Search

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]

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]

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]

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]

This paper presents the results of long-term monitoring of insecticide resistance in populations of agricultural pests in Russia. Over the last 45 years, resistance developments were recorded for 36 arthropod pest species in 11 agricultural crops and pastures in relation to nearly all commonly used plant protection products. Development of group, cross and multiple resistance has been revealed in populations of many economically important pests. Toxicological and phenotypical (for Colorado potato beetle) methods have been devised to monitor the development of pesticide resistance. Based on experience over the last century, systems aimed at preventing the development of pest resistance to insecticides and acaricides are elaborated. These systems are based on resistance monitoring and using plant protection measures which minimize the toxic pressure on agroecosystems. [ABSTRACT FROM AUTHOR]

There is growing evidence that heavy metals in general, and mercurial compounds in particular, are immunotoxic. The purpose of this study was to explore the mechanism of MeHg in inducing cell death of mouse peritoneal neutrophils. In this paper we demonstrate that MeHg induces apoptosis and necrosis depending on MeHg concentration. In vitro exposure of mouse peritoneal neutrophils to MeHg resulted in a time- and concentration-dependent cell death. MeHg (15 μM) induced neutrophil necrosis in 13 min. The type of cell death was attributed to necrosis based on cells permeable to the fluorescent dye, propidium iodide and DNA appeared as a smear. With fura-2 microfluorimetric technique, we found that the entry of external Ca2+ into the cytosol played a crucial role in inducing cell necrosis by 15 μM MeHg. However, at lower concentrations, MeHg (10 μM)-induced apoptosis is confirmed by the observation of morphological features characterised by apoptotic bodies and fragmented DNA ladder. MeHg (10 μM) caused an immediate fall in pHi as revealed by the pH-sensitive fluorescent probe 2′7′-bis (carboxyethyl)-5(6)-carboxyfluorescein. We have found that MeHg induced cellular acidification prior to DNA fragmentation so as the other two apoptosis-inducing agents (ZnCl2 and EGTA). Furthermore, acid-activated endonuclease was increased by MeHg in neutrophils, which we considered to play a possible role in chromatin digestion leading to apoptosis. Taken together, these findings indicate that MeHg induces necrosis at higher concentrations by a rapid increase of [Ca2+]i and apoptosis at lower concentrations by acid activation of endonuclease. [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]

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]

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]

Summary: Immune checkpoint inhibition with monoclonal antibodies is becoming increasingly commonplace in cancer medicine, having contributed to a widening of therapeutic options across oncological indications. Disruption of immune tolerance is the key mechanism of action of checkpoint inhibitors and although immune‐related adverse events are a typical class effect of these compounds, the relationship between toxicity and response is not fully understood. Awareness and vigilance are paramount in recognizing potentially life‐threatening toxicities and managing them in a timely manner. In this review article, we provide an overview of the clinical features, pathological findings and management principles of common immune‐related toxicities, attempting to provide mechanistic insight into an increasingly common complication of cancer therapy. [ABSTRACT FROM AUTHOR]

Fluorotelomer alcohols (FTOHs) are fluorinated intermediates used in manufacturing specialty polymer and surfactants, with 8:2 FTOH the homologue of largest production. FTOHs were found to pose acute toxicity, hepatotoxicity, nephrotoxicity, developmental toxicity and endocrine‐disrupting risks, whereas research regarding immunotoxicity and its underlying mechanism, especially on specific immune cells is limited. Here, we investigated the immunotoxicity of 8:2 FTOH on immature immune cells in an in vitro system. We observed that exposure of HL‐60 cells, a human promyelocytic leukemic cell line, to 8:2 FTOH reduced cell viability in a dose‐ and time‐dependent manner. In addition, 8:2 FTOH exposure caused G1 cell cycle arrest in HL‐60 cells, while it showed no effect on apoptosis. Exposure to 8:2 FTOH inhibited the mRNA expression of cell cycle‐related genes, including CCNA1, CCNA2, CCND1, and CCNE2. Moreover, exposure to 8:2 FTOH inhibited the mRNA expression of granulocytic differentiation‐related genes of CD11b, CSF3R, PU.1, and C/EPBε in HL‐60 cells. Furthermore, 8:2 FTOH exhibited no effect on intracellular ROS level, while hydralazine hydrochloride (Hyd), one reactive carbonyl species (RCS) scavenger, partially blocked 8:2 FTOH‐caused cytotoxicity in HL‐60 cells. Overall, the results obtained in the study show that 8:2 FTOH poses immunotoxicity in immature immune cells and RCS may partially underline its mechanism. [ABSTRACT FROM AUTHOR]

8:2 Fluorotelomer alcohol (8:2 FTOH) is widely used in houseware and industrial goods and is ubiquitous in the surrounding environment. 8:2 FTOH has been linked to hepatoxicity, nephrotoxicity, and reproductive toxicity, as well as endocrine‐disrupting effects. However, as of yet, the research regarding immunotoxicity of 8:2 FTOH remains largely limited. In the present study, adult male C57BL/6 mice were administered with 10, 30, and 100 mg/kg/d 8:2 FTOH by gavage for 28 days to investigate its immunotoxicity in vivo. The results showed that exposure to 8:2 FTOH caused increases in liver weight and histological changes in the liver, including vacuolation, cell swelling, immune cell infiltration, karyopyknosis and nuclear swelling. No histological change in either the spleen or the thymus was observed after administration of 8:2 FTOH. In addition, exposure to 8:2 FTOH reduced the concentration of IL‐1β in serum, and mRNA levels of IL‐1β, IL‐6, and TNF‐α in both the thymus and spleen. CXCL‐1 mRNA expression was downregulated in both the liver and thymus after 8:2 FTOH administration, while only IL‐1β mRNA expression was upregulated in the liver. Moreover, the exposure of primary cultured splenocytes to 8:2 FTOH inhibited the ConA‐stimulated proliferation of splenocytes at concentrations of 30 and 100 μM, and the LPS‐stimulated proliferation of splenocytes at 100 μM. Furthermore, 8:2 FTOH inhibited the level of secreted IFN‐γ in ConA‐stimulated splenocytes. The results obtained in the study demonstrated that 8:2 FTOH posed potential immunotoxicity and liver injury in mice. Our findings will provide novel data for the health risk assessment of 8:2 FTOH. [ABSTRACT FROM AUTHOR]

Heavy metal contamination may have adverse effects on wetland biota, particularly on amphibians. Severe immunotoxic effects elicited in Euphlyctis hexadactylus (Indian green frog) because of metal exposure (Cd, Cr, Cu, Pb, and Zn) in the Bellanwila-Attidiya Sanctuary, a polluted urban wetland in Sri Lanka, provided the rationale for the present study. We evaluated the biochemical and histopathological effects of this metal contamination with a reference E. hexadactylus population and a laboratory exposure group that was subjected to 28 d of exposure to a mixture of Cd, Cr, Cu, Pb, and Zn (5 ppm in each mixture). A histopathological scoring for the semiquantification of tissue damage was established. Results of the biochemical and histopathological markers were remarkably consistent between the 2 exposure scenarios, providing validation for the heavy metal exposure hypothesis. Damage to liver, kidney, lung, and skin of metal-exposed E. hexadactylus quantified multiple impairments absent in the reference frogs. Liver injuries complemented significantly elevated aspartate transaminase (AST), alanine transaminase (ALT), γ-glutamyl transferase (γ-GT), and alkaline phosphatases in frog liver homogenate, indicating hepatocellular leakage and loss of functional and structural integrity of the hepatocyte membrane in both field- and laboratory-exposed frogs. Significant elevation of Kupffer cell hypertrophy, pigmentation, inflammatory cell infiltrates and hepatic inflammation, extramedullary hematopoiesis, karyocytomegaly of hepatocytes ( p < 0.05) of the liver, and degeneration of epithelia and necrosis of the lung, manifested as impairments in both metal exposure scenarios. Significantly reduced serum total protein and albumin and significantly elevated urea and creatinine in metal-exposed frogs were indicative of hepatic and renal dysfunction, respectively. The present study affirms histopathology-related biochemical alterations as potential biomarkers for heavy metal toxicity in amphibians. Environ Toxicol Chem 2017;36:2855-2867. © 2017 SETAC [ABSTRACT FROM AUTHOR]

The International Agency for Research on Cancer has classified carbon black (CB) as a possible (Group 2B) human carcinogen. Given that most CB manufacturing processes result in the emission of various types of chemicals, it is uncertain if the adverse health effects that have been observed in CB-exposed workers are related to CB specifically or are due to other exposures. To address this issue, we conducted a cross-sectional molecular epidemiology study in China of 106 male factory workers who were occupationally exposed to pure CB and 112 unexposed male workers frequency-matched by age and smoking status from the same geographic region. Repeated personal exposure measurements were taken in workers before biological sample collection. Peripheral blood from all workers was used for the complete blood cell count and lymphocyte subsets analysis. Compared to unexposed workers, eosinophil counts in workers exposed to CB were increased by 30.8% ( P = 0.07) after adjusting for potential confounders. When stratified by smoking status, statistically significant differences in eosinophils between CB exposed and unexposed workers were only present among never smokers ( P = 0.040). Smoking is associated with alterations in various cell counts; however, no significant interaction between CB exposure and smoking status for any cell counts was observed. Given that inflammation, characterized in part by elevated eosinophils in peripheral blood, may be associated with increased cancer risk, our findings provide new biologic insights into the potential relationship between CB exposure and lung carcinogenesis. Environ. Mol. Mutagen. 57:589-604, 2016. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The article focuses on the guidelines for assessing immunotoxicity. The serum IgM/IgG would be expected to be decreased rather than increased by an immunosuppressive compound. It is rather simplistic to expect that immunotoxicity will lead to suppression of immunoglobulin levels. Effects on isotype switching for instance will result in increased levels of IgM and decreased levels of IgG. Immunotoxic effects on regulatory T cells may result in increased Ig levels. For example, cyclophosphamide, a widely known immunotoxicant, will increase Ig responses at lower concentrations, which affects suppressor cells and decrease Ig responses at higher concentrations.

The article discusses the highlights of the 20th European Symposium on Quantitative Structure-Activity Relationships (EuroQSAR) that was held in Saint Petersburg, Russia from August 31 to September 4, 2014. Topics include the navigation of chemical-biological space, the bioinformatics approaches to multi-target quantitative structure-activity relationships (QSAR), and the computational toxicology in drug and chemical safety assessment.

Nanocellulosics are among the most promising innovations for a wide-variety of applications in materials science. Although nanocellulose is presently produced only on a small scale, its possible toxic effects should be investigated at this early stage. The aim of the present study was to examine the potential genotoxicity and immunotoxicity of two celluloses in vitro - cellulose nanocrystals (CNC; mean fibril length 135 nm, mean width 7.3 nm) and a commercially available microcrystalline (non-nanoscale) cellulose (MCC; particle size ∼50 µm). Both celluloses showed 55% cytotoxicity at approximately 100 µg/ml after 4-h, 24-h, and 48-h treatment of human bronchial epithelial BEAS 2B cells, as determined by luminometric detection of ATP and cell count (dead cells identified by propidium iodide). Neither of the materials was able to induce micronuclei (MN) in binucleate or mononucleate BEAS 2B cells after a 48-h treatment (2.5-100 µg/ml). In human monocyte-derived macrophages, MCC induced a release (measured by enzyme-linked immunosorbent assay; ELISA) of the pro-inflammatory cytokines tumor necrosis factor α (TNF-α) and (after lipopolysaccharide-priming) interleukin 1β (IL-1β) after a 6-h exposure to a dose of 300 µg/ml, but CNC (30-300 µg/ml) did not. In conclusion, our results show that nanosized CNC is neither genotoxic nor immunotoxic under the conditions tested, whereas non-nanosized MCC is able to induce an inflammatory response. More studies are needed, especially in vivo, to further assess if CNC and other nanocelluloses induce secondary genotoxic effects mediated by inflammation. Environ. Mol. Mutagen. 56:171-182, 2015. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

ABSTRACT Polybrominated diphenyl ethers (PBDEs) are an emerging contaminant of concern with low level exposures demonstrating toxicity in laboratory animals and wildlife, although immunotoxicity studies have been limited. Bottlenose dolphin peripheral blood leukocytes (PBLs) and mouse splenocytes were exposed to environmentally relevant DE-71 (a penta-PBDE mixture) concentrations (0-50 µg ml−1) in vitro. Natural killer (NK) cell activity and lymphocyte (B and T cell) proliferation were evaluated using the parallelogram approach for risk assessment. This study aimed to substantiate results from field studies with dolphins, assess the sensitivities between the mouse model and dolphins, and to evaluate risk using the parallelogram approach. In mouse cells, NK cell activity increased at in vitro doses 0.05, 0.5 and 25 µg DE-71 ml−1, whereas proliferation was not modulated. In dolphin cells, NK cell activity and lymphocyte proliferation was not altered after in vitro exposure. In vitro exposure of dolphin PBLs to DE-71 showed similar results to correlative field studies; NK cell activity in mice was more sensitive to in vitro exposure than dolphins, and the parallelogram approach showed correlation with all three endpoints to predict risk in bottlenose dolphins. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Immunization with a T-cell dependent antigen has been promoted as a reliable and sensitive tool for assessing the influence of putative immunotoxic exposures or agents on immune function. Keyhole limpet haemocyanin (KLH) is a very large, copper-containing protein molecule derived from the haemolymph of the inedible mollusc, Megathura crenulata. KLH is a highly immunogenic T-cell dependent antigen that is used increasingly in immunotoxicological studies, particularly in those involving animals. This report systematically reviews the human clinical studies that have used trans-cutaneous KLH immunization for assessment of the influence of various physiological and disease states and exposures on immune function over the last 20 years (1994-2013). These studies varied in their immunization protocols, formulation of KLH, dose, site and route of administration and immunoassay platforms developed to assess KLH-specific responses. KLH immunization has been well tolerated with only mild to moderate adverse effects reported. Though very promising as a model antigen candidate in immunotoxicology research, more work on standardizing immunization and immunoassay protocols is required. [ABSTRACT FROM AUTHOR]

Preclinical Development Toxicology, Formulation Drug Delivery, PharmacokineticsClinical Development Phases I ‐ III Regulatory, Quality, Manufacturing An increasing number of immunomodulatory monoclonal antibodies (mAbs) and IgG Fc fusion proteins are either approved or in early ‐ to ‐ late stage clinical trials for the treatment of chronic inflammatory conditions, autoimmune diseases and organ transplant rejection. The exquisite specificity of mAbs, in combination with their multi ‐ functional properties, high potency, long half ‐ life (permitting intermittent dosing and prolonged pharamcological effects), and general lack of off ‐ target toxicity makes them ideal therapeutics. Dosing with mAbs for these severe and debilitating but often non life ‐ threatening diseases is usually prolonged, for several months or years, and not only affects adults, including sensitive populations such as woman of child ‐ bearing potential (WoCBP) and the elderly, but also children. Immunosuppression is usually a therapeutic goal of these mAbs and when administered to patients whose treatment program often involves other immunosuppressive therapies, there is an inherent risk for frank immunosuppression and reduced host defence which when prolonged increases the risk of infection and cancer. In addition when mAbs interact with the immune system they can induce other adverse immune ‐ mediated drug reactions such as infusion reactions, cytokine release syndrome, anaphylaxis, immune ‐ complex ‐ mediated pathology and autoimmunity. An overview of the nonclinical safety assessment and risk mitigation strategies utilized to characterize these immunomodulatory mAbs and Fc fusion proteins to support first ‐ in human (FIH) studies and futher clinical development in inflammatory disease indications is provided. Specific emphasis is placed on the design of studies to qualify animal species for toxicology studies, early studies to investigate safety and define PK/PD relationships, FIH ‐ enabling and chronic toxicology studies, immunotoxicity, developmental, reproductive and juvenile toxicity studies and studies to determine the potential for immunosuppression and reduced host defence against infection and cancer. Nonclinical strategies to facilitate clinical and market entry in the most efficient timeframe are presented. [ABSTRACT FROM AUTHOR]

ABSTRACT Mycotoxin zearalenone (ZEN) is a secondary metabolite produced by some Fusarium species that contaminate a large variety of grains and feedstuffs worldwide. ZEN has been associated with a wide variety of adverse health effects including hepatotoxic, hematologic, immunotoxic and genotoxic. In order to better understand the mechanism of ZEN toxicity, a proteomic approach was applied to characterize cellular responses of hepatocarcinoma cells (HepG2) to ZEN exposure. Protein extracts from cultured HepG2 cells treated with 100 µ m ZEN for 8 h, as well as extracts from control cells. The screening method applied to compare the proteome was based on the stable isotope approach of isobaric tagging for relative and absolute quantification (iTRAQ). This study identified 982 proteins, among which peptides and their corresponding proteins were identified and quantified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Ingenuity pathways analysis software was then used to determine the biological functions and canonical pathways associated with the ZEN-responsive proteins. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The current study describes the effect of cypermethrin, fluoxetine, and thiabendazole, at environmentally relevant concentrations, on the expression of heat shock protein 70 (HSP70) and interleukin 1β (IL-1β), using Xenopus laevis larvae as animal model. Cytokines and interleukins are considered good predictors of the immunotoxic potential of xenobiotics. Tadpoles at stage 47 (normal tables of X. laevis) were exposed under static conditions to: 0.3 and 30 µg/L fluoxetine, 0.7 µg/L thiabendazole, and 0.24 µg/L cypermethrin. The effects were evaluated at 7, 24, and 72 h, and 6 and 9 d. Randomly chosen tadpoles were used as genetic material for detection of hsp70 and IL-1β mRNA induction through reverse transcription PCR. Tadpoles exposed to 30 µg/L fluoxetine showed mRNA expression of both genes at all exposure times, whereas at 0.3 µg/L a peak response for hsp70 was observed after 24 h, and the increase in IL-1β mRNA was statistically significant with respect to the control 72 h after exposure. Thiabendazole induced a high expression of mRNA for both hsp70 and IL-1β at all exposure times. Cypermethrin increased the hsp70 mRNA levels, with a peak at 24 h, and provoked high expression of IL-1β mRNA at all exposure times. Considering the relationship between HSP70 and IL-1β and their involvement (mainly of IL-1β) in immune responses, certain changes observed in their expression could be considered warning indicators of potential immunotoxic effects of these substances on Xenopus. Environ. Toxicol. Chem. 2010;29:2536-2543. © 2010 SETAC [ABSTRACT FROM AUTHOR]

The aryl hydrocarbon receptor (AHR) is a protein best known for its role in mediating toxicity. Over 30 years of research has uncovered additional roles for the AHR in xenobiotic metabolism and normal vascular development. Activation of the AHR has long been known to cause immunotoxicity, including thymic involution. Recent data suggesting a role for the AHR in regulatory T-cell (Treg) and T-helper 17 (Th17) cell development have only added to the excitement about this biology. In this review, we will attempt to illustrate what is currently known about AHR biology in the hope that data from fields as diverse as evolutionary biology and pharmacology will help elucidate the mechanism by which AHR modifies immune responses. We also will discuss the complexities of AHR pharmacology and genetics that may influence future studies of AHR in the immune system. [ABSTRACT FROM AUTHOR]

Ochratoxin A (OTA) is an immunosuppressant fungal compound, produced by toxigenic species of Aspergillus and Penicillium fungi in a wide variety of climates and geographical regions. The contamination of food by this mycotoxin takes place primarily during preharvest periods. Almost all types of food can be contaminated. In addition, its chemical stability against heat and during industrial food processing makes OTA one of the most abundant food contaminating mycotoxins. Due in part to its long serum half-life in man, almost 100% of all human blood samples from some geographic regions may be positive for OTA. The immunosuppressant activity of OTA is characterized by size reduction of vital immune organs, such as thymus, spleen, and lymph nodes, depression of antibody responses, alterations in the number and functions of immune cells, and modulation of cytokine production. The immunotoxic activity of OTA probably results from degenerative changes and cell death following necrosis and apoptosis, in combination with slow replacement of affected immune cells, due to inhibition of protein synthesis. [ABSTRACT FROM AUTHOR]

In a recent publication by Putman et al. (2003), salmeterol, morphine/methadone and buprenorphine were quoted as examples of pharmaceutical drugs whose immunotoxicity has only been revealed by conduct of specific immune function tests in non-clinical studies. Review of the published non-clinical data for these drugs has shown that there is no clear evidence of immunotoxicity of salmeterol in these studies, and in addition, there are no clinical issues regarding adverse immunological effects of this drug. Of the opioid drugs, only very minor evidence of immunosuppression by morphine, and marginal evidence of slight immunostimulation by buprenorphine were detected in the non-clinical immune function assays performed at high doses. Methadone showed no effects on immune function assays in animals. As some immunomodulation by opioid drugs might have been expected based on the known pharmacological properties of this drug class, the marginal effects, or lack of effects observed in the immune function tests does raise a question about the sensitivity and specificity of the assays to detect clinically relevant changes. This review has suggested that, based on the cited examples, there is no strong case for routine non-clinical immune function testing of all new pharmaceutical products. A more rigorous evaluation of non-clinical immune function tests, and their ability to discriminate between clinically relevant and non-clinically relevant immunosuppression, is needed before definitive regulatory guidance in this area can be finalized. [ABSTRACT FROM AUTHOR]

The ε-toxin of Cl. welchii Type D has been isolated in an immunologically and electrophoretically homogeneous state, by elution from DEAE cellulose. Such a preparation, containing 10,000 Lf mg. N, sedimented as a single symmetrical peak in the ultracentrifuge, but still contained some non-protein N. The molecular weight of ε-toxin was estimated as 38,000 and its toxicity in mice as 280,000 MLD mg. protein N. Its combination with horse antitoxin was studied by neutralization tests in vivo, by the flocculation reaction (optimum proportions), by quantitative precipitation and by double diffusion in agar gel. The immunological and chemical relationships between the non-toxic ε-precursor and the active toxin derived from it by tryptic (or other enzymic) hydrolysis, and toxoid made from either material by treatment with β-propiolactone, were also investigated. [ABSTRACT FROM AUTHOR]

Although interest and funding in nanotechnology for oncological applications is thriving, translating these novel therapeutics through the earliest stages of preclinical assessment remains challenging. Upon intravenous administration, nanomaterials interact with constituents of the blood inducing a wide range of associated immunotoxic effects. The literature on the immunological interactions of nanomaterials is vast and complicated. A small change in a particular characteristic of a nanomaterial (e.g., size, shape, or charge) can have a significant effect on its immunological profile in vivo, and poor selection of specific assays for establishing these undesirable effects can overlook this issue until the latest stages of preclinical assessment. This work describes the current literature on unintentional immunological effects associated with promising cancer nanomaterials (liposomes, dendrimers, mesoporous silica, iron oxide, gold, and quantum dots) and puts focus on what is missing in current preclinical evaluations. Opportunities for avoiding or limiting immunotoxicity through efficient preclinical assessment are discussed, with an emphasis placed on current regulatory views and requirements. Careful consideration of these issues will ensure a more efficient preclinical assessment of cancer nanomedicines, enabling a smoother clinical translation with less failures in the future. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) deliver biologically active cargos from donor cells to recipient cells for intercellular communication. Since the existence of RNA cargo was discovered, EVs have been considered to be useful drug-delivery systems. Specifically, EVs from bovine milk (mEV) are one of the most promising platforms, since bovine milk is a scalable source of EVs for mass production. However, it is still difficult to isolate pure EVs from bovine milk owing to the complexity of raw materials. Furthermore, the biocompatibility and immunotoxicity of mEVs are still unclear. In this study, we developed a new method for isolating bovine milk-derived EVs by employing acid treatment and ultracentrifugation. Isolated mEVs are spherical in shape, measure 120 nm in diameter and contain typical EV marker proteins, such as tetraspanins. Compared with the previously reported method, our method can isolate purer mEVs. When mEVs are contacted with the mouse macrophage cell line Raw264.7, mEVs are readily taken up by the cells without a cytotoxic effect, suggesting that mEVs can deliver the cargo molecules into cells. While systemic administration of mEVs into mice resulted in the absence of systemic toxicity, certain types of cytokines were slightly induced. No anaphylaxis effect was observed after serial administration of mEVs in mice. Thus, mEVs isolated using our method are well tolerated in vivo and may be useful for the drug-delivery application. [ABSTRACT FROM AUTHOR]

Cadmium is a nonessential heavy metal and a well-known persistent environmental pollutant. It causes a variety of toxic effects, including immunotoxicity. The exact mechanism of its cellular effects still is unclear. Cell-cycle regulation is an important factor that modulates cell death; however, cadmium-mediated cell-cycle arrest leading to cell death in murine macrophages has not been investigated. Cadmium at 20 µM induced both apoptotic and necrotic death in murine macrophage (J774A.1) cultures at 24 h. Cadmium at 20 µM triggered re-entry of G0/G1 to the next phase and increased the number of cells in the G2/M phase at 24 h. Phosphorylation of extracellular signal-regulated kinase (ERK) correlated with the cyclin-dependent kinase inhibitor p21WAF1/CIP1 induction. Inhibition of ERK activation by PD98059 resulted in G0/G1 arrest and partially released the cadmium-mediated G2/M arrest. Inhibition of ERK phosphorylation by PD98059 strongly attenuated cadmium-induced necrotic cell death, but did not prevent caspase-3 activation and DNA fragmentation. Necrosis rather than apoptosis was caused by cadmium-induced ERK signaling in J774A.1 cells. A scavenger of reactive oxygen species (ROS), N-acetylcystein, decreased cadmium-induced ERK activation and necrotic cell death, suggesting that cadmium induces the ROS-ERK-p21WAF1/CIP1 signaling pathway, leading to G2/M arrest and cell death. These findings may be important in further understanding the cellular mechanisms of cadmium toxicity to provide information to assess objectively risk for this metal. [ABSTRACT FROM AUTHOR]

Recent pinniped die-offs have led to the speculation that persistent organic pollutants (POPs) are immunomodulatory, making individuals more susceptible to viral infections. Eighteen healthy harbor seal (Phoca vitulina) pups (aged 3-4 weeks) were live-captured from southern British Columbia, Canada, and maintained temporarily in captivity for an immunotoxicological assessment. The relationships between mitogen-induced peripheral blood lymphocyte proliferation and blubber concentrations of three major immunotoxic POP classes (the polychlorinated biphenyls [PCBs], polychlorinated dibenzo-p-dioxins [PCDDs], and the polychlorinated dibenzofurans [PCDFs]) were evaluated. A significant body weight--independent positive correlation was observed between both T-cell mitogen (phytohemagglutinin [PHA])- and B-cell mitogen (lipopolysaccharide [LPS])-induced lymphocyte proliferation and the blubber concentrations of total PCB. Best subset regression analysis revealed that total PCBs, and not total PCDD or total PCDF, explained 24 and 29% of the changes in both T-cell mitogen--and B-cell mitogen--induced lymphocyte proliferation, respectively. Further regression analysis performed on the PCB classes measured in this study showed that di-ortho PCBs accounted for 25 and 30% of the changes in both T-cell and B-cell lymphocyte proliferation, respectively. Results suggest that POPs, and PCBs in particular, are associated with changes in lymphocyte proliferation, something that could result in increased susceptibility to infections in harbor seal pups. Further research is needed to evaluate the relative roles of natural and contaminant-related influences on the immune system of marine mammals. [ABSTRACT FROM AUTHOR]

The fungicide chlorothalonil (TCIN), with both agricultural and horticultural applications, is a common aquatic pollutant. The immunotoxic potential of WIN was investigated following a 20-h in vitro exposure of striped bass (Morone saxatilus) macrophages to a range of sublethal concentrations. Cells from the anterior kidney were separated by density -gradient centrifugation to obtain a macrophage-enriched cellpopulation. Following WIN exposure, reactive oxygen species (ROS) production was evaluated using luminol-augmented chemiluminescence; phagocytic capacity was measured by the ingestion of fluorescein isothiocyanate conjugated yeast and NADPH production was estimated by monitoring the reduction of a water-soluble tetrazolium, 3-(4,5dimethylthiazol-2-yl)-5-(3-carboxymethoxyphe nyt)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt. Results indicate that TCIN, at concentrations ~:250 l.Lg/L, decreased ROS production in both zymosan- and phorbol myristateacetate (PMA)-stimulated cells in a dose-dependent manner. The PMA-stimulated NADPH production coincident with the respiratory burst was also decreased at concentration ~-250 mu g/L. The WIN did not appear to alter phagocytic ability. Taken together, these results indicate that the mechanism of toxicity affects the activation or function of the NADPH oxidase but not the uptake of particles by phagocytosis. andthat these effects can probably be localized to the signal transduction pathway or the assemblage of NADPH oxidase. [ABSTRACT FROM AUTHOR]