In vivo immune activation of splenocytes following exposure to tar from Asian sand dust.

Air pollution, especially that initiated by particulate matter (PM), has been implicated as a risk factor for several inflammatory diseases. Previously, it was reported that PM enhances immune responses. PM includes the tar fraction that contains polycyclic aromatic hydrocarbons (PAHs), which produce adverse health effects in exposed individuals. However, the influence of the tar fraction (as a component of PM) on splenocytes is not fully understood. The aim of this study was to determine the effects of the tar fraction extracted from PM collected from the atmosphere in Fukuoka, Japan, on mouse splenocytes. ICR mice were administered tar (1 or 5 µg/mouse) intratracheally 4 times at 2-week intervals, and splenocytes from the tar-treated mice were extracted and examined. The parameters determined were proliferation, cytokine concentrations and transcription factors activation. Following tar treatment, splenocyte proliferation increased relative to controls. Concanavalin A (ConA)-induced interleukin (IL)-2 formation and ConA- or lipopolysaccharide (LPS)-induced interferon-γ production were elevated in splenocytes from tar-exposed mice. However, the production of tumor necrosis factor-α and IL-6 induced by LPS was not markedly changed following tar treatment. Further, nuclear factor of activated T cells, but not nuclear factor-κB, was enhanced in splenocytes of tar-exposed mice. Data indicate that tar-activated splenocytes and PM-bound PAHs might contribute to T cell activation in the spleen.

Long term trends in atmospheric concentrations of polycyclic aromatic hydrocarbons and nitropolycyclic aromatic hydrocarbons: A study of Japanese cities from 1997 to 2014.

Total suspended particulate matter (TSP) was collected during the summer and winter in five Japanese cities spanning Hokkaido to Kyushu (Sapporo, Kanazawa, Tokyo, Sagamihara and Kitakyushu) from 1997 to 2014. Nine polycyclic aromatic hydrocarbons (PAHs) with four to six rings, including pyrene (Pyr) and benzo[a]pyrene (BaP), were identified using high-performance liquid chromatography (HPLC) with fluorescence detection. Two nitropolycyclic aromatic hydrocarbons (NPAHs), 1-nitropyrene (1-NP) and 6-nitrobenzo[a]pyrene (6-NBaP), were identified by HPLC with chemiluminescence detection. A comparison of PAH and NPAH concentrations and [NPAH]/[PAH] ratios such as [1-NP]/[Pyr] and [6-NBaP]/[BaP] revealed the following characteristics in the five cities: (1) In Sapporo, Kanazawa, Tokyo and Sagamihara, the concentrations of PAHs and NPAHs were high at the beginning of the sampling period and then steadily decreased, with NPAHs decreasing faster than PAHs. The large initial [1-NP]/[Pyr] ratios suggest that the major contributor was automobiles but subsequent decreases in this ratio suggest decreased automobile contributions. (2) By contrast, PAH concentrations in Kitakyushu did not decrease during the sampling period, though concentrations of NPAHs decreased. The consistently smaller [1-NP]/[Pyr] ratio and larger [6-NBaP]/[BaP] ratio in Kitakyushu suggests that the major contributor of PAHs was not automobiles but iron manufacturing which uses a large amount of coal. The sudden increase in atmospheric PAH concentrations in the winter of 2014 may also be due to iron manufacturing.

Urban PM2.5 exacerbates allergic inflammation in the murine lung via a TLR2/TLR4/MyD88-signaling pathway.

Nevertheless its mechanism has not been well explained yet, PM2.5 is recognized to exacerbate asthma. In the present study, the roles of toll-like receptor (TLR) 2, TLR4 and MyD88, in exacerbation of allergen-induced lung eosinophilia caused by urban PM2.5 was investigated. TLR2-, TLR4-, MyD88-deficient and WT BALB/c mice were intratracheally challenged with PM2.5 +/- ovalbumin (OVA) four times at 2-week intervals. PM2.5 increased neutrophil numbers and KC in bronchoalveolar lavage fluid and caused slight peribronchiolar inflammation in WT mice. However, these changes were attenuated, but not completely suppressed in gene-deficient mice, especially in MyD88-/- mice. In WT mice, PM2.5 + OVA exacerbated OVA-related lung eosinophilia. This exacerbation includes increase of IL-5, IL-13, eotaxin and MCP-3; infiltration of eosinophils into the airway submucosa; proliferation of goblet cells in the airway epithelium; and the production of antigen-specific IgE and IgG1 in serum. All these effects were stronger in TLR2-/- mice than in TLR4-/- mice. In MyD88-/- mice, this pro-inflammatory mediator-inducing ability was considerably weak and lung pathology was negligible. These results suggest that urban PM2.5 may exacerbate allergic inflammation in the murine lung via a TLR2/TLR4/MyD88-signaling pathway. PM2.5-bound trace microbial elements, such as lipopolysaccharide may be a strong candidate for exacerbation of murine lung eosinophilia.

PM2.5-induced lung inflammation in mice: Differences of inflammatory response in macrophages and type II alveolar cells.

Particulate matter 2.5 (

Differences in allergic inflammatory responses in murine lungs: comparison of PM2.5 and coarse PM collected during the hazy events in a Chinese city.

Urban particulate matter (PM) is associated with an increase in asthma. PM2.5 (

Effects of Fetal Exposure to Asian Sand Dust on Development and Reproduction in Male Offspring.

In recent experimental studies, we reported the aggravating effects of Asian sand dust (ASD) on male reproduction in mice. However, the effects of fetal ASD exposure on male reproduction have not been investigated. The present study investigated the effects of fetal ASD exposure on reproduction in male offspring. Using pregnant CD-1 mice, ASD was administered intratracheally on days 7 and 14 of gestation, and the reproduction of male offspring was determined at 5, 10, and 15 weeks after birth. The secondary sex ratio was significantly lower in the fetal ASD-exposed mice than in the controls. Histologic examination showed partial vacuolation of seminiferous tubules in immature mice. Moreover, daily sperm production (DSP) was significantly less in the fetal ASD-exposed mice than in the controls. DSP in the fetal ASD-exposed mice was approximately 10% less than the controls at both 5 and 10 weeks. However, both the histologic changes and the DSP decrease were reversed as the mice matured. These findings suggest that ASD exposure affects both the fetal development and the reproduction of male offspring. In the future, it will be necessary to clarify the onset mechanisms of ASD-induced male fetus death and male reproductive disorders.

PM2.5 collected in China causes inflammatory and oxidative stress responses in macrophages through the multiple pathways.

Air pollution continues to increase in East Asia, particularly in China, and is considered to cause serious health problems. In this study, we investigated the toxicological properties of particulate matter ≤2.5mm (PM2.5) collected in an urban area in China (Shenyang), focusing on inflammation and oxidative stress tightly linked to respiratory diseases. Exposure to PM2.5 significantly increased the expression levels of inflammatory (interleukin-1ß and cyclooxygenase-2) and oxidative stress (heme oxygenase1) genes in the mouse macrophages. PM2.5-caused inflammatory response was strongly suppressed by endotoxin neutralizer (polymyxin B) and knock-out of toll-like receptor 4, while oxidative stress was not. On the other hand, an antioxidant (N-acetylcystein) suppressed oxidative stress, but not inflammatory response. These results suggest that PM2.5 in the atmospheric environment of China causes inflammation and oxidative stress in macrophages via separate pathways.

Differences in allergic inflammatory responses between urban PM2.5 and fine particle derived from desert-dust in murine lungs.

The biological and chemical natures of materials adsorbed onto fine particulate matter (PM2.5) vary by origin and passage routes. The exacerbating effects of the two samples-urban PM2.5 (U-PM2.5) collected during the hazy weather in a Chinese city and fine particles (ASD-PM2.5) collected during Asian sand dust (ASD) storm event days in Japan-on murine lung eosinophilia were compared to clarify the role of toxic materials in PM2.5. The amounts of ß-glucan and mineral components were higher in ASD-PM2.5 than in U-PM2.5. On the other hand, organic chemicals, including polycyclic aromatic hydrocarbons (PAHs), were higher in U-PM2.5 than in ASD-PM2.5. When BALB/c mice were intratracheally instilled with U-PM2.5 and ASD-PM2.5 (total 0.4 mg/mouse) with or without ovalbumin (OVA), various biological effects were observed, including enhancement of eosinophil recruitment induced by OVA in the submucosa of the airway, goblet cell proliferation in the bronchial epithelium, synergic increase of OVA-induced eosinophil-relevant cytokines and a chemokine in bronchoalveolar lavage fluid, and increase of serum OVA-specific IgG1 and IgE. Data demonstrate that U-PM2.5 and ASD-PM2.5 induced allergic inflammatory changes and caused lung pathology. U-PM2.5 and ASD-PM2.5 increased F4/80(+) CD11b(+) cells, indicating that an influx of inflammatory and exudative macrophages in lung tissue had occurred. The ratio of CD206 positive F4/80(+) CD11b(+) cells (M2 macrophages) in lung tissue was higher in the OVA+ASD-PM2.5 treated mice than in the OVA+U-PM2.5 treated mice. These results suggest that the lung eosinophilia exacerbated by both PM2.5 is due to activation of a Th2-associated immune response along with induced M2 macrophages and the exacerbating effect is greater in microbial element (ß-glucan)-rich ASD-PM2.5 than in organic chemical-rich U-PM2.5.

Desert dust induces TLR signaling to trigger Th2-dominant lung allergic inflammation via a MyD88-dependent signaling pathway.

Asian sand dust (ASD) is known to exacerbate asthma, although its mechanism is not yet well understood. In this study, when the effects on inflammatory response by LPS present in ASD was investigated by measuring the gene expression of cytokines and chemokines in RAW264.7 cells treated with ASD and/or polymyxin B (PMB), the ASD effects were attenuated by PMB, but not completely. When an in vitro study was performed using bone marrow-derived macrophages (BMDMs) from WT, TLR2(-/-), TLR4(-/-), and MyD88(-/-) BALB/c mice and BMDMs from WT, TLR2(-/-), TLR4(-/-), TLR2/4(-/-), TLR7/9(-/-), and MyD88(-/-) C57BL/6J mice, cytokine (IL-6, IL-12) production in BMDMs was higher in ASD-stimulated TLR2(-/-) cells than in TLR4(-/-) cells, whereas it was lower or undetectable in TLR2/4(-/-) and MyD88(-/-) cells. These results suggest that ASD causes cytokine production predominantly in a TLR4/MyD88-dependent pathway. When WT and TLRs 2(-/-), 4(-/-), and MyD88(-/-) BALB/c mice were intratracheally challenged with OVA and/or ASD, ASD caused exacerbation of lung eosinophilia along with Th2 cytokine and eosinophil-relevant chemokine production. Serum OVA-specific IgE and IgG1 similar to WT was observed in TLRs 2(-/-), 4(-/-) mice, but not in MyD88(-/-) mice. The Th2 responses in TLR2(-/-) mice were attenuated remarkably by PMB. These results indicate that ASD exacerbates lung eosinophilia in a MyD88-dependent pathway. TLRs 2 and 4 signaling may be important in the increase in lung eosinophilia. Also, the TLR4 ligand LPS and TLR2 ligand like ß-glucan may be strong candidates for exacerbation of lung eosinophilia.

Spatial correlativity of atmospheric particulate components simultaneously collected in Japan.

The simultaneous sampling of total suspended particles was performed at 14 sites in Japan during July 2008-June 2009. The spatial correlativity of each particulate composition toward Osaka was obtained for nine selected sites to overview the chemical composition and geographical distribution of particulate components across a wide range of areas nationwide. The spatial correlatives of atmospheric particulate components were extended to an even wider range of areas up to 950 km distance (meso-alpha scale region, >200 km) for a far-reaching distance analysis unique in the literature. Overall, the spatial correlations of ionic species and both organic and elemental carbons were significant, suggesting their shared advections, including their long-range transport from East Asia. Although sulfate ions are widely dispersed across Japan, such is not necessarily correlated with organic and elemental carbon, possibly indicating that the sulfate emission source, including long-range transport, differs from that of carbonaceous particulates. By contrast, the characteristics of spatial correlatives of metallic constituents vary; for example, particulate Pb and Cd show a significantly wide range of spatial correlatives to Osaka, while Mn-though limited to cities neighboring Osaka-shows significant spatial correlations. Other metallic constituents showed no significant spatial correlatives, indicating the effects of local pollutants. Moreover, the extent of the spatial dispersion of the particulate components and the relationships among chemical components were analyzed via factor analysis to highlight the effects of long-range inflow and local original emissions. In this treatment, 13 particulate components among the 19 measured were implicated in long-range transport.

PM2.5-rich dust collected from the air in Fukuoka, Kyushu, Japan, can exacerbate murine lung eosinophilia.

PM2.5 can exacerbate asthma. Organic substances adsorbed on PM2.5-rich dust (PM2.5rd) were inactivated by heating at 360 °C. To characterize the role of organic substances, the effects of PM2.5rd and heated PM2.5-rich dust (H-PM2.5 rd) on allergic lung inflammation were investigated. BALB/c mice were intratracheally administered PM2.5rd or H-PM2.5rd with or without ovalbumin (OVA) four times at 2-week intervals. PM2.5rd, but not H-PM2.5rd, caused neutrophilic alveolitis and bronchitis. In the presence of OVA, PM2.5rd caused severe eosinophil infiltration and goblet cells proliferation in airways, along with a marked induction of the Th2 cytokines interleukin (IL)-4 and IL-13, and the eosinophil-related cytokine IL-5 in bronchoalveolar lavage fluid (BALF). OVA + H-PM2.5rd caused a weaker response. PM2.5rd showed adjuvant effects on OVA-specific immunoglobulin E (IgE) and IgG1 production, but H-PM2.5rd showed minimal effects. These findings suggested that PM2.5rd-bound substances might aggravate lung eosinophilia. To clarify the roles of TLR2, TLR4, and MyD88 on cytokine production in PM2.5rd, murine bone marrow-derived macrophages (BMDMs) from wild-type (WT), TLR2(-/-), TLR4(-/-), and MyD88(-/-) BALB/c mice were stimulated with dust. Cytokine production was low or undetectable in TLR4(-/-) cells, but occurred from TLR2(-/-) cells, and production by MyD88(-/-) cells was higher than by TLR4(-/-) cells. These results suggest that TLR4 and TLR2 ligands (LPS and ß-glucan, respectively) mainly contributed to cytokines production induced by PM2.5rd. In addition to chemical substances, PM2.5-bound microbial substances might act in inflammatory and allergic lung diseases.

Prevalence and Characteristics of Chemical Intolerance: A Japanese Population-Based Study.

Population-based cross-sectional study was performed to estimate the prevalence of chemical intolerance and to examine the characteristics of the sample. A Web-based survey was conducted that included 7,245 adults in Japan. The criteria for chemical intolerance proposed by Skovbjerg yielded a prevalence of 7.5% that was approximately consistent with that reported from a Danish population-based survey. Female gender, older age, and renovation in the house during the past 7 years were positively associated with chemical intolerance. Improvements in the condition were observed with daily ventilation habits. Medical history of atopic dermatitis, allergic rhinitis, food allergy, multiple chemical sensitivity, and depression were associated with chemical intolerance. Fatigue, depressed mood, and somatic symptoms were also positively correlated with chemical intolerance. Better elucidation of the causes, comorbidities, concomitants, and consequences of chemical intolerance has the potential to provide effective solutions for its prevention and treatment.

Aggravation of ovalbumin-induced murine asthma by co-exposure to desert-dust and organic chemicals: an animal model study.

BACKGROUND: The organic chemicals present in Asian sand dust (ASD) might contribute to the aggravation of lung eosinophila. Therefore, the aggravating effects of the Tar fraction from ASD on ovalbumin (OVA)-induced lung eosinophilia were investigated. METHODS: The Tar fraction was extracted from ASD collected from the atmosphere in Fukuoka, Japan. ASD collected from the Gobi desert was heated at 360°C to inactivate toxic organic substances (H-ASD). ICR mice were instilled intratracheally with 12 different test samples prepared with Tar (1 µg and 5 µg), H-ASD, and OVA in a normal saline solution containing 0.02% Tween 80. The lung pathology, cytological profiles in the bronchoalveolar lavage fluid (BALF), inflammatory cytokines/chemokines in BALF and OVA-specific immunoglobulin in serum were investigated. RESULTS: Several kinds of polycyclic aromatic hydrocarbons (PAHs) were detected in the Tar sample. H-ASD + Tar 5 µg induced slight neutrophilic lung inflammation. In the presence of OVA, Tar 5 µg increased the level of eosinophils slightly and induced trace levels of Th2 cytokines IL-5 and IL-13 in BALF. Also mild to moderate goblet cell proliferation and mild infiltration of eosinophils in the submucosa of airway were observed. These pathological changes caused by H-ASD + OVA were relatively small. However, in the presence of OVA and H-ASD, Tar, at as low a level as 1 µg, induced severe eosinophil infiltration and proliferation of goblet cells in the airways and significantly increased Th2 cytokines IL-5 and IL-13 in BALF. The mixture showed an adjuvant effect on OVA-specific IgG1 production. CONCLUSIONS: These results indicate that H-ASD with even low levels of Tar exacerbates OVA-induced lung eosinophilia via increases of Th2-mediated cytokines. These results suggest that ASD-bound PAHs might contribute to the aggravation of lung eosinophila.

Lung inflammation by fungus, Bjerkandera adusta isolated from Asian sand dust (ASD) aerosol and enhancement of ovalbumin-induced lung eosinophilia by ASD and the fungus in mice.

BACKGROUND: Bjerkandera adusta (B. adusta) is one of the most important etiological fungi associated with chronic cough. However, precise details of the inflammatory response to exposure are not well understood yet. B. adusta was recently identified in Asian sand dust (ASD) aerosol. Therefore, in the present study the exacerbating effects of ASD on B. adusta-induced lung inflammation and B. adusta + ASD on ovalbumin (OVA)-induced murine lung eosinophilia were investigated using experimental mice. METHODS: In order to prepare testing samples, B. adusta obtained from ASD aerosol was inactivated by formalin and ASD collected from the atmosphere was heated to remove toxic organic substances (H-ASD). CD-1 mice were instilled intratracheally with 12 different samples prepared with various combinations of B. adusta, H-ASD, and OVA in a normal saline solution. The lung pathology, cytological profiles in bronchoalveolar lavage fluid (BALF), and the levels of inflammatory cytokines/chemokines in BALF were investigated. RESULTS: H-ASD aggravated the lung eosinophilia induced by B. adusta alone, which also aggravated the lung eosinophilia induced by OVA. The mixture of OVA, H-ASD, and B. adusta caused serious fibrous thickening of the subepithelial layer, eosinophil infiltration, and proliferation of goblet cells in the airways along with remarkable increases of IL-13, eotaxin, IL-5, and MCP-3 in BALF. CONCLUSIONS: The results of the present study demonstrated that B. adusta isolated from ASD aerosol induces allergic lung diseases. H-ASD enhanced allergic reactions caused by OVA or B. adusta. A mixture of B. adusta, H-ASD, and OVA caused the most remarkable exacerbation to the allergic airway inflammation via remarkable increases of pro-inflammatory mediators.

Indoor volatile organic compounds and chemical sensitivity reactions.

Studies of unexplained symptoms observed in chemically sensitive subjects have increased the awareness of the relationship between neurological and immunological diseases due to exposure to volatile organic compounds (VOCs). However, there is no direct evidence that links exposure to low doses of VOCs and neurological and immunological dysfunction. We review animal model data to clarify the role of VOCs in neuroimmune interactions and discuss our recent studies that show a relationship between chronic exposure of C3H mice to low levels of formaldehyde and the induction of neural and immune dysfunction. We also consider the possible mechanisms by which VOC exposure can induce the symptoms presenting in patients with a multiple chemical sensitivity.

Effects of two Asian sand dusts transported from the dust source regions of Inner Mongolia and northeast China on murine lung eosinophilia.

The quality and quantity of toxic materials adsorbed onto Asian sand dust (ASD) are different based on dust source regions and passage routes. The aggravating effects of two ASDs (ASD1 and ASD2) transported from the source regions of Inner Mongolia and northeast China on lung eosinophilia were compared to clarify the role of toxic materials in ASD. The ASDs contained different amounts of lipopolysaccharides (LPS) and ß-glucan (ASD1ASD2). CD-1 mice were instilled intratracheally with ASD1, ASD2 and/or ovalbumin (OVA) four times at 2-week intervals. ASD1 and ASD2 enhanced eosinophil recruitment induced by OVA in the submucosa of the airway, with goblet cell proliferation in the bronchial epithelium. ASD1 and ASD2 synergistically increased OVA-induced eosinophil-relevant cytokines interleukin-5 (IL-5), IL-13 (ASD1ASD2) in bronchoalveolar lavage fluid. ASD2 aggravating effects on lung eosinophilia were greater than ASD1. The role of LPS and ß-glucan in ASD2 on the production of pro-inflammatory mediators was assessed using in vitro bone marrow-derived macrophages (BMDMs) from wild type, Toll-like receptor 2-deficient (TLR2-/-), TLR4-/-, and MyD88-/- mice (on Balb/c background). ASD2-stimulated TLR2-/- BMDMs enhanced IL-6, IL-12, TNF-α, MCP-1 and MIP-1α secretion compared with ASD2-stimulated TLR4-/- BMDMs. Protein expression from ASD2-stimulated MyD88-/- BMDM were very low or undetectable. The in vitro results indicate that lung eosinophilia caused by ASD is TLR4 dependent. Therefore, the aggravation of OVA-related lung eosinophilia by ASD may be dependent on toxic substances derived from microbes, such as LPS, rather than SiO2.

Intratracheal administration of fullerene nanoparticles activates splenic CD11b+ cells.

Fullerene nanoparticles ("Fullerenes"), which are now widely used materials in daily life, have been demonstrated to induce elevated pulmonary inflammation in several animal models; however, the effects of fullerenes on the immune system are not fully understood. In the present study, mice received fullerenes intratracheally and were sacrificed at days 1, 6 and 42. Mice that received fullerenes exhibited increased proliferation of splenocytes and increased splenic production of IL-2 and TNF-α. Changes in the spleen in response to fullerene treatment occurred at different time-points than in the lung tissue. Furthermore, fullerenes induced CDK2 expression and activated NF-κB and NFAT in splenocytes at 6 days post-administration. Finally, CD11b(+) cells were demonstrated to function as responder cells to fullerene administration in the splenic inflammatory process. Taken together, in addition to the effects on pulmonary responses, fullerenes also modulate the immune system.

Dysregulation of immune responses in an allergic mouse model following low-level toluene exposure.

To investigate the effect of low-level toluene inhalation on immune regulation in an allergic mouse model, C3H/HeN mice were exposed to 0, 5, 50, or 500ppm of toluene for 6h/day, 5 days/week for 3 or 6 weeks. For allergic mouse model, half of the mice in each group were immunized with ovalbumin (OVA). Allergic mice exposed to toluene for 3 weeks did not exhibit any changes in their plasma, lung or spleen samples. Although exposure to toluene alone for 6 weeks did not increase the number of inflammatory cells in bronchoalveolar lavage (BAL) fluid, coexposure to 50ppm toluene and OVA increased the number of BAL cells. Histological changes and increased amounts of fibronectin were observed in the lungs of OVA-immunized, 50-ppm-toluene-exposed mice. Exposure to 500ppm significantly increased the expressions of transcription factors STAT3, STAT4 and STAT5a mRNAs in spleen. In spleens from the allergic mouse model, the expressions of STAT3, STAT4, STAT5a, STAT6, GATA3 and Foxp3 mRNAs were significantly enhanced following exposure to 50ppm toluene for 6 weeks, but the expression of T-bet mRNA was not increased. Regarding the Th1/Th2 balance, the expressions of IL-4 and IL-12 mRNAs were enhanced in the spleens of toluene-exposed mice. Total IgG1 antibody production in the plasma was significantly increased in the 50-ppm-toluene-exposed allergic mouse model. These results indicate that low-level toluene exposure might dysregulate the allergic responses to OVA in C3H/HeN mice.

Modification of the relationship between urinary 8-OHdG and hippuric acid concentration by GSTM1, GSTT1, and ALDH2 genotypes.

Urinary hippuric acid (HA) has been widely used as a biological marker of occupational exposure to toluene, although it is no longer valid for low levels of toluene exposure. Toluene exposure is known to induce oxidative DNA damage and the metabolism is affected by genetic polymorphisms of some metabolizing enzymes. Therefore, genetic polymorphisms of these metabolizing enzymes must be considered in the evaluation of oxidative stress caused by toluene exposure. We evaluated the relationship between urinary 8-hydroxydeoxyguanosine (8-OHdG), a marker of oxidative DNA damage, and urinary HA in individuals without occupational exposure to toluene and characterized the possible roles of GSTM1, GSTT1, and aldehyde dehydrogenase 2 (ALDH2) genotypes in the relationships between these markers. In this study, we enrolled 92 healthy Koreans. Urinary HA and 8-OHdG levels were measured and the correlations between them were statistically tested according to the GSTM1, GSTT1, and ALDH2 genotypes. HA did not significantly correlate with urinary 8-OHdG in overall subjects. However, the correlation between them showed a statistical significance in individuals with GSTM1-null, GSTT1-null, and ALDH2 *2/*2 genotypes (r = 0.766, p < 0.01). This study shows that the relationship between urinary HA and 8-OHdG concentration is modified by genetic polymorphisms of some metabolizing enzymes such as GSTM1, GSTT1, and ALDH2.

Thymocytes are activated by toluene inhalation through the transcription factors NF-κB, STAT5 and NF-AT.

Toluene has been extensively examined for effects on the central nervous system. To investigate the influence of low-level inhalation of toluene on the naive immune cells, male C3H/HeN mice were exposed to filtered air (control) and 50 ppm of toluene for 3 weeks. Low-level exposure resulted in (1) increased proliferation of thymocytes, (2) IL-2 production induced in thymocytes and (3) activation of the transcription factors NF-κB, STAT5 and NF-AT in thymocytes. These results suggest that thymocytes are sensitive cells and T cell activators are candidates for biomarkers for low-level exposure to toluene on naive immune cells.