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

Silver nanoparticles (Ag NPs) have been used in many studies due to their inhibitory properties on microorganisms such as bacteria and viruses. In recent years, due to global problems such as environmental pollution, the green synthesis (biosynthesis) method is frequently preferred because it is simple and low cost and does not require the use of toxic substances. The aim of this study is to synthesize silver nanoparticles (Ag NPs) from Ceratonia siliqua L. leaves and investigate their antioxidant and immunotoxic properties using Galleria mellonella last instar larvae. The UV spectrophotometer, TEM, XRD and FTIR measurements were used to characterize the Ag NPs. In this study, it was determined that the effects on antioxidant enzyme activities (SOD, CAT, GPx, GST), acetylcholinesterase (AChE) and total hemocyte count (THC) as well as phenoloxidase activity determine their effect on antioxidant defence and the immune system in model organism G. mellonella larvae. We observed that green synthesized Ag NPs accumulate in the midgut of the larvae and led to the increasing of CAT and SOD activities. GST and AChE activities were increased in the fat body of the larvae; otherwise, it was decreased in the midgut. Moreover, increases were found in THC and phenoloxidase activity. Consequently, green synthesized silver nanoparticles led to oxidative stress and immunotoxic effects on G. mellonella larvae. [ABSTRACT FROM AUTHOR]

Hexaflumuron (HEX) insecticide is widely used in agriculture practices to fight crop insects. The toxicological effect of HEX on Nile tilapia (Oreochromis niloticus) was investigated in this study. Two hundred and forty fish (35.50 ± 1.45 g) were divided into six groups in four replicates (40 fish/group; 10 fish/replicate) and were exposed to six distinct HEX concentrations (0, 2, 4, 6, 8, and 10 mg L−1) for 96-h. The 96-h lethal concentration 50 (96-h LC50) of HEX was calculated to be 7.19 mg L−1. The fish exhibited reduced surface and middle swimming, aggressiveness, and tail-spreading behaviors with increasing bottom swimming and resting patterns after HEX exposure. HEX exposure resulted in body bleeding and fin rot. The erythrogram (red blood cell count, hemoglobin, and packed cell volume %) was significantly reduced with increased mean corpuscular volume by HEX exposure. HEX exposure decreased the white blood cells (WBCs) and differential WBC counts. Acute HEX exposure raised 8-hydroxy-2-deoxyguanosine level while lowering brain acetylcholine esterase activity. HEX exposure caused hepato-renal dysfunction and increased stress-related parameters (glucose and cortisol). Exposure to HEX reduced the immune responses (lysozyme, nitric oxide, immunoglobulin M, and complement 3). A substantial decrease in the antioxidant variables (reduced glutathione content and catalase) with increasing the malondialdehyde was noted by HEX exposure. Moreover, histopathological changes resulted from HEX exposure in the gills, liver, kidney, and spleen. These results indicate that HEX exposure induced behavioral changes, hepato-renal dysfunction, and immune-antioxidant disruption, indicating a possible physiological disruption in O. niloticus. [ABSTRACT FROM AUTHOR]

Introduction: Vogt-Koyanagi-Harada (VKH) disease is a multisystem syndrome characterized by uveitis and exudative retinal detachments in the absence of ocular trauma or surgery. Neurological and cutaneous manifestations can also occur. Prior case reports have associated immune checkpoint inhibitors with a VKH-like disease. Case Presentation: A 64-year-old woman presented with 3 months of epigastric pain, and subsequent endoscopy showed a large mass in the gastroesophageal junction. Staging imaging showed an FDG-avid para-aortic node, making the disease stage IV, and she was treated with systemic therapy with FOLFOX. Molecular profiling showed HER2 amplification and PDL1 positivity, so trastuzumab and pembrolizumab were added. PET and esophagogastroduodenoscopy with biopsies showed a complete radiologic and pathologic response to treatment. Chemotherapy was stopped, and she continued on trastuzumab and pembrolizumab maintenance. After about 18 months of treatment with pembrolizumab, she presented with painful blurry vision in both eyes. Ophthalmologic evaluation showed panuveitis, serous retinal detachment, bilateral uveal edema, and secondary angle closure, consistent with VKH-like uveitis. She was treated with local and systemic corticosteroids. Pembrolizumab was assessed as the most likely causative agent and was discontinued. Her ophthalmologic exam improved, and her visual acuity returned to baseline. She continues on trastuzumab maintenance, and most recent imaging shows no evidence of disease. Conclusion: Oncologists should be aware of VKH-like disease as a possible immune-related adverse event and seek urgent ophthalmologic consultation when such symptoms arise. [ABSTRACT FROM AUTHOR]

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

Deoxyribonucleic acid (DNA) nanostructures have been extensively explored in biomedical applications and have emerged as a promising platform for drug delivery, bioanalysis, and therapeutics. Their in vivo behaviors have received much attention, a prerequisite for clinical applications. Herein, the pharmacokinetics, immunogenicity, and immunotoxicity of two representative DNA nanostructures: DNA tetrahedron (TDN) and DNA nanoparticle (DNP) are studied. The pharmacokinetics of DNA nanostructures are monitored in a mouse model via tracking of 32P radiolabeled, and the half‐lives of TDN and DNP are 9.88 and 19.80 min, respectively. TDN and DNP preferentially accumulate in the liver and kidney in one half‐life and are metabolized through liver, kidney, and excreta after 24 h. Meanwhile, TDN and DNP elicit a weak pro‐inflammatory immune response with low immunogenicity and are non‐immunotoxic, as shown by immunotoxicity evaluation, histopathology, and serum biochemical index analysis. This research shows that the DNA nanostructures of TDN and DNP are safe for biological systems, indicating that TDN and DNP can be developed as promising therapeutic platforms in biomedicine. [ABSTRACT FROM AUTHOR]

Immune function is an important physiological function in the human body that plays a crucial role in maintaining human health. Pyrethroid pesticides (PYRs) and their metabolites can have immunotoxic effects on the body, increasing the risk of immune-related diseases. This review summarizes the effects of PYRs exposure on the body’s immune organs, immune cells, and immune molecules, as well as the immunotoxic mechanisms, and provides a summary and outlook on the immunotoxicity caused by early-life PYRs exposure, offering new ideas and recommendations for human studies on the immunotoxicity of PYRs exposure. [ABSTRACT FROM AUTHOR]

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

There is a need for the assessment of respiratory hazard potential and mode of action of carbon nanotubes (CNTs) before their approval for technological or medical applications. In CNT-exposed lungs, both alveolar macrophages (MФs), which phagocytose CNTs, and alveolar epithelial type II cells (AECII cells), which show tissue injury, are impacted but cell–cell interactions between them and the impacted mechanisms are unclear. To investigate this, we first optimized an air–liquid interface (ALI) transwell coculture of human AECII cell line A549 (upper chamber) and human monocyte cell line THP-1 derived macrophages (lower chamber) in a 12-well culture by exposing macrophages to CNTs at varying doses (5–60 ng/well) for 12–48 h and measuring the epithelial response markers for cell differentiation/maturation (proSP-C), proliferation (Ki-67), and inflammation (IL-1β). In optimal ALI epithelial-macrophage coculture (3:1 ratio), expression of Ki-67 in AECII cells showed dose dependence, peaking at 15 ng/well CNT dose; the Ki-67 and IL-1β responses were detectable within 12 h, peaking at 24–36 h in a time-course. Using the optimized ALI transwell coculture set up with and without macrophages, we demonstrated that direct interaction between CNTs and MФs, but not a physical cell–cell contact between MФ and AECII cells, was essential for inducing immunotoxicity (proliferative and inflammatory responses) in the AECII cells. [ABSTRACT FROM AUTHOR]

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Introduction Bisphenols are widely used in the production of polycarbonate plastics and resin coatings. Bisphenol A (BPA) is suggested to cause a wide range of unwanted effects and "low dose toxicity". With the search for alternative substances to BPA, the use of other bisphenol derivatives namely bisphenol F (BPF) and bisphenol S (BPS) has increased. Methods In the current study, we aimed to evaluate the in silico predicted inhibitory concentration 50s (pIC50s) of bisphenol derivatives on immune and apoptotic markers and DNA damage on HepG2 cells. Moreover, apoptotic, genotoxic and immunotoxic effects of BPA, BPF and BPS were determined comparatively. Effects of bisphenols on apoptosis were evaluated by detecting different caspase activities. The genotoxic effects of bisphenols were evaluated by measuring the levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG) and 8-oxoguanine glycosylase (OGG1). To determine the immunotoxic effect of bisphenol derivatives, the levels of interleukin 4 (IL-4) and interleukin 10 (IL-10), transforming growth factor beta (TGF-β) and tumor necrosis factor-alpha (TNF-α), which are known to be expressed by HepG2 cells, were measured. Results: In silico data indicate that all of the bisphenols may cause alterations in immune and apoptotic markers as well as DNA damage at low doses. İn vitro data revealed that all bisphenol derivatives could affect immune markers at inhibitory concentration 30s (IC30s). In addition, BPF and BPS may also have apoptotic immunotoxic effects. Conclusion Both in silico and in vivo research are needed further to examine the toxic effects of alternative bisphenol derivatives. [ABSTRACT FROM AUTHOR]

Introduction: Vogt-Koyanagi-Harada (VKH) disease is a multisystem syndrome characterized by uveitis and exudative retinal detachments in the absence of ocular trauma or surgery. Neurological and cutaneous manifestations can also occur. Prior case reports have associated immune checkpoint inhibitors with a VKH-like disease. Case Presentation: A 64-year-old woman presented with 3 months of epigastric pain, and subsequent endoscopy showed a large mass in the gastroesophageal junction. Staging imaging showed an FDG-avid para-aortic node, making the disease stage IV, and she was treated with systemic therapy with FOLFOX. Molecular profiling showed HER2 amplification and PDL1 positivity, so trastuzumab and pembrolizumab were added. PET and esophagogastroduodenoscopy with biopsies showed a complete radiologic and pathologic response to treatment. Chemotherapy was stopped, and she continued on trastuzumab and pembrolizumab maintenance. After about 18 months of treatment with pembrolizumab, she presented with painful blurry vision in both eyes. Ophthalmologic evaluation showed panuveitis, serous retinal detachment, bilateral uveal edema, and secondary angle closure, consistent with VKH-like uveitis. She was treated with local and systemic corticosteroids. Pembrolizumab was assessed as the most likely causative agent and was discontinued. Her ophthalmologic exam improved, and her visual acuity returned to baseline. She continues on trastuzumab maintenance, and most recent imaging shows no evidence of disease. Conclusion: Oncologists should be aware of VKH-like disease as a possible immune-related adverse event and seek urgent ophthalmologic consultation when such symptoms arise.

BackgroundThe respiratory toxicity of inhaled polyhexamethylene guanidine (PHMG) has been extensively studied since the humidifier disinfectant incident. However, the impacts of inhalation of PHMG on the immune system are not comprehensively studied yet. ObjectiveTo explore the effects of inhalation of PHMG disinfectant aerosol on major immune organs and immune cells in mice. MethodsThirty male C57BL/6J mice (6-8 weeks old) were randomly divided into three groups: control, low-dose (0.1 mg·m−3 PHMG), and high-dose (1.0 mg·m−3 PHMG), with ten mice in each group. The mice were administered by oral-nasal inhalation of PHMG aerosol for 4 h per day, 5 d per week for 4 weeks consecutively. After designed treatment, venous blood was collected from the inner canthus of the eyes of mice and peripheral hematological indicators were measured with a blood analyzer. Then the mice were sacrificed by cervical dislocation and the lung, thymus, spleen, and femur were isolated. Lung, thymus, and spleen were weighed and organ coefficients were calculated, and single cell suspensions of thymus, spleen, and bone marrow were prepared to analyze lymphocytes phenotypes and proportions by flow cytometry. ResultsThe body weight of mice in the high-dose group was lower than that of mice in the control group (P0.05). Leukocyte count [(1.49±0.22)×109·L−1], lymphocyte count [(0.96±0.36)×109·L−1] and its proportion [(63.13±14.96)%] in the peripheral blood of mice in the high-dose group were lower than those in the control group [(2.69±0.25)×109·L−1, (2.33±0.28)×109·L−1, and (86.23±3.40)%, respectively] (P

Diesel exhaust (DE) is an air pollutant containing gaseous compounds and particulate matter. Diesel engines are common on gas extraction and oil sites, leading to complex DE exposure to a broad range of compounds through occupational settings. The US EPA concluded that short-term exposure to DE leads to allergic inflammatory disorders of the airways. To further evaluate the immunotoxicity of DE, the effects of whole-body inhalation of 0.2 and 1 mg/m3 DE (total carbon; 6 h/d for 4 days) were investigated 1-, 7-, and 27-days post exposure in Sprague-Dawley rats using an occupationally relevant exposure system. DE exposure of 1 mg/m3 increased total cellularity, number of CD4+ and CD8+ T-cells, and B-cells at 1 d post-exposure in the lung lymph nodes. At 7 d post-exposure to 1 mg/m3, cellularity and the number of CD4+ and CD8+ T-cells decreased in the LLNs. In the bronchoalveolar lavage, B-cell number and frequency increased at 1 d post-exposure, Natural Killer cell number and frequency decreased at 7 d post-exposure, and at 27 d post-exposure CD8+ T-cell and CD11b+ cell number and frequency decreased with 0.2 mg/m3 exposure. In the spleen, 0.2 mg/m3 increased CD4+ T-cell frequency at 1 and 7 d post-exposure and at 27 d post-exposure increased CD4+ and CD8+ T-cell number and CD8+ T-cell frequency. B-cells were the only immune cell subset altered in the three tissues (spleen, LLNs, and BALF), suggesting the induction of the adaptive immune response. The increase in lymphocytes in several different organ types also suggests an induction of a systemic inflammatory response occurring following DE exposure. These results show that DE exposure induced modifications of cellularity of phenotypic subsets that may impair immune function and contribute to airway inflammation induced by DE exposure in rats.

Abstract Poly-ε-caprolactone (PCL) has been widely used as biocompatible materials in tissue engineering. They have been used in mammalian cell proliferation to polarization and differentiation. Their modified versions had regulatory activities on mammalian macrophages in vitro. There are also studies suggesting different nanofiber diameters might alter the biological activities of these materials. Based on these cues, we examined the inflammatory activities and adherence properties of mammalian macrophages on electrospun PCL nanofibrous scaffolds formed with PCL having different nanofiber diameters. Our results suggest that macrophages could easily attach and get dispersed on the scaffolds. Macrophages lost their inflammatory cytokine TNF and IL6 production capacity in the presence of LPS when they were incubated on nanofibers. These effects were independent of the mean fiber diameters. Overall, the scaffolds have potential to be used as biocompatible materials to suppress excessive inflammatory reactions during tissue and organ transplantation by caging and suppressing the inflammatory cells.

Xin-Mei Hu,1,* Can-Can Wang,1,* Yu Xiao,1 Yu Liu,1 Hong-Ri Huang,2 Peng Jiang,1 Ying-Kai Wang,1 Yun-Jin Lin,1 Liang-Cheng Li,3 Zhong-Quan Qi1 1Medical College, Guangxi University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China; 2Department of Research and Development, Guangxi Taimei Rensheng Biotechnology Co., Ltd, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China; 3School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhong-Quan Qi, Guangxi University, Da-Xue-Dong Road No. 100, Xixiangtang District, Nanning, Guangxi Zhuang Autonomous Region, 530004, People’s Republic of China, Tel +8613806001271, Email yxyyz@gxu.edu.cn Liang-Cheng Li, Xiamen University, No. 4221-115, Rm 355, Xiang’an District, Xiang’an, Xiamen Fujian Province, 361102, People’s Republic of China, Tel +8618359206906, Email lchli2013@xmu.edu.cnPurpose: In recent years, exosomes have been proved to be used to treat many diseases. However, due to the lack of uniform quality control standards for exosomes, the safety of exosomes is still a problem to be solved, especially now more and more exosomes are used in clinical trials, and its non-clinical safety evaluation is particularly important. However, there is no safety evaluation standard for exosomes at present. Therefore, this study will refer to the evaluation criteria of therapeutic biological products, adopt non-human primates to evaluate the non-clinical safety of human umbilical cord mesenchymal stem cell exosomes from the general pharmacology and immunotoxicity, aiming at establishing a safety evaluation system of exosomes and providing reference for the clinical application of exosomes in the future.Methods: 3.85 × 1012 exosomes derived from human umbilical cord mesenchymal stem cells were injected into cynomolgus monkeys intravenously. The changes of general clinical conditions, hematology, immunoglobulin, Th1/Th2 cytokines, T lymphocytes and B lymphocytes, and immune organs were observed before and within 14 days after injection.Results: The results showed that exosomes did not have obvious pathological effects on the general clinical conditions, blood, coagulation function, organ coefficient, immunoglobulin, Th1/Th2 cytokines, lymphocytes, major organs, and major immune organs (spleen, thymus, bone marrow) of cynomolgus monkeys. However, the number of granulocyte-macrophage colonies in exosomes group was significantly higher than that in control group.Conclusion: To sum up, the general pharmacological results and immunotoxicity results showed that the injection of 3.85 × 1012 exosomes may have no obvious adverse reactions to cynomolgus monkeys. This dose of exosomes is relatively safe for treatment, which provides basis research for non-clinical safety evaluation of exosomes and provides reliable research basis for future clinical application of exosomes.Keywords: exosomes, cynomolgus monkeys, safety, immunotoxicity

Aflatoxin B1 (AFB1) and fumonisin B1 (FB1) are mycotoxins widely found as cereal contaminants, and their co-consumption is associated with liver cancer. Both are immunotoxic, but their interactions have been little studied. This work was aimed to evaluate in mouse spleen mononuclear cells (SMC) the effects of the exposure to AFB1 (5–50 µM), FB1 (25–250 µM), and AFB1–FB1 mixtures (MIX) on the in vitro differentiation of regulatory T cells (Treg and Tr1-like) and Th17 cells, as well as elucidate the contribution of aryl hydrocarbon receptor (Ahr) in such effects. AFB1 and mainly MIX induced cytotoxicity in activated CD4 cells via Ahr signaling. AFB1 (5 µM) increased the Treg cell differentiation, but its combination with FB1 (25 µM) also reduced Th17 cell expansion by Ahr-dependent mechanisms. Therefore, this mixture could enhance the Treg/Th17 cell ratio and favor immunosuppression and escape from tumor immunosurveillance to a greater extent than individual mycotoxins. Whereas, AFB1-FB1 mixtures at medium–high doses inhibited the Tr1-like cell expansion induced by the individual mycotoxins and affected Treg and Th17 cell differentiation in Ahr-independent and dependent manners, respectively, which could alter anti-inflammatory and Th17 immune responses. Moreover, individual FB1 altered regulatory T and Th17 cell development independently of Ahr. In conclusion, AFB1 and FB1 interact by modifying Ahr signaling, which is involved in the immunotoxicity as well as in the alteration of the differentiation of Treg, Tr1-like, and Th17 cells induced by AFB1-FB1 mixtures. Therefore, Ahr is implicated in the regulation of the anti- and pro-inflammatory responses caused by the combination of AFB1 and FB1. [ABSTRACT FROM AUTHOR]

With the expansion of nanomaterials (NMs) usage, concerns about their toxicity are increasing, and the wide variety of NMs makes it difficult to assess their toxicity. Therefore, the development of a high-throughput, accurate, and certified method to evaluate the immunotoxicity of NMs is required. In this study, we assessed the immunotoxicity potential of various NMs, such as nanoparticles of silver, silica, and titanium dioxide, using the human Cell Line Activation Test (h-CLAT) at the cellular level. After exposure to silver nanoparticle dispersions, the expression levels of CD86 and CD54 increased, suggesting the activation of antigen-presenting cells (APCs) by silver nanoparticles. Quantification of silver ions eluted from silver nanoparticles and the activation of APCs by silver ions suggested that it was due to the release of silver ions. Silica nanoparticles also increased the expression of CD86 and/or CD54, and their activation ability correlated with the synthesis methods and hydrodynamic diameters. The ability of titanium dioxide to activate APCs differed depending on the crystal type and hydrodynamic diameter. These results suggest a potential method to evaluate the immunotoxicity potential of various NMs based on their ability to activate APCs using human monocytic THP-1 cells. This method will be valuable in assessing the immunotoxicity potential and elucidating the immunotoxic mechanisms of NMs. [ABSTRACT FROM AUTHOR]

Florpyrauxifen‐benzyl (FPB) is a new arylpicolinate systemic herbicide that has been used to control or suppress the majority of herbicide‐resistant biotype weeds in rice. To our knowledge, the impact of FPB on the immune system remains undetected thus far. Hence, this work aimed to address the toxic effects of FPB and the possible related mechanisms on the spleen of exposed mice. Initially, an acute toxicological test was performed to ascertain the median lethal dose (LD50) of FPB for 24 h which was found to be 371.54 mg/kg b.wt. For mechanistic evaluation of FPB toxicity, three sublethal doses (1/20th, 1/10th, and 1/5th LD50) were orally administered to mice for 21 consecutive days. Changes in spleen relative weight, oxidative status, apoptotic and inflammatory markers, histopathological alterations were evaluated. Following the FPB exposure, significant (p < 0.05) decline in spleen index, apoptotic features, histolopathological changes were observed. Additionally, excessive oxidative stress in spleen tissues was monitored by downregulating antioxidant enzymes and upregulating the oxidant parameters. Furthermore, exposure to FPB resulted in notable activation of the NF‐қB signaling pathway, accompanied by elevated levels of pro‐inflammatory cytokines (namely, IL‐1β and TNF‐α) as well as CD3 and CD19 levels have decreased significantly in spleen tissues. Collectively, FPB exposure exhibited apoptosis, oxidative stress, immunosuppression, and inflammatory response in a dose‐dependent manner, leading to spleen tissue damage and immunotoxicity. Further studies on FPB is recommended to outstand its hazards on ecosystems. [ABSTRACT FROM AUTHOR]

Ionic liquid tetrafluoroborated‐1‐tetradecyl‐3‐methylimidazole salt ([C14mim]BF4) immunotoxicity was investigated in rats using three exposure groups (12.5, 25, and 50 mg kg−1), one recovery group (50 mg kg−1), and a control group without any treatment. The findings demonstrated that, at low doses, [C14mim]BF4 could raise WBC, NEU, and MID and lysozyme levels as well as spleen T‐lymphocyte stimulation index in rats, however at high doses, the aforementioned indices were dramatically lowered. As the dose was raised, the proportion of RBC and PLT in the blood as well as CD4+ and CD8+ in the spleen increased, but the quantity of immunoglobulin IgG, IgA, and IgM in the serum as well as the number of NK cells in the spleen considerably dropped. Even though there were varying degrees of improvement 30 days after ceasing exposure, all these changes were unable to return to normal, and the number of NK cells was further decreased. The study demonstrates that [C14mim]BF4 can damage the specific immunity and non‐specific immunity of rats, and cause immune dysfunction. [ABSTRACT FROM AUTHOR]

The physiological and molecular responses of leukocytes are altered by organophosphate pesticides. Some reports have shown that diazinon causes immunotoxic effects; diazoxon, the oxon metabolite of diazinon, is attributed to influence the immune response by affecting the leukocyte cholinergic system. In this study, the in vitro effects of diazoxon on molecules involved in cell signaling (cAMP, IP3, DAG, JAK1, and STAT3), which play a crucial role in the activation, differentiation, and survival of leukocytes, were evaluated. Data indicate that diazoxon leads to a decrease in cAMP concentration and an increase in basal IP3 levels. However, diazoxon does not affect basal levels of JAK1 and STAT3 phosphorylation. Instead, diazoxon inhibits leukocyte responsiveness to phorbol myristate acetate and ionomycin, substances that, under normal conditions, enhance JAK/STAT signaling. These findings demonstrate that diazoxon significantly affects key molecular parameters related to cell signaling. [ABSTRACT FROM AUTHOR]

Objective To investigate the characteristics and risk factors of immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs) . Methods Monitoring conditions were established by using the Chinese Hospital Pharmacovigilance System. The hospitalized cases of camrelizumab, sintilimab, tislelizumab, and pembrolizumab in the hospital from 2020 to 2022 were searched, and positive alarm cases were obtained. The incidence of irAEs was analyzed. The nested case-control study method was used to set up the case group and the control group, and the influencing factors were analyzed by χ2 test. Results Among the 3 653 hospitalized patients, 910 alarm cases were detected, and 107 cases were finally determined to have irAEs by clinical pharmacist evaluation, including 58 cases of common irAEs and 49 cases of severe irAEs. A total of 128 cases of irAEs occurred in 107 patients. The positive detection rate of the monitoring model was 2. 93% (107/3 653) . Endocrine toxicity[18. 75% (24/128) ], pulmonary toxicity [16. 41% (21/18) ], skin toxicity[14. 06% (18/128) ], liver toxicity[10. 94% (14/128) ], and cardiac toxicity[9. 38% (12/128) ]ranked high. Of the 107 patients, 81 were improved, 20 were cured, four were not improved, and 2 died. There was a statistically significant difference in the incidence of irAEs between patients with and without surgery (P＜0. 05) . Conclusion It is feasible to carry out the active monitoring of irAEs induced by ICIs by using the Chinese Hospital Pharmacovigilance System. It can reflect the occurrence of adverse drug reactions to a certain extent, reduce and prevent the risk of clinical medication, and also provide new methods and ideas for drug safety evaluation. [ABSTRACT FROM AUTHOR]

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

Herein, we investigated whether L-ascorbic acid (L-AA) and α-tocopherol (α-T) co-administration has the potential to alleviate arsenic-induced immunotoxicities in the thymus, spleen, and circulating leukocytes. Forty-eight adult male Wistar rats were randomly divided into four groups before the treatment: group I (control); group II (sodium arsenite, 3 mg/kg/day/rat); group III (sodium arsenite + L-AA (200 mg/kg/day/rat) and α-T (400 mg/kg/day/rat)); group IV (L-AA and α-T). The result showed that sodium arsenite exposure (consecutive 30 days) caused weight reduction, structural alterations in the thymus and spleen, accompanied by a decrease in thymocyte and splenocyte count. Decreased superoxide dismutase and catalase activity, increased malondialdehyde and protein–carbonyl content, reduced Nrf2 and Bcl2 expression, and increased p-ERK, NF-kβ, Bax, and cleaved-caspase-3 expression were also observed in the thymus and spleen of arsenic-exposed rats. Enhanced plasma ACTH and corticosterone, ROS-induced apoptosis of lymphocytes were also observed. L-AA and α-T co-administration has the potential to abrogate the deleterious impact of arsenic on the thymus, spleen, and circulating lymphocytes. Whole transcriptome analysis of leukocytes revealed that arsenic treatment augmented the expression of Itga4, Itgam, and MMP9 genes, which might help in transient migration of the leukocytes through the endothelial cell layer. Co-administration with L-AA and α-T maintained Itga4, Itgam, and MMP9 gene expression within leukocytes at a lower level. [ABSTRACT FROM AUTHOR]

Introduction: Monoclonal antibodies (mAbs) are important therapeutics. However, the enhanced potential for aggregation has become a critical quality parameter during the production of mAbs. Furthermore, mAb aggregation may also present a potential health risk in a clinical setting during the administration of mAb therapeutics to patients. While the extent of immunotoxicity in patient populations is uncertain, reports show it can lead to immune responses via cell activation and cytokine release. In this study, an autologous in vitro skin test designed to predict adverse immune events, including skin sensitization, was used as a novel assay for the assessment of immunotoxicity caused by mAb aggregation. Material and Methods: Aggregation of mAbs was induced by a heat stress protocol, followed by characterization of protein content by analytical ultra-centrifugation and transmission electron microscopy, revealing a 4% aggregation level of total protein content. Immunotoxicity and potential skin sensitization caused by the aggregates, were then tested in a skin explant assay. Results: Aggregated Herceptin and Rituximab caused skin sensitization, as shown by histopathological damage (grade II–III positive response) together with positive staining for Heat Shock Protein 70 (HSP70). Changes in T cell proliferation were not observed. Cytokine analysis revealed a significant increase of IL-10 for the most extreme condition of aggregation (65 °C at pH3) and a trend for an overall increase of IFN-γ, especially in response to Rituximab. Conclusions: The skin explant assay demonstrated that aggregated mAbs showed adverse immune reactions, as demonstrated as skin sensitization, with histopathological grades II-III. The assay may, therefore, be a novel tool for assessing immunotoxicity and skin sensitization caused by mAb aggregation. [ABSTRACT FROM AUTHOR]

The use of immunophenotyping during immunotoxicity investigations was first popularized in the 1980 s and has since become more integrated into diagnostic and non-clinical assessments. The data provided from immunophenotyping can serve as an initial source of information to guide decisions for additional, more advanced, immunotoxicity testing as well as for human health safety and risk assessment of drugs and chemicals. However, comprehensive guidance describing applications of immunophenotyping data in immunotoxicity investigations is lacking, particularly among regulatory bodies. Therefore, a critical examination is needed for the appropriate interpretations and potential misinterpretations of such data during the assessment of drug safety and chemical risk. As such, the current uses and implications of immunophenotyping data in human health safety and risk assessments has been evaluated to provide additional context for the application of current methodologies and guidelines. In addition, case studies are presented to highlight the challenges of interpreting immunophenotyping results along with incorporating the findings into immunotoxicity investigations. Based on the analyses of current approaches and methodologies, a decision flow is presented for use of immunophenotyping data during risk informed decision making.

Lanthanide-doped upconversion nanoparticles (Ln-UCNPs) have been considered promising materials for various fields, such as biomedical and industrial applications. However, data and reports regarding its toxicity and environmental risks are scarce. Under these circumstances, data must be obtained to fully understand potential toxicity and adverse outcome pathways. In the present study, the toxicity of uncoated Ln-UCNP cores (NaYF4:Yb, Er) was systematically assessed in zebrafish embryos during early developmental stages. Ln-UCNPs were found to have multiple toxic effects, such as effects on survival rates, delayed hatching times, shorter body lengths, altered heart rates and blood circulation (significantly reduced), and neurobehavioral impairments in response to photoperiod stimulation. Bioimaging showed that Ln-UCNPs were distributed on the chorion, eyes, and skin at 72 hpf. However, it accumulates in the pharynx, esophagus, and intestine after oral administration. Ln-UCNPs disrupt the diversity and abundance of host-associated microorganisms (gut microbiota) leading to an increase in the prevalence of harmful bacteria in zebrafish. Transcriptomic and Ingenuity Pathway Analysis (IPA) predicted Interleukin-8 (IL-8) signaling, neuroinflammation, cardiac hypertrophy signaling pathways, immune and inflammation-related response interferon-gamma (ifnγ), and miR-155 as key mediators in regulatory effects. Based on this, a causal network was built showing the strong links between the induced gene expression of differentially expressed genes (DEGs), such as nitric oxide synthase 2 (nos2) and tumor necrosis factor (tnf) upon Ln-UCNPs treatment, and with the downstream adverse outcomes, in particular, the promotion of apoptosis, liver damage, and inflammatory response. Finally, RT-qPCR analysis confirmed the up-regulated expression of nos2 and tnf in the exposed larvae, consistent with the observation of an increased number of fluorescence-labelled neutrophils and macrophages in lyz: DsRed transgenic zebrafish until 120 hpf exposure, which together demonstrated the proinflammatory effects of Ln-UCNPs on organisms. In conclusion, we illustrated the developmental toxicity, disruption of gut-microbiome, and proinflammatory effects of Ln-UCNP cores on zebrafish, and the causal network from IPA analysis may help further elucidate the adverse outcome pathway of Ln-UCNPs.

ABSTRACT: Aflatoxin B1 (AFB1) is a mycotoxin which is responsible for severe damage to the immune system of humans and livestock. Licochalcone A (Lico A), a polyphenol derived from turmeric, has attracted great attention due to its wonderful antioxidant properties. Ferroptosis, an iron-dependent cell death related to oxidative stress, which plays a crucial role in the resistance of phytochemical to immune-associated injury. Nevertheless, effects of Lico A on the bursa of broilers exposed to AFB1 remain unclear. In this work, broilers were fed diets supplemented with 2 mg/kg of AFB1 and 50 mg/kg of Lico A. Meanwhile, various concentrations of Lico A and AFB1 (15 μM) were used to stimulate macrophages. These results revealed that AFB1 resulted in more severe bursa atrophy and relative weight reduction; the expression of pro-ferroptosis protein ACSL4 and the content of malondialdehyde (MDA) were significantly elevated, while the expression of anti-ferroptosis proteins GPX4, xCT, FSP1 and the content of Glutathione (GSH) was obviously reduced. However, Lico A treatment effectively reversed these effects in the bursa of broilers. Meanwhile, in bursa and macrophages, Lico A mitigated the expression of AFB1-induced apoptosis-associated protein (Caspase-3, Bax, Bcl-2) as well as antioxidant protein (Nrf2, GCLM, HO-1). Importantly, ferroptosis was also observed in macrophages induced by AFB1. Lico A efficaciously alleviated AFB1-induced mitochondrial membrane potential decrease and reactive oxygen species (ROS) production in macrophages; in contrast, Lico A evidently inhibited AFB1-triggered ROS generation and cytotoxicity, which was disabled by the addition of Erastin. Moreover, Liproxstatin-1 significantly inhibited ROS generation induced by AFB1. In summary, the present study elucidates that the main mechanism by which Lico A attenuates AFB1-induced immunotoxicity is through the suppression of ferroptosis, apoptosis, mitochondrial damage and oxidative stress, which is promising for the improvement of immunotoxic effects of AFB1.

Animal derived materials have been widely used in biomedical products owing to their good biocompatibility and appropriate mechanical properties. It is crucial to evaluate the immunotoxicity of such materials in preclinical testing to prevent severe immune responses in patients. In this study, a pipeline of immunotoxicity tests was established to evaluate animal-derived materials before de-cellularization and final products. This pipeline contains a serial of animal tests on BALB/c mice and an in vitro quantification test for a-Gal antigen. It is well-recognized that the interaction between materials and patients profoundly alters immune responses, thus, a comprehensive dataset including body weight, immune organ coefficient, histopathology, peripheral hematology, serum immunoglobulin level, spleen lymphocyte proliferation rate, and their subpopulation was created and analyzed using the SPSS tool. These results clearly suggested that the de-cellularized materials possessed better biocompatibility, in addition, the a-Gal antigen content was effectively decreased by 96.0 ​% after de-cellularization. Thus, this study confirmed that this multi-step enzymatic de-cellularization treatment is a potent method to reduce the immunotoxicity of animal-derived biomaterials. Moreover, the experimental pipeline will likely be transferable to other biomedical materials and products.

BackgroundThe ability to induce chronic inflammation and immunosuppression are two key characteristics of carcinogens and important forms of immunotoxicity. The National Toxicology Program (NTP) evaluated the immunotoxicity of two per- and polyfluoroalkyl substances (PFASs), PFOA (perfluorooctanoic acid) and PFOS (perfluorooctane sulfonate), in 2016. However, the potential pro-inflammatory and immunosuppressive effects of other PFASs remain largely uncharacterized.MethodsWe developed an expanded set of search terms pertaining to the chronic inflammatory and immunosuppressive effects of PFASs based on those of the International Agency for Research on Cancer (IARC) and NTP. To confirm searching effectiveness and scope, we compared our search term results with those of IARC and NTP for both PFASs and two other known carcinogens, chromium (VI) and benzene. Systematic evidence maps (SEMs) were also produced using Tableau to visualize the distribution of study numbers and types reporting immunotoxic effects and specific biomarkers elicited by PFAS exposures.ResultsIn total, 1155 PFAS studies were retrieved, of which 321 qualified for inclusion in our dataset. Using our search terms, we identified a greater number of relevant studies than those obtained using IARC and NTP's search terms. From the SEM findings, increased cytokine production strengthened an association between PFAS exposure and chronic inflammation, and decreased B-cell activation and altered levels of T-cell subtypes and immunoglobulins confirmed PFAS-induced immunosuppression.ConclusionOur SEM findings confirm that several PFASs commonly found in both in the environment, including those that are lesser-known, may induce immunosuppression and chronic inflammation, two key characteristics of carcinogens. This approach, including development of search terms, study screening process, data coding, and evidence mapping visualizations, can be applied to other key characteristics of chemical carcinogens.

Due to their peculiar physicochemical properties, nanoparticles (NPs) have the potential to have a detrimental impact on molecular (proteins and nucleic acids), subcellular, cellular, tissue, and organism levels. However, available works on the harmful effects of the water-borne ionizable NPs, such as aluminum oxide nanoparticles (ALNPs) on fish are scarce. Therefore, the toxic impacts of ALNPs on hematological, biochemical, and immunological responses in Nile Tilapia fish were investigated in this work. Additionally, the possible benefits of the promising chamomile essential oil (CEO) as dietary supplement in alleviating such impacts were also targeted. For this, four fish groups were used. The control group received only the basic diet, CEO group (basic diet + 2 mg CEO/kg diet), ALNP group (basic diet with exposure to5.08 mg ALNPs/L water, and ALNPs/CEO group (basal diet + 2 mg CEO/kg diet + 5.08 mg ALNPs/L). Fish exposed to ALNPs showed declines in the growth performance and fish survivability in addition to changes seen in the hematological and protein profiles and stress variables. Along with decreased resistance to the Aeromonas hydrophila challenge, there were also substantial decreases in all humoral immune indicators. In addition to increased mRNA expressions of immune genes in the hepatic tissues. CEO significantly modulated the toxic effects of ALNPs suggesting its utilization as a valuable dietary supplement for fish [ABSTRACT FROM AUTHOR]

Mycotoxins are secondary metabolites produced by pathogenic fungi. They often contaminate various crops, and are detrimental to human and animal health. Mycotoxins have a variety of toxic effects, such as neurotoxicity, hepatotoxicity, immunotoxicity, teratogenicity, and carcinogenicity. However, the mechanism of immunotoxicity is still unclear. Dendritic cells （DCs）, as the most potent antigen presenting cells, play a vital role in initiating innate and adaptive immune responses. Previous studies have found that mycotoxins can affect the endocytosis of DCs, the ability to stimulate T cell activation, the secretion of cytokines and chemokines. Thus, this review is aim to summarize the effects of mycotoxins on DCs-mediated immune responses, which may provide reference for researches to clarify the immunotoxicity mechanism of mycotoxins. [ABSTRACT FROM AUTHOR]

Significance: Reactive oxygen species (ROS), the reactive oxygen-carrying chemicals moieties, act as pleiotropic signal transducers to maintain various biological processes/functions, including immune response. Increased ROS production leads to oxidative stress, which is implicated in xenobiotic-induced adverse effects. Understanding the immunoregulatory mechanisms and immunotoxicity is of interest to developing therapeutics against xenobiotic insults. Recent Advances: While developmental studies have established the essential roles of ROS in the establishment and proper functioning of the immune system, toxicological studies have demonstrated high ROS generation as one of the potential mechanisms of immunotoxicity induced by environmental chemicals, including heavy metals, pesticides, aromatic hydrocarbons (benzene and derivatives), plastics, and nanoparticles. Mitochondrial electron transport and various signaling components, including NADH oxidase, toll-like receptors (TLRs), NF-κB, JNK, NRF2, p53, and STAT3, are involved in xenobiotic-induced ROS generation and immunotoxicity. Critical Issues: With many studies demonstrating the role of ROS and oxidative stress in xenobiotic-induced immunotoxicity, rigorous and orthogonal approaches are needed to achieve in-depth and precise understanding. The association of xenobiotic-induced immunotoxicity with disease susceptibility and progression needs more data acquisition. Furthermore, the general methodology needs to be possibly replaced with high-throughput precise techniques. Future Directions: The progression of xenobiotic-induced immunotoxicity into disease manifestation is not well documented. Immunotoxicological studies about the combination of xenobiotics, age-related sensitivity, and their involvement in human disease incidence and pathogenesis are warranted. Antioxid. Redox Signal. 40, 691–714. [ABSTRACT FROM AUTHOR]

Exposure to PFASs is associated to several adverse health effects, such as immunotoxicity. Immunotoxic effects of PFOA and PFOS, including a reduced antibody response in both experimental animals and humans, have been reported. However, there is limited understanding of the underlying mechanisms involved. Moreover, there is only a restricted amount of immunotoxicity data available for a limited number of PFASs. In the current study the effects of 15 PFASs, including short- and long-chain perfluorinated carboxylic and sulfonic acids, fluorotelomer alcohols, and perfluoralkyl ether carboxylic acids were studied on the expression of recombinant activating gene 1 (RAG1) and RAG2 in the Namalwa human B lymphoma cell line, and on the human IL-2 promotor activity in Jurkat T-cells. Concentration-response data were subsequently used to derive in vitro relative potencies through benchmark dose analysis. In vitro relative potency factors (RPFs) were obtained for 6 and 9 PFASs based on their effect on RAG1 and RAG2 gene expression in Namalwa B-cells, respectively, and for 10 PFASs based on their inhibitory effect on IL-2 promotor activity in Jurkat T-cells. The most potent substances were HFPO-TA for the reduction of RAG1 and RAG2 gene expression in Namalwa cells (RPFs of 2.1 and 2.3 respectively), and PFDA on IL-2 promoter activity (RPF of 9.1). RAG1 and RAG2 play a crucial role in V (D)J gene recombination, a process for acquiring a varied array of antibodies crucial for antigen recognition. Hence, the effects observed in Namalwa cells might indicate a PFAS-induced impairment of generating a diverse range of B-cells essential for antigen recognition. The observed outcomes in the Jurkat T-cells suggest a possible PFAS-induced reduction of T-cell activation, which may contribute to a decline in the T-cell dependent antibody response. Altogether, the present study provides potential mechanistic insights into the reported PFAS-induced decreased antibody response. Additionally, the presented in vitro models may represent useful tools for assessing the immunotoxic potential of PFASs and prioritization for further risk assessment. [ABSTRACT FROM AUTHOR]

Introduction: The Adverse Outcome Pathway (AOP) concept facilitates rapid hazard assessment for human health risks. AOPs are constantly evolving, their number is growing, and they are referenced in the AOP-Wiki database, which is supported by the OECD. Here, we present a study that aims at identifying welldefined biological areas, as well as gaps within the AOP-Wiki for future research needs. It does not intend to provide a systematic and comprehensive summary of the available literature on AOPs but summarizes and maps biological knowledge and diseases represented by the already developed AOPs (with OECD endorsed status or under validation). Methods: Knowledge from the AOP-Wiki database were extracted and prepared for analysis using a multi-step procedure. An automatic mapping of the existing information on AOPs (i.e., genes/proteins and diseases) was performed using bioinformatics tools (i.e., overrepresentation analysis using Gene Ontology and DisGeNET), allowing both the classification of AOPs and the development of AOP networks (AOPN). Results: AOPs related to diseases of the genitourinary system, neoplasms and developmental anomalies are the most frequently investigated on the AOP-Wiki. An evaluation of the three priority cases (i.e., immunotoxicity and non-genotoxic carcinogenesis, endocrine and metabolic disruption, and developmental and adult neurotoxicity) of the EU-funded PARC project (Partnership for the Risk Assessment of Chemicals) are presented. These were used to highlight under- and over-represented adverse outcomes and to identify and prioritize gaps for further research. Discussion: These results contribute to a more comprehensive understanding of the adverse effects associated with the molecular events in AOPs, and aid in refining risk assessment for stressors and mitigation strategies. Moreover, the FAIRness (i.e., data which meets principles of findability, accessibility, interoperability, and reusability (FAIR)) of the AOPs appears to be an important consideration for further development. [ABSTRACT FROM AUTHOR]

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

Objective: The present study was designed to investigate the nephroprotective and immunoprotective effects of S-adenosyl-L-methionine (SAMe) in comparison to N-acetylcysteine (NAC) against ochratoxin A (OTA) - intoxication. Methods: Forty-eight adult male Sprague-Dawley rats were categorized into four groups: Control; OTA intoxication (5 mg OTA/kg diet); OTA + NAC, rats received 200 mg NAC/day before feeding balanced diet contaminated with OTA; and (OTA + SAMe). Rats received 200 mg SAMe/day dissolved in distilled water orally just before feeding a balanced diet contaminated with OTA. Results: OTA administration altered serum kidney function biomarkers. These effects were pronouncedly alleviated by treatment with NAC. Results revealed a correlation between OTA-induced immunotoxicity and the reduced white blood cell (WBC) count. Treatments with SAMe significantly improved the WBCs count and hemoglobin concentration. Conclusion: NAC and SAMe have a protective role against nephrotoxicity and immunotoxicity induced by continuous administration of OTA. NAC was more effective in reducing OTA nephrotoxicity, whereas SAMe was more potent than NAC in reducing OTA immunotoxicity. [ABSTRACT FROM AUTHOR]

Di(2-ethylhexyl) phthalate (DEHP) is a common plasticizer that can affect immune system development and susceptibility to infection. Aging processes (measured as epigenetic age acceleration (EAA)) may mediate the immune-related effects of prenatal exposure to DEHP. This study's objective was to examine associations between prenatal DEHP exposure, EAA at three months of age, and the number of upper respiratory infections (URIs) from 12 to 18 months of age using a sample of 69 maternal–child pairs from a Canadian pregnancy cohort. Blood DNA methylation data were generated using the Infinium HumanMethylation450 BeadChip; EAA was estimated using Horvath's pan-tissue clock. Robust regressions examined overall and sex-specific associations. Higher prenatal DEHP exposure (B = 6.52, 95% CI = 1.22, 11.81) and increased EAA (B = 2.98, 95% CI = 1.64, 4.32) independently predicted more URIs. In sex-specific analyses, some similar effects were noted for boys, and EAA mediated the association between prenatal DEHP exposure and URIs. In girls, higher prenatal DEHP exposure was associated with decreased EAA, and no mediation was noted. Higher prenatal DEHP exposure may be associated with increased susceptibility to early childhood URIs, particularly in boys, and aging biomarkers such as EAA may be a biological mechanism. Larger cohort studies examining the potential developmental immunotoxicity of phthalates are needed. [ABSTRACT FROM AUTHOR]

BACKGROUND: The involvement of Perchloroethylene (PCE) in the development of autoimmune diseases has been reported. However, few studies investigated immunotoxicity in PCE-exposed workers. OBJECTIVE: To study changes in the oxidative stress and cytokine profile of young female dry-cleaning workers exposed to PCE. METHODS: Thirty-eight exposed workers and 38 unexposed controls were recruited. All the participants were young nonsmoker females. Individual interviews were conducted by a physician. Blood samples were collected and hematological tests were performed by an automated Coulter Counter. Plasma PCE levels were determined using gas chromatography/flame ionization detection. Plasma total antioxidant capacity (TAC), Catalase (CAT), Superoxide dismutase (SOD), and Malondialdehyde (MDA) levels were measured using the colorimetric method. The levels of plasma cytokines interleukin-1β (IL-1β), IL-2, IL-4, IL-6, IL-8, tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) were measured by commercially kits. RESULTS: The levels of plasma PCE averaged 561±96 ng/ml in the exposed group compared with 1.3±0.5 ng/ml in the controls. The hematological tests failed to find abnormalities in the exposed workers. Exposed workers presented significantly increased plasma levels of MDA, SOD and CAT. There were no significant differences between the two groups for level of plasma TAC. Significantly increased plasma IL-1β and TNF-α and decreased IL-2 and IL-8 levels were seen in the exposed workers. There were no significant differences between the two groups for IL-4, IL-6, and IFN-γ. CONCLUSION: PCE exposure resulted in changed cytokine profile in dry-cleaning workers, suggesting the potential immunotoxicity of PCE at low exposure levels. [ABSTRACT FROM AUTHOR]

Cadmium (Cd)–induced immunotoxicity has become a matter of public health concern owing to its prevalence in the environment consequently, great potential for human exposure. Zinc (Zn) has been known to possess antioxidant, anti-inflammatory, and immune-boosting properties. However, the ameliorating influence of Zn against Cd-induced immunotoxicity connecting the IDO pathway is lacking. Adult male Wistar rats were exposed to normal drinking water with no metal contaminants (group 1), group 2 received drinking water containing 200 μg/L of Cd, group 3 received drinking water containing 200 μg/L of Zn, and group 4 received Cd and Zn as above in drinking water for 42 days. Cd exposure alone significantly triggered the splenic oxidative-inflammatory stress, increased activities of immunosuppressive tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenases (IDO) activities/protein expression, and decreased CD4+ T cell count, and a corresponding increase in the serum kynurenine concentration, as well as alterations in the hematological parameters and histologic structure when compared with the control (p < 0.05). Zn alone did not have any effect relative to the control group while co-exposure significantly (p < 0.05) assuaged the Cd-induced alterations in the studied parameters relative to the control. Cd-induced modifications in IDO 1 protein expression, IDO/TDO activities, oxidative-inflammatory stress, hematological parameters/CD4+ T cell, and histological structure in the spleen of rats within the time course of the investigation were prevented by Zn co-exposure via inhibition of Cd uptake. [ABSTRACT FROM AUTHOR]

Chiral pesticides exhibit enantioselective differences in processes such as biological absorption, metabolism, and toxic effects. Organisms have different physiological characteristics at different developmental stages. Therefore, conducting enantiomeric toxicity studies at different developmental stages of organisms can help deepen the understanding of the ecological effects of chiral pesticides. This study focused on trans-tetramethrin (Tet) and investigated the enantioselectivity in bioconcentration, developmental toxicity, estrogenic effects, and immunotoxicity of Tet's racemate ((±)-Tet) and its two enantiomers ((+)-Tet and (−)-Tet) in three developmental stages of zebrafish: embryos, yolk sac larvae, and juveniles. The results showed that Tet exhibited different enantioselectivity in lethal, bioconcentration, and teratogenic effects on zebrafish at different developmental stages. The LC50 value was (+)-Tet > (±)-Tet > (−)-Tet, with embryos being the most sensitive, followed by juveniles and yolk sac larvae. The enantioselective bioconcentration was (±)-Tet > (+)-Tet > (−)-Tet, and the bioconcentration effect was greater in embryos than that in yolk sac larvae and juveniles. Developmental toxicity indicated that (+)-Tet and (±)-Tet had higher teratogenic effects on yolk sac larvae than on embryos. Tet exhibited different enantioselective effects on the expression of zebrafish estrogen-related genes and innate immune-related genes at different developmental stages. These results will contribute to a more comprehensive assessment of the aquatic toxicity and environmental risks of chiral pesticides. [ABSTRACT FROM AUTHOR]

Inorganic arsenic is a well-established environmental toxicant linked to acute liver injury, fibrosis, and cancer. While oxidative stress, pyroptosis, and ferroptosis are known contributors, the role of PTEN-induced kinase 1 (PINK1)-mediated mitophagy in arsenic-induced hepatic immunotoxicity remains underexplored. Our study revealed that acute arsenic exposure prompts differentiation of hepatic dendritic cells (DCs) and T helper (Th) 1, Th2, Th17, and regulatory T (Treg) cells, alongside increased transcription factors and cytokines. Inorganic arsenic triggered liver redox imbalance, leading to elevated alanine transaminase (ALT), hydrogen peroxide (H2O2), malondialdehyde (MDA), and activation of nuclear factor erythroid 2-related factor (Nrf2)/heme oxygenase-1 (HO-1) pathway. PINK1-mediated mitophagy was initiated, and its inhibition exacerbates H2O2 accumulation while promoting DCs/Th1/Th2/Treg differentiation in the liver of arsenic-exposed mice. Mitoquinone (MitoQ) pretreatment relieved arsenic-induced acute liver injury and immune imbalance by activating Nrf2/HO-1 and PINK1-mediated mitophagy. To our knowledge, this is the first report identifying PINK1-mediated mitophagy as a protective factor against inorganic arsenic-induced hepatic DCs/Th1/Th2 differentiation. This study has provided new insights on the immunotoxicity of inorganic arsenic and established a foundation for exploring preventive and therapeutic strategies targeting PINK1-mediated mitophagy in acute liver injury. Consequently, the application of mitochondrial antioxidant MitoQ may offer a promising treatment for the metalloid-induced acute liver injury.

ABSTRACT: Gliotoxin (GT) belongs to the epipolythiodioxopiperazine (ETP) family, which is considered a crucial virulence determinant among the secondary metabolites produced by Aspergillus fumigatus. The metabolites are commonly found in food and feed, contributing to the invasion and immune escape of Aspergillus fumigatus, thereby posing a significant threat to the health of livestock, poultry, and humans. Heterophil extracellular traps (HETs), a novel form of innate immune defense, have been documented in the chicken's innate immune systems for capturing and eliminating invading microbes. However, the effects and mechanisms of GT on the production of duck HETs in vitro remain unknown. In this study, we first confirmed the presence of HETs in duck innate immune systems and further investigated the molecular mechanism underlying GT-induced HETs release. Our results demonstrate that GT can trigger typical release of HETs in duck. The structures of GT-induced HETs structures were characterized by DNA decoration, citrullinated histones 3, and elastase. Furthermore, NADPH oxidase, glycolysis, ERK1/2 and p38 signaling pathway were found to regulate GT-induced HETs. In summary, our findings reveal that gliotoxin activates HETs release in the early innate immune system of duck while providing new insights into the immunotoxicity of GT towards ducks.

The widespread use of sex toys has sparked concerns about potential health risks associated with the leaching of micro/nanoplastics (M/NPs) and phthalates. In this in silico toxicity analysis, we investigated the immunotoxicity potential of compounds mechanically produced from sex toys. The research focuses on understanding their interactions with critical human cytochrome P450 enzymes (CYP34A and CYP2D6), which are central to drug metabolism and immune function. Four types of M/NPs (polyethylene terephthalate - PET, polyvinyl chloride - PVC, polydimethylsiloxane - PDMS, polyisoprene) and eight phthalates (Diethyl phthalate - DEP, Bis(4-methyl-2-pentyl) phthalate, Bis(2-methoxyethyl) phthalate, Benzyl butyl phthalate - BBP, Dibutyl Phthalate - DBP, Diethylhexyl phthalate - DEHP, Dinonyl phthalate - DNP, Di-n-octyl phthalate - DnOP) from sex toys were analyzed. Molecular dynamics and docking simulations were conducted to assess the binding affinity of these compounds to the enzymes. PET exhibited the highest toxicity, with a binding affinity of -8.3 kcal/mol and -8.9 kcal/mol for CYP3A4 and CYP2D6, respectively, surpassing control values (-7.8 kcal/mol and -6.3 kcal/mol). BBP showed considerable toxicity, binding strongly to CYP3A4 (-7.8 kcal/mol) and CYP2D6 (-9.1 kcal/mol). PDMS and DEP were the lowest toxic compounds in both groups. Molecular interactions revealed hydrogen bonds, pi interactions, and unfavorable donor-donor effects between compounds and specific amino acid residues within the enzymes. While these in silico findings provide insights, they underscore the need for comprehensive chemical analyses and absorption studies to validate health risks. This research emphasizes the necessity of evaluating the toxicity of M/NPs and phthalates from sex toys, promoting further investigations to protect individuals' health during product use.

Hydrogen sulfide (H2S) is a typical odour compound mainly causing respiratory and central nervous system symptoms. However, the immunotoxicity of inhaled H2S and the underlying mechanisms remain largely unknown. In this study, a low-dose inhalation exposure to H2S was arranged to observe inflammatory response and immunotoxicity in lung tissue of rats. Low concentrations of H2S exposure affected the immune level of pulmonary tissue and peripheral blood. Significant pathological changes in lung tissue in the exposure group were observed. At low concentration, H2S not only induced the upregulation of AQP-4 and MMP-9 expression but also stimulated immune responses, initiating various anti-inflammatory and inflammatory factors, altering tissue homeostatic environments. The TNF and chemokine signaling pathway played an important role which can promote the deterioration of pulmonary inflammatory processes and lead to lung injury and fibrosis. Excessive immune response causes an inflammatory effect and blood-gas barrier damage. These data will be of value in evaluating future occupational health risks and providing technical support for the further development of reliable, sensitive, and easy-to-use screening indicators of exposure injury.

Abstract Background Fipronil (FPN) is a broad-spectrum pesticide and commonly known as low toxicity to vertebrates. However, increasing evidence suggests that exposure to FPN might induce unexpected adverse effects in the liver, reproductive, and nervous systems. Until now, the influence of FPN on immune responses, especially T-cell responses has not been well examined. Our study is designed to investigate the immunotoxicity of FPN in ovalbumin (OVA)-sensitized mice. The mice were administered with FPN by oral gavage and immunized with OVA. Primary splenocytes were prepared to examine the viability and functionality of antigen-specific T cells ex vivo. The expression of T cell cytokines, upstream transcription factors, and GABAergic signaling genes was detected by qPCR. Results Intragastric administration of FPN (1–10 mg/kg) for 11 doses did not show any significant clinical symptoms. The viability of antigen-stimulated splenocytes, the production of IL-2, IL-4, and IFN-γ by OVA-specific T cells, and the serum levels of OVA-specific IgG1 and IgG2a were significantly increased in FPN-treated groups. The expression of the GABAergic signaling genes was notably altered by FPN. The GAD67 gene was significantly decreased, while the GABAR β2 and GABAR δ were increased. Conclusion FPN disturbed antigen-specific immune responses by affecting GABAergic genes in vivo. We propose that the immunotoxic effects of FPN may enhance antigen-specific immunity by dysregulation of the negative regulation of GABAergic signaling on T cell immunity.

Background: Fipronil (FPN) is a broad-spectrum pesticide and commonly known as low toxicity to vertebrates. However, increasing evidence suggests that exposure to FPN might induce unexpected adverse effects in the liver, reproductive, and nervous systems. Until now, the influence of FPN on immune responses, especially T-cell responses has not been well examined. Our study is designed to investigate the immunotoxicity of FPN in ovalbumin (OVA)-sensitized mice. The mice were administered with FPN by oral gavage and immunized with OVA. Primary splenocytes were prepared to examine the viability and functionality of antigen-specific T cells ex vivo. The expression of T cell cytokines, upstream transcription factors, and GABAergic signaling genes was detected by qPCR. Results: Intragastric administration of FPN (1–10 mg/kg) for 11 doses did not show any significant clinical symptoms. The viability of antigen-stimulated splenocytes, the production of IL-2, IL-4, and IFN-γ by OVA-specific T cells, and the serum levels of OVA-specific IgG1 and IgG2a were significantly increased in FPN-treated groups. The expression of the GABAergic signaling genes was notably altered by FPN. The GAD67 gene was significantly decreased, while the GABAR β2 and GABAR δ were increased. Conclusion: FPN disturbed antigen-specific immune responses by affecting GABAergic genes in vivo. We propose that the immunotoxic effects of FPN may enhance antigen-specific immunity by dysregulation of the negative regulation of GABAergic signaling on T cell immunity. [ABSTRACT FROM AUTHOR]