification and/or risk assessment, and to establish a criteria to classify compounds as immunotoxicants. [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]

An understanding of polychlorinated biphenyl (PCB) congener‐specific effects on cell membrane and intercellular communication is important within the studies of PCB absorption, organ‐related PCB accumulation and exertion of toxic responses. Toxic potential of PCBs is linked to various deleterious effects on human health, including neurotoxicity, immunotoxicity, reproductive toxicity and genotoxicity and, recently in 2016 International Agency for Research on Cancer (IARC) has upgraded the classification of PCBs to Group 1 "Carcinogenic to humans." Proposed mechanisms of aforementioned PCBs adverse effects at cellular membrane level are: (i) downregulation of gap junction intercellular communication and/or connexins; (ii) compromised membrane integrity; and (iii) altered tight junction barrier function. This study, based on an extensive literature survey, shows the progress in scientific research of each of these three levels with the aim of pointing out the earliest toxic events of PCBs, which can result in serious cell/tissue/organ damage. Polychlorinated biphenyl (PCB) effects are linked to neurotoxicity, immunotoxicity, reproductive toxicity, genotoxicity and carcinogenicity. Proposed PCB mechanisms of action at cellular membrane level are: (i) downregulation of gap junction intercellular communication and/or connexins; (ii) compromised membrane integrity; and (iii) altered tight junction barrier function. This study shows the progress in scientific research of each of these three levels with the aim of indicating the earliest toxic events, which can lead to serious cell/tissue/organ damage. [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]

Aqueous film-forming foams (AFFFs) are complex per- and polyfluoroalkyl substance (PFAS)-containing mixtures used extensively as fire suppressants. AFFF-impacted groundwater and surface water have contaminated drinking water with PFASs in many communities, raising concerns about health effects from drinking water exposures. As individual PFASs have been identified as immune hazards, the immunotoxicity of complex PFAS mixtures is also a concern. Adult female and male C57BL/6 mice were given a commercial AFFF formulation for 10 days via gavage; administered dose was based on combined content of perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) measured in the formulation (0, 1.88, 3.75, 7.5, or 10 mg PFOS+PFOA/kg body weight). A PFOA positive control of 7.5 mg/kg body weight was also given. Compared with the 0 mg/kg group, the following changes were noted: Body weights of males exposed to 7.5 and 10 mg PFOS+PFOA/kg were reduced by 15%, on average; female body weights did not differ. Average relative liver weights were increased 50%–200% in males and 37.5%–193% in females and liver peroxisome proliferation was increased 2- to 12-fold in all doses of both sexes. Antigen-specific antibody production was suppressed, on average, by 13% in males and by 12.4% in females across all doses. Spleen cellularity and lymphocyte subpopulations did not differ by dose for either sex. Our data indicate that though this complex PFAS mixture contained fairly low PFOA content, it induced changes in C57BL/6 mice similar to changes induced by PFOA alone, likely due to the presence of PFOS and many other PFASs. [ABSTRACT FROM AUTHOR]

The in vivo toxicity of Gd2O3:Eu3+ nanoparticles (NPs) used as dual‐modal nanoprobes for molecular imaging has not been studied, and the corresponding molecular mechanism of immunotoxicity remains unknown. In this study, we investigated the cytotoxicity, in vitro apoptosis, and in vivo immunotoxicity of Gd2O3:Eu3+ NPs. The NPs showed little immunotoxicity to BALB/c mice. We explored the possible role of the phosphoinositide 3‐kinase (PI3K) signaling pathway and found that reactive oxygen species could act as secondary messengers in cellular signaling, inhibiting PI3K expression in the liver. The immune suppression caused by PI3K inhibition helped the mice adapt to stress. The immunotoxicities caused by Gd2O3:Eu3+ and gadodiamide, a commonly used contrast agent, were not significantly different, and the mice were able to tolerate the immunotoxicity caused Gd2O3:Eu3+ NPs in vitro and in vivo experiments. The results suggest that Gd2O3:Eu3+ NPs are sufficiently biocompatible to be used safely in preclinical applications and show promise as bio‐imaging agents. Moreover, the in vivo molecular mechanism of immunotoxicity caused by the Gd2O3:Eu3+ NPs provides a platform for further research on the immunotoxicity of nano‐sized biomaterials. [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]

The current study was carried out to evaluate the effects of dietary supplementation of Coriandrum sativum seed powder (CP) and extract (CE) on some immune functions of Oreochromis niloticus, without or with exposure to the immunotoxicant metal lead (Pb). Fish (n = 300) were divided into ten groups, in triplicate. First group (Cont) was fed on the basal control diet. Second (CP20) and third (CP30) groups were fed on CP‐supplemented diets at 20 mg/kg and 30 mg/kg respectively, while fourth (CE20) and fifth (CE30) groups were fed on CE‐supplemented diets at 20 mg/kg and 30 mg/kg respectively. Fish of the sixth (Cont‐Pb), seventh (CP20‐Pb), eighth (CP30‐Pb), ninth (CE20‐Pb) and tenth (CE30‐Pb) groups were exposed to lead (Pb) at 20.2 mg/L and received same diets presented to groups; Cont, CP20, CP30, CE20 and CE30 respectively. The experiment lasted for 45 days. CP and CE dietary supplementation not only significantly enhanced the immune functions, serum lysozyme, nitric oxide, bactericidal activities and relative expression of interleukin‐1β (IL‐1β) of O. niloticus in a concentration‐dependent manner, but also ameliorated the lead‐induced immunosuppressive effects, especially in CE30 received groups. Additionally, lead‐induced fish mortality and levels of lead residues in fish musculature were significantly reduced in response to feeding on CP‐ and CE‐supplemented diets, especially in CE30. Therefore, it could be concluded that coriander dietary supplementation, especially the extract (CE) at 30 mg/kg diet, could be used to enhance the immune response of O. niloticus and to counteract the immunotoxic effects of lead exposure. [ABSTRACT FROM AUTHOR]