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Purpose: Random noise-moving images (noises) can make glaucoma patients with no subjective symptoms aware of visual field abnormalities. To explore this concept, we developed a noise using computer graphics (CG) and investigated the difference in the subjective perception of visual field abnormalities between CG and conventional analog noises. Methods: We enrolled individuals with glaucoma (205 eyes), preperimetric glaucoma (PPG; 19 eyes), and normal eyes (35 eyes). For a CG noise, a series of still images was made by randomly selecting five monochromatic tones on 2-mm square dots, and these images were drawn at 60 frames per second (fps) to create a noise-moving image. The participants were asked to describe their perceived shadows on a paper. The results were categorized as follows based on the pattern deviation probability map of the Humphrey field analyzer (HFA): "agreement," "partial agreement," "disagreement," and "no response." The glaucoma stage was classified into four stages, from M1 to M4, based on the HFA's mean deviation. Result: The detection rates (agreement and partial agreement) were 80.5% and 65.4% for the CG and analog noises, respectively, with CG noise showing a significantly higher detection rate in all glaucoma eyes (P < 0.001). The detection rates tended to increase as the glaucoma stage progressed, and in Stage M3, these were 93.9% and 78.8% for the CG and analog noises, respectively. The PPG eyes did not exhibit subjective abnormalities for both noises. The specificity values were 97.1% and 100% for the CG and analog noises, respectively. Conclusion: The CG noise is more effective than the analog noise in evaluating the subjective perception of visual field abnormalities in patients with glaucoma. [ABSTRACT FROM AUTHOR]

Aim: Styrene monomer (SM) is a basic chemical used as a raw material for polystyrene and unsaturated polyester resins and in the production of synthetic resins, synthetic rubbers, paints, and adhesives. To date, it is unclear whether SM is associated with the aggravation of atopic dermatitis. The aim was to investigate the effects of SM on atopic dermatitis-like skin lesions induced by mite allergen in NC/Nga mice. Methods: Male mice were injected intradermally with mite allergen on their right ears. In the presence of an allergen, SM (3.5 or 350 μg/animal/week) was administered by intraperitoneal injection. We evaluated clinical scores, ear thickening, histologic findings, and the protein expressions of cytokines and chemokines. Results: Macroscopic and microscopic examinations demonstrated that exposure to SM at a dose of 3.5 μg caused an exacerbation of atopic dermatitis-like skin lesions related to mite allergen. These changes were consistent with the level of histamine in the ear tissue as an overall trend. In contrast, 350-μg SM did not show significant enhancement effects. Conclusion: These results indicate that SM exacerbated atopic dermatitis-like skin lesions at hundred-fold lower levels than the level that causes no observed adverse effects as determined by histologic changes in rodent livers. SM could be at least partly responsible for the recent increase in atopic dermatitis. Styrene monomer (SM) is classified as an International Agency for Research on Cancer group 2B carcinogen and includes neurotoxicity and respiratory disorders. However, the effects of SM as a chemical substance on existing allergic pathophysiology have not been elucidated yet. This study demonstrated that SM exacerbated murine atopic dermatitis-like skin lesions at hundred-fold lower levels than the level that causes no observed adverse effects as determined by histologic changes in rodent livers, which was concomitant with the local level of histamine. These data hasten a need for comprehensive research to clarify the chemical pollutants' effects of doses much lower than NOAEL on vulnerable pathophysiologies such as allergy/atopy. [ABSTRACT FROM AUTHOR]

Bisphenol S (BPS) is increasingly being used as an alternative for bisphenol A; however, its health effects remain unclear. We investigated the effects of oral exposure to low-dose BPS on allergic asthma. C3H/HeJ male mice were intratracheally administered with allergen (ovalbumin (OVA), 1 μg/animal) every 2 weeks from 6 to 11 weeks old. BPS was ingested by drinking water at doses equivalent to 0.04, 0.4, and 4 μg/kg/day. We then examined pulmonary inflammation, airway hyperresponsiveness, serum OVA-specific immunoglobulin (Ig) levels, Th2 cytokine/chemokine production, and mediastinal lymph node (MLN) cell activities. Compared with OVA alone, moderate-dose BPS (BPS-M) with OVA significantly enhanced pulmonary inflammation, airway hyperresponsiveness, and OVA-specific IgE and IgG1. Furthermore, interleukin (IL)-5, IL-13, IL-33, and CCL11/Eotaxin protein levels in the lungs increased. Conversely, these allergic responses were reduced in the high-dose BPS+OVA group. In MLN cells, BPS-M with OVA increased the total cell count and activated antigen-presenting cells including conventional dendritic cell subset (cDC2). After OVA restimulation, cell proliferation and Th2 cytokine production (IL-4, IL-5, and IL-13) in the culture supernatant also increased. Therefore, oral exposure to low-dose BPS may exacerbate allergic asthmatic responses by enhancing Th2-polarized responses and activating the MLN cells. [ABSTRACT FROM AUTHOR]

There is increasing concern about multiple high concentration exposure to toxins in disaster and emergency situations. However, conventional toxicology testing methods may not adequately address these situations. Thus, we assessed whether the toxic effects of exposure in the adulthood differ depending on the presence or absence of neonatal exposure to Tris (1,3‐dichloro‐2‐propyl) phosphate (TDCIPP) in male rats to investigate the effects of exposure history of chemicals. In the neonatal stage [postnatal days (PNDs) 1–7], animals were treated with either sesame oil (5 ml/kg/day) as a control or TDCIPP (250 mg/kg/day) dissolved in sesame oil. In adulthood (PND 101–107), animals were treated with either sesame oil (5 ml/kg/day) or TDCIPP (650 mg/kg/day). One day after the final administration, dissection was performed, and body and organ weight, hematology, blood biochemistry, and histopathology were examined. The results demonstrated that the toxic effects of TDCIPP exposure in adulthood on adrenal gland size, serum iron content, and unsaturated iron binding capacity were enhanced by TDCIPP exposure in the neonatal stage. From these findings, it was indicated that the toxic effects of TDCIPP exposure in the adult stage are affected by pediatric exposure. These results suggest that the toxic effects of high‐dose and long‐term unsteady exposure to chemicals in large‐scale disasters may change based on the exposure history of chemicals. Conventional toxicology tests may not address intermittent disasters. We assessed the toxic effects of transient high concentration toxin exposure to Tris (1,3‐dichloro‐2‐propyl) phosphate (TDCIPP) in the neonatal and adult stages. Rats exposed to TDCIPP in both stages exhibited significantly higher adrenal weight, lower serum iron levels, and higher unsaturated iron binding capacity than rats treated with TDCIPP exposure only in adulthood, indicating that the effects of adult toxin exposure are affected by neonatal exposure. [ABSTRACT FROM AUTHOR]

Background: Benzo[a]pyrene (BaP) affects the immune system and causes mutagenic and carcinogenic effects. Purpose: We aimed to evaluate the effects of systemic exposure to BaP on mite allergen–induced atopic dermatitis (AD)–like skin lesions in mice. Methods: Mite allergen (Dermatophagoides pteronyssinus ; Dp) was injected intradermally into the right ears of NC/Nga male mice on eight occasions every 2–3 days. Benzo[a]pyrene was administered intraperitoneally in the equivalent doses of 0, 2, 20, 200, or 2000 μg/kg/day, once a week on four occasions. Results: AD-like skin inflammation related to mite allergen worsened by BaP exposure at 2, 20 µg/kg/day doses; this was in parallel with eosinophil and mast cell infiltration and mast cell degranulation. A trend was also observed toward increased proinflammatory molecule expression, including macrophage inflammatory protein-1 alpha, interleukin (IL)-4, IL-13, and IL-18, in the ear tissue. However, 200 or 2000 µg/kg/day BaP attenuated the enhancing effects. In the regional lymph nodes, 2 µg/kg/day BaP with Dp enhanced antigen-presenting cell and T cell activation compared with Dp alone. Conclusions: This suggests that BaP exposure can aggravate Dp-induced AD-like skin lesions through TH2-biased responses in the inflamed sites and the activation of regional lymph nodes. Therefore, BaP may be responsible for the recent increase in AD incidence. [ABSTRACT FROM AUTHOR]

Tris(1,3-dichloro-2-propyl)phosphate (TDCIPP) is an organophosphorus flame retardant that is an alternative to brominated flame retardants. Although TDCIPP can adversely affect human health, information about its effects on immune and allergic responses is scarce. We aimed to investigate the effects of dietary exposure to TDCIPP using less than the human tolerable daily intake (TDI) in allergic asthmatic mice. Male C3H/HeJSlc mice were fed a chow diet containing TDCIPP equivalent to 0.02 μg/kg/day (low; L), 0.2 μg/kg/day (medium; M), or 2 μg/kg/day (high; H) and were intratracheally administered ovalbumin (OVA, 1 μg/animal) every 2 weeks from 5 to 11 weeks of age. In OVA-treated mice, TDCIPP-H exposure tended to enhance pulmonary inflammation compared with vehicle exposure. TDCIPP dose-dependently decreased mRNA level of G protein-coupled estrogen receptor (GPER) in the lungs with or without OVA. OVA + TDCIPP-H treatment tended to increase the total cell number and promoted CD4+ cell activation compared with OVA alone treatment in mediastinal lymph nodes. In splenocytes, an increase in the fraction of Breg cells, but not of total B and T cells, and an increase in IL-5 in cell culture supernatants following OVA re-stimulation in OVA + TDCIPP-H-treated mice was observed compared with OVA-alone-treated mice. Moreover, OVA + TDCIPP-H exposure decreased Gr-1 expression in bone marrow (BM) cells. These results suggested that dietary exposure to TDCIPP at TDI level slightly enhances allergic diseases, such as allergic asthma, via GPER regulation at inflamed sites and secondary lymphoid tissue and BM cell alternations. [ABSTRACT FROM AUTHOR]

Bisphenol A (BPA) is a raw material of polycarbonate and epoxy resin. It is used for various household electrical appliances, electronic equipment, office automation equipment, medical equipment, mobile phones, paints for automobiles, internal surface coating of cans, and adhesives for civil engineering and construction. BPA is a well‐known endocrine‐disrupting chemical, and it was reported that BPA has an adverse effect on the nervous and immune systems. However, BPA‐induced memory impairment and changes in neuroimmune biomarkers in the allergic asthmatic subject are not known yet. We aim to investigate the dietary exposure effect of BPA on brain function and biomarkers using allergic an asthmatic mouse model. Five‐week‐old male C3H/HeJSlc mice were fed two doses of BPA [0.901, 9.01 μg/kg/day] contained chow diet from 5 to 11 weeks old and ovalbumin (OVA) was given by intratracheal instillation every 2 weeks. Memory function was determined by a novel object recognition test. Genes related to memory and immune markers in the hippocampus were investigated with the real‐time polymerase chain reaction (RT‐PCR) method. In this study, impaired novel object recognition occurred in BPA‐exposed mice in the presence of an allergen. Moreover, upregulation of expression level of neuroimmune biomarkers such as N‐methyl‐D‐aspartate receptor, tumor necrosis factor‐α, ionized calcium‐binding adapter molecule‐1, cyclooxygenase‐2, and heme oxygenase‐1 in the hippocampus was observed in BPA‐exposed allergic asthmatic mice. These findings show that BPA exposure can induce neuroinflammation and which triggers impairment of memory function in mice with allergic asthma. Our study indicated that dietary exposure to BPA may affect higher brain functions by modulating neuroimmune biomarkers in allergic asthmatic subjects. Dietary BPA exposure affects neuroimmune biomarkers. Dietary BPA exposure impaired memory in allergic asthmatic mice. Neuroimmune activation was observed in BPA in the presence of allergen. [ABSTRACT FROM AUTHOR]

The widespread use of tris(1,3‐dichloro‐2‐propyl) phosphate (TDCIPP) as a flame retardant has led to its release to the environment. Thus, the toxicological effects of TDCIPP on humans and animals are of importance. For better understanding of its potential toxicities, TDCIPP (250, 500, or 650 mg/kg/day) or vehicle control was administrated orally to adult male Wistar‐Imamichi rats for 7 days. After the final administration of compounds, organ weights, histopathology, blood biochemistry, and hematology were examined. Hepatic toxicity was observed at doses ≥ 500 mg/kg/day of TDCIPP, and renal toxicity was observed at 650 mg/kg/day. The anti‐androgenic activity of TDCIPP was previously confirmed in vitro and in vivo, but weights of epididymis, an androgen‐dependent organ, were not affected by TDCIPP treatment in adults. Serum alkaline phosphatase activity was significantly decreased in all TDCIPP‐treated rats independent of dose. Hemoglobin concentration, hematocrit, red blood cell count, and reticulocyte count were decreased in all TDCIPP‐treated rats, but mean corpuscular volume, total iron‐binding capacity, and serum iron were normal, suggesting that renal anemia was caused by TDCIPP. Together with previous reports on effects of anti‐androgenic substances on red blood cell indices, anemia caused by TDCIPP could be due to its anti‐androgenic activity. These considerations will contribute to further assessment of the toxicity of the compound. Tris(1,3‐dichloro‐2‐propyl) phosphate (TDCIPP) was administrated orally to adult male Wistar‐Imamichi rats for 7 days. Serum ALP activity was significantly decreased in all TDCIPP‐treated rats independent of dose. Hemoglobin concentration, hematocrit, red blood cell count, and reticulocyte count were decreased by TDCIPP, suggesting that renal anemia is possibly caused by its anti‐androgenic activity. These considerations will contribute to further assessment of the toxicity of the compound. [ABSTRACT FROM AUTHOR]

Abstract Background Although fungi have been implicated as initiating/deteriorating factors for allergic asthma, their contributing components have not been fully elucidated. We previously isolated soluble β-glucan from Candida albicans (CSBG) (Ohno et al., 2007). In the present study, the effects of CSBG exposure on airway immunopathology in the presence or absence of other immunogenic allergen was investigated in vivo, and their cellular mechanisms were analyzed both in vivo and in vitro. Methods In vivo, ICR mice were divided into 4 experimental groups: vehicle, CSBG (25 μg/animal), ovalbumin (OVA: 2 μg/animal), and CSBG + OVA were repeatedly administered intratracheally. The bronchoalveolar lavage cellular profile, lung histology, levels of cytokines and chemokines in the lung homogenates, the expression pattern of antigen-presenting cell (APC)-related molecules in the lung digests, and serum immunoglobulin values were studied. In vitro, the impacts of CSBG (0–12.5 μg/ml) on the phenotype and function of immune cells such as splenocytes and bone marrow-derived dendritic cells (BMDCs) were evaluated in terms of cell proliferation, the surface expression of APC-related molecules, and OVA-mediated T-cell proliferating activity. Results In vivo, repeated pulmonary exposure to CSBG induced neutrophilic airway inflammation in the absence of OVA, and markedly exacerbated OVA-related eosinophilic airway inflammation with mucus metaplasia in mice, which was concomitant with the amplified lung expression of Th2 cytokines and IL-17A and chemokines related to allergic response. Exposure to CSBG plus OVA increased the number of cells bearing MHC class II with or without CD80 in the lung compared to that of others. In vitro, CSBG significantly augmented splenocyte proliferation in the presence or absence of OVA. Further, CSBG increased the expression of APC-related molecules such as CD80, CD86, and DEC205 on BMDCs and amplified OVA-mediated T-cell proliferation through BMDCs. Conclusion CSBG potentiates allergic airway inflammation with maladaptive Th immunity, and this potentiation was associated with the enhanced activation of APCs including DC.

BACKGROUND: Hexabromocyclododecane (HBCD) is an additive flame retardant used in the textile industry and in polystyrene foam manufacturing. Because of its lipophilicity and persistency, HBCD accumulates in adipose tissue and thus has the potential of causing metabolic disorders through disruption of lipid and glucose homeostasis. However, the association between HBCD and obesity remains unclear. OBJECTIVES: We investigated whether exposure to HBCD contributes to initiation and progression of obesity and related metabolic dysfunction in mice fed a normal diet (ND) or a high-fat diet (HFD). METHODS: Male C57BL/6J mice were fed a HFD (62.2 kcal% fat) or a ND and treated orally with HBCD (0, 1.75, 35, or 700 µg/kg body weight) weekly from 6 to 20 weeks of age. We examined body weight, liver weight, blood biochemistry, histopathological changes, and gene expression profiles in the liver and adipose tissue. RESULTS: In HFD-fed mice, body and liver weight were markedly increased in mice treated with the high (700 µg/kg) and medium (35 µg/kg) doses of HBCD compared with vehicle. This effect was more prominent in the high-dose group. These increases were paralleled by increases in random blood glucose and insulin levels and enhancement of microvesicular steatosis and macrophage accumulation in adipose tissue. HBCD-treated HFD-fed mice also had increased mRNA levels of Pparg (peroxisome proliferator-activated receptor-γ) in the liver and decreased mRNA levels of Glut4 (glucose transporter 4) in adipose tissue compared with vehicle-treated HFD-fed mice. CONCLUSIONS: Our findings suggest that HBCD may contribute to enhancement of diet-induced body weight gain and metabolic dysfunction through disruption of lipid and glucose homeostasis, resulting in accelerated progression of obesity. 10.1289/ehp.1307421, Introduction Hexabromocyclododecane (HBCD) (for chemical structure, see Supplemental Material, Figure S1) is a brominated flame retardant (BFR) that is incorporated into plastics, electrical and electronic products, textiles, and other materials [...]

Tris(2‐butoxyethyl) phosphate (TBEP) is a major organophosphorus flame retardant and has been widely increasing as a substitute for brominated flame retardants. TBEP may have adverse effects on human health; however, its impact on immune and allergic responses remains largely uncharacterized. In this study, the effects of low‐dose TBEP comparable with the level of actual human exposure to that of human tolerable daily intake on allergic asthmatic mice were explored. Five‐week‐old C3H/HeJSlc male mice consumed a diet containing approximately 0.02, 0.2 or 2 μg/kg/day TBEP and were intratracheally administrated ovalbumin (OVA) (1 μg/mouse every 2 weeks from 5 to 11 weeks of age). Exposure to 2 μg/kg/day TBEP with OVA tended to enhance allergic pulmonary inflammation and significantly elevated mRNA levels of interleukin‐5, eotaxin‐1 and estrogen receptor alpha (ERα) compared with OVA alone. In mediastinal lymph nodes (MLNs), TBEP (0.2 or 2 μg/kg/day) with OVA significantly increased in total cell number and promoted conventional dendritic cell activation than OVA alone; MLN cell proliferation by OVA restimulation was also enhanced in these groups. In the bone marrow (BM), TBEP (0.02 or 0.2 μg/kg/day) with OVA resulted in a net decrease in total cell number and fraction of CCR2+Gr‐1+ cells; the fraction of Gr‐1+ cells increased. In conclusion, oral exposure to low‐dose TBEP levels equivalent to tolerable daily intake may exacerbate allergic pulmonary inflammation by promoting a skewed T‐helper 2 cell response, upregulation of ERα and dysregulation of both MLN and BM microenvironments. We investigated the effects of oral exposure to low‐dose tris(2‐butoxyethyl) phosphate (TBEP) on allergic asthma mice. TBEP slightly enhanced allergic pulmonary inflammation via increase in the mRNA levels of interleukin‐5, eotaxin‐1 and estrogen receptor alpha. In mediastinal lymph nodes, TBEP + ovalbumin significantly increased total cell number and promoted conventional dendritic cell activation and allergen‐restimulated cell proliferation. Furthermore, there was slight dysregulation in the bone marrow microenvironments. Oral exposure to low‐dose TBEP levels equivalent to tolerable daily intake may exacerbate allergic responses. [ABSTRACT FROM AUTHOR]

Benzo[a]pyrene (BaP) can induce developmental and reproductive toxicity; however, the full scope of its immunotoxic effects remains unknown. This study aimed to assess effects of lactational exposure to low-dose BaP (comparable to human exposure) on potential allergic\non-allergic immune responses in murine offspring. Lactating C3H/HeJ dams were orally dosed with BaP at 0, 0.25, 5.0, or 100 pmol/animal/week) at post-natal days [PND] 1, 8, and 15. Five-weeks-old pups then received intratracheally ovalbumin (OVA) every 2 weeks for 6 weeks. Following the final exposure, mice were processed to permit analyses of bronchoalveolar lavage (BAL) fluid cell profiles as well as levels of lung inflammatory cytokines and chemokines, serum OVA-specific immunoglobulin, and mediastinal lymph node (MLN) cell activation/proliferation. In OVA-sensitized male offspring, lactational low-dose BaP exposure led to enhanced (albeit not significantly) macrophage, neutrophil, and eosinophil infiltration to, and increased T-helper (TH)-2 cytokine production in, the lungs. In females, BaP exposure, regardless of dose, led to slightly enhanced lung levels of macrophages and eosinophils, and of inflammatory molecules. Protein levels of interleukin (IL)-33 in the OVA + BaP (middle dose) group, and interferon (IFN)-γ in the OVA + BaP (low dose) group, were higher than that of the OVA (no BaP) group. Ex vivo studies showed lactational exposure to BaP partially induced activation of T-cells and antigen-presenting cells (APCs) in the MLN cells of both male and female offspring, with or without OVA sensitization. Further, IL-4 and IFNγ levels in MLN culture supernatants were elevated even without OVA-re-stimulation in OVA + BaP groups. In conclusion, lactational exposure to low-dose BaP appeared to exert slight effects on later allergic and non-allergic immune responses in offspring by facilitating development of modest TH2 responses and activating MLN cells. In addition, lactational exposures to BaP might give rise to gender differences in allergic/non-allergic immune responses of offspring. [ABSTRACT FROM AUTHOR]

Benzo[a]pyrene (BaP) reportedly has mutagenic and adjuvant activities. We aimed to determine the effects of low-dose BaP administration on allergic airway inflammation and mediastinal lymph node (MLN) cell activation/proliferation in mice. Male C3H/HeJ mice were intratracheally administered ovalbumin (OVA) every 2 weeks and/or BaP (0, 0.05, 1 and 20 pmol per animal per week) once per week for 6 weeks. The cellular profile of bronchoalveolar lavage (BAL) fluid, histological changes, inflammatory cytokines/chemokines in the lungs, OVA-specific immunoglobulin (Ig) in serum and MLN cell activation/proliferation were examined. BaP administration of 20 pmol with OVA enhanced neutrophil and macrophage accumulation in the lungs. Compared with OVA administration, BaP administration with OVA tended to enhance pulmonary eosinophilia and goblet cell hyperplasia. Furthermore, it increased the levels of interleukin (IL)-5, IL-13, IL-33, monocyte chemoattractant protein-1 and eotaxin in the lungs, and OVA-specific IgG1 in serum, although not dose-dependently. Compared with the vehicle group, IL-6 and tumor necrosis factor-alpha levels were higher in the OVA + 1 pmol BaP group and IL-12 production was higher in the OVA + 20 pmol BaP group. Ex vivo studies showed that co-exposure to OVA and BaP activated the MHC class II and CD86 expression in MLN cells. Exposure to BaP with OVA increased IL-4, IL-5 and interferon gamma levels in culture supernatants of OVA-re-stimulated MLN cells. In conclusion, low-dose BaP can, at least in part, enhance allergic airway inflammation by facilitating Th2 responses and activating MLN cells; a high BaP dose may contribute to activating both Th1 and Th2 responses. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

ABSTRACT Phthalate esters in plastics act as adjuvants for immunoglobulin production, which aggravates allergic disease. However, the effects of alkylphenols (used as plasticizers and surfactants) on atopic dermatitis have not been studied in detail. Therefore, the goal of the present study was to investigate the effects of the alkylphenols 4-nonylphenol (NP), 4- tert-octylphenol (OP) and 4- tert-butylphenol (BP) in a murine model of atopic dermatitis. NC/Nga mice were intraperitoneally administered NP, OP or BP and were subcutaneously injected with mite allergen in one ear to induce atopic dermatitis-like skin lesions (ADSLs). The condition of the skin was observed, and the levels of immunoglobulin in serum and inflammatory cytokines in lesions were determined. NP exacerbated mite allergen-induced ADSLs according to dose. OP and BP also significantly exacerbated skin lesions but not as a function of dose. Alkylphenols tended to increase the levels of IgE and antigen-specific IgG1 in serum. Further, the treatment of the alkylphenols increased the expression in lesions of inflammatory cytokines, interleukin-4 and monocyte chemotactic protein-3. Thymic stromal lymphopoietin levels increased according to ADSL severity. In contrast, the levels of the T-helper 1 cytokines (interleukin-18 and interferon-gamma) decreased. NP, OP or BP may enhance T-helper 2-type immune responses in NC/Nga mice, which aggravates mite allergen-induced ADSLs. Therefore, the uptake of very low levels of alkylphenols may contribute to the increase in the incidence of atopic dermatitis. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

ABSTRACT Particulate matter can exacerbate respiratory diseases such as asthma. Diesel exhaust particles are the substantial portion of ambient particulate matter with a <2.5 µm diameter in urban areas. Epidemiological data indicate increased respiratory health effects of particulate matter in obese individuals; however, the association between obesity and diesel exhaust particle-induced airway inflammation remains unclear. We aimed to investigate the differences in susceptibility to airway inflammation induced by exposure to diesel exhaust particles between obese mice (db/db) and lean mice (db/+m). Female db/db and db/+m mice were intratracheally administered diesel exhaust particles or vehicle every 2 weeks for a total of seven times. The cellular profile of bronchoalveolar lavage fluid and histological changes in the lungs were assessed and the lungs and serum were analyzed for the generation of cytokines, chemokines and soluble intercellular adhesion molecule 1. Diesel exhaust particle exposure-induced eosinophilic infiltration in db/+m mice accompanied by T-helper 2 cytokine, chemokine and soluble intercellular adhesion molecule 1 expression in the lungs. In contrast, it induced mild neutrophilic airway inflammation accompanied by elevated cytokines and chemokines in db/db mice. The lungs of db/db mice exhibited decreased expression of eosinophil activators/chemoattractants such as interleukin-5, interleukin-13 and eotaxin compared with those of db/+m mice. In addition, serum eotaxin and monocyte chemotactic protein-1 levels were significantly higher in db/db mice than in db/+m mice. In conclusion, obesity can affect susceptibility to diesel exhaust particle-induced airway inflammation, which is possibly due to differences in local and systemic inflammatory responses between lean and obese individuals. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

ABSTRACT Epidemiologic studies have reported that Asian sand dust (ASD) particles can affect respiratory health; however, the mechanisms remain unclear. We investigated the effects of ASD on airway epithelial cells and immune cells, and their contributing factors to the effects. Human airway epithelial cells were exposed to ASD collected on 1-3 May (ASD1) and on 12-14 May (ASD2) 2011 in Japan and heat-treated ASD1 for excluding heat-sensitive substances (H-ASD) at a concentration of 0, 3, 30 or 90 µg ml-1 for 4 or 24 h. Furthermore, bone marrow-derived dendritic cells (BMDC) from atopic prone mice were differentiated by culture with granulocyte-macrophage colony-stimulating factor (GM-CSF) then these BMDC were exposed to the ASD for 24 h. Also splenocytes as mixture of immune cells were exposed to the ASD for 72 h. All ASD dose dependently reduced viability of airway epithelial cells. Non-heated ASD showed a dose-dependent increase in the protein release of interleukin (IL)-6 and IL-8. The raises induced by ASD1 were higher than those by ASD2. ASD1 and ASD2 also elevated ICAM-1 at the levels of mRNA, cell surface protein and soluble protein in culture medium. In contrast, H-ASD did not change most of these biomarkers. Non-heated ASD showed enhancement in the protein expression of DEC205 on BMDC and in the proliferation of splenocytes, whereas H-ASD did not. These results suggest that ASD affect airway epithelial cells and immune cells such as BMDC and splenocytes. Moreover, the difference in ASD events and components adhered to ASD can contribute to the health effects. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Context: Subcutaneous injection of low dose of phthalates causes adjuvant effects on immunoglobulin production. Moreover, intraperitoneal injection of di-(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DINP) at doses lower than the no-observed-adverse-effect level (NOAEL) causes aggravation of atopic dermatitis-like skin lesions (ADSLs) in mouse models. However, the effects of oral exposure to these phthalates, including their effect on atopic dermatitis (AD) symptoms, remain unclear. Objective: To investigate the effects of oral administration of DEHP and DINP at doses lower than the NOAEL on AD in an NC/Nga mouse model. Materials and methods: NC/Nga mice were subcutaneously injected with mite-allergen ( Dermatophagoides pteronyssinus) to induce ADSLs and orally administered varying doses of DEHP (0, 8.3, 166.3 or 3325 µg/animal) or DINP (0, 6.6, 131.3 or 2625 µg/animal) once a week for four weeks. Skin disease symptomatology was subsequently evaluated and immunoglobulin production levels in serum and inflammatory cytokine levels in lesion sites were measured. Results: Oral administration of low doses of both DEHP and DINP tended to increase infiltration of eosinophils; degranulation of mast cells and local expression of inflammatory cytokines, interleukin-13 and macrophage inflammatory protein-1 alpha in subcutaneous tissue, whereas DINP administration tended to aggravate allergen-induced ADSL production. Conclusions: Oral administration of both DEHP and DINP at doses lower than the NOAEL tends to increase the allergic response in animal AD models, but only DINP administration slightly aggravates allergen-induced ADSL production. [ABSTRACT FROM AUTHOR]

ABSTRACT Brominated flame retardants (BFRs) are widely used in consumer products. Their toxicological effects as endocrine disruptors have been partly examined. However, their immunological effects have not been elucidated. To evaluate the effects of BFRs on immune responses, we investigated whether BFRs affect phenotypes and the function of immune cells in vitro. Here we examined the commercial pentabromodiphenyl ether mixture (DE-71), octabromodiphenyl ether mixture (DE-79), decabromodiphenyl ether mixture (DE-83R), hexabromocyclododecane (HBCD) and tetrabromobisphenol A (TBBPA). Splenocytes and bone marrow (BM) cells were prepared from atopic prone NC/Nga mice. Splenocytes were exposed to each BFR for 24 h. BM cells were cultured with granulocyte macrophage-colony stimulating factor (GM-CSF) for 8 days and BM-derived dendritic cells (BMDCs) were exposed to each BFR for 24 h. In another experiment, BM cells were cultured with GM-CSF in the presence of each BFR for 6 days during BMDC differentiation. After exposure, cell surface molecule expression and cytokine production were investigated. Each BFR increased MHC class II and CD86 expression and interleukin (IL)-4 production in splenocytes. DE-71, HBCD and TBBPA increased T cell receptor (TCR) expression in splenocytes. In both experiments, all BFRs except TBBPA increased DEC205 expression in BMDCs. BMDCs that differentiated in the presence of HBCD showed enhanced MHC class II, CD80, CD86 and CD11c expression. The results demonstrate that some BFRs may stimulate immune cells. BFRs can induce or enhance immune/allergic responses by increasing antigen presentation-related molecule expression and IL-4 production. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

ABSTRACT Previously, we demonstrated that maternal exposure to phthalates enhances atopic dermatitis in male mouse offspring. However, whether phthalate exposure affects neuroimmune biomarkers in allergic mice has not yet been studied. Di-(2-ethylhexyl) phthalate (DEHP) and di-isononyl phthalate (DINP) are environmental chemicals that are commonly used as plasticizers. This study was designed to investigate the expression levels of neuroimmune biomarkers in the hypothalamus of a murine model of allergic asthma after phthalate exposure throughout juvenility until adulthood. Six-week-old C3H/HeJ Jcl male mice were treated with DEHP or DINP (0, 0.02, 0.4 or 8 nmol per body per week) and ovalbumin (OVA; 1 µg per body per 2 weeks) for 7 weeks intratracheally. On the day after the completion of the phthalate and OVA treatment, the hypothalamus from each mouse was collected, and the mRNA expression levels of neuroimmune biomarkers were examined using a real-time RT-PCR analysis. The mRNA expression levels of the proinflammatory cytokines interleukin (IL)-1 β and tumor necrosis factor (TNF)- α, the chemokine CCL3, the transcription factor nuclear factor (NF)- κB, the oxidative stress marker heme-oxygenase (HO)1, a nerve growth factor, and the microglia marker Iba1 were remarkably up-regulated in the hypothalami of mice treated with 8 nmol of DEHP in the presence of the allergen. However, no significant changes were observed, except for reductions in the TNF- α and CCL2 mRNA levels, in mice exposed to DINP combined with the allergen. This study is the first report to show that high-dose DEHP exposure throughout juvenility until adulthood may induce neuroinflammation by modulating neuroimmune biomarkers in the hypothalami of allergic mice. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Previous studies have shown that inhaled particles exacerbate asthma and allergic rhinitis. Several factors related to the particle may play a role in immune-stimulating activity; however, the underlying mechanisms remain unclear. We carried out in vitro studies to investigate the effects of TiO2 particle exposure on antigen presenting activity and expression of the associated cell-surface molecules (Ia, B7.1, B7.2) in rat derived monocytes and alveolar macrophages, in terms of two aspects of the particles: (1) size (59 nm (ST) and 350 nm (LT) particles), and (2) the timing of particle exposure (before antigen exposure or co-administered). Results indicated that particle exposure prior to antigen exposure led to decreased antigen presenting activity in both types of cell. This decrease was greater with ST particles. In monocytes, the expression of cell surface molecules decreased similarly with both particles. Conversely, alveolar macrophages showed greater expression of Ia with ST than with LT exposures. Ia expression was confirmed to be functionally active by a mixed lymphocyte reaction. It is possible that particle exposure might result in poor antigen processing, thereby leading to decreased antigen presenting activity. Co-exposure of particles and antigen induced an increase in antigen presenting activity with both types of particle; however, ST exposure induced greater antigen presenting activity. The expression of Ia also increased similarly with both particle sizes. This suggests that, in a co-exposure situation, antigen may be processed without intensive retardation by particles, and factors other than Ia may affect antigen presenting activity. In conclusion, both size and timing of exposure to TiO2 particles affect antigen presenting activity of monocytes and alveolar macrophages. [ABSTRACT FROM AUTHOR]

Abstract: Phthalate esters as plasticizers have been widespread in the environment and may be associated with development of allergic diseases such as asthma and atopic dermatitis. However, the underlying mechanisms have not been fully elucidated. The present study investigated the effects of di-(2-ethylhexyl) phthalate (DEHP) on immune cells from atopic prone NC/Nga mice in vitro. Bone marrow-derived dendritic cells (BMDC) as a professional antigen-presenting cell and splenocytes as mixture of immune cells were used. BMDC were differentiated by culture with granulocyte macrophage-colony stimulating factor (GM-CSF) in the presence of DEHP (0.1–10μM) for 6 days. In another experiments, BMDC were differentiated by culture with GM-CSF for 8 days then these BMDC were exposed to DEHP (0.1–100μM) for 24h. Splenocytes were exposed to DEHP for 24h (0.1–100μM) or 72h (0.1–1000nM). After the culture, the phenotypic markers and the function of BMDC and splenocytes were evaluated. BMDC differentiated in the presence of DEHP showed enhancement in the expression of MHC class II, CD86, CD11c and DEC205, and in their antigen-presenting activity. On the other hand, the function of the differentiated BMDC was not activated by DEHP although DEHP partly enhanced their expression of DEC205. DEHP-exposed splenocytes showed increases in their TCR and CD3 expression, interleukin-4 production, and antigen-stimulated proliferation. These results demonstrate that DEHP enhances BMDC differentiation but not activation and also enhances Th2 response in splenocytes from atopic prone mice. The enhancement might contribute to the aggravating effect of DEHP on allergic disorders. [Copyright &y& Elsevier]

Although diesel exhaust particles (DEP) exacerbate murine allergic asthma, the mechanisms remain unclarified. This study elucidated the effects of pulmonary exposure to DEP on extrathoracic allergen-induced CD4 polarization using an ex vivo system in asthmatic mice. Mice were divided into 4 groups, and vehicle, DEP, ovalbumin (OVA), or DEP + OVA was intratracheally instilled biweekly 5 times. Twenty-four h after the last intratracheal instillation, the spleen was removed. Mononuclear cells were isolated from the spleen and stimulated in vitro with OVA; thereafter, the number of separated CD4+ cells was counted. The number of separated CD4+ cells was significantly greater in the OVA or the DEP + OVA group than in the vehicle group. Furthermore, the number was significantly greater in the DEP + OVA than in the DEP or the OVA group. Taken together, in vivo DEP exposure amplified extrathoracic CD4 polarization in asthmatic subjects. [ABSTRACT FROM AUTHOR]