Occupational exposure to diesel engine exhaust and serum levels of microRNAs in a cross-sectional molecular epidemiology study in China

Diesel engine exhaust (DEE) is an established lung carcinogen, but the biological mechanisms of diesel-induced lung carcinogenesis are not well understood. MicroRNAs (miRNAs) are small noncoding RNAs that play a potentially important role in regulating gene expression related to lung cancer. We conducted a cross-sectional molecular epidemiology study to evaluate whether serum levels of miRNAs are altered in healthy workers occupationally exposed to DEE compared to unexposed controls. We conducted a two-stage study, first measuring 405 miRNAs in a pilot study of six DEE-exposed workers exposed and six controls. In the second stage, 44 selected miRNAs were measured using the Fireplex circulating miRNA assay that profiles miRNAs directly from biofluids of 45 workers exposed to a range of DEE (Elemental Carbon (EC), median, range: 47.7, 6.1–79.7 μg/m³) and 46 controls. The relationship between exposure to DEE and EC with miRNA levels was analyzed using linear regression adjusted for potential confounders. Serum levels of four miRNAs were significantly lower (miR-191-5p, miR-93-5p, miR-423-3p, miR-122-5p) and one miRNA was significantly higher (miR-92a-3p) in DEE exposed workers compared to controls. Of these miRNAs, miR-191-5p (p_trend = .001, FDR = 0.04) and miR-93-5p (p_trend = .009, FDR = 0.18) showed evidence of an inverse exposure–response with increasing EC levels. Our findings suggest that occupational exposure to DEE may affect circulating miRNAs implicated in biological processes related to carcinogenesis, including immune function.     

Effect of prenatal exposure to diesel exhaust on dopaminergic system in mice

Diesel exhaust (DE) is composed of particles and gaseous compounds. It has been reported that DE causes pulmonary and cardiovascular disease. We have previously reported that fetal exposure to DE had deleterious effects to the reproductive system of mice offspring. However, there is still little known about the effects of prenatal exposure to DE to the central nervous system (CNS). In the present study, we found that prenatal exposure to DE induced reduction of locomotion, furthermore, dopamine (DA) turnover was significantly decreased in the striatum and nucleus accumbens. These results suggest that prenatal exposure to DE has an effect on the CNS. Hypolocomotion could be due to a decrease in DA turnover associated with DA nervous system abnormality. The present study provides the possibility that maternally inhaled DE might influence the development of central dopaminergic system and result in behavior disorder.     

Nrf2 is closely related to allergic airway inflammatory responses induced by low-dose diesel exhaust particles in mice

We have recently reported that disruption of nuclear erythroid 2 P45-related factor 2 (Nrf2) enhances susceptibility to airway inflammatory responses induced by low-dose diesel exhaust particles (DEP) in mice. C57BL/6 Nrf2 knockout (Nrf2^−/−) mice and wild-type (Nrf2^+/+) mice were further exposed to low-dose DEP for 7 h/day, 5 days/week, for a maximum of 8 weeks. After exposure to DEP for 5 weeks, allergic airway inflammation was generated in the mice by intraperitoneal sensitization with OVA followed by intranasal challenge. Nrf2^−/− mice exposed to relatively low-dose DEP showed significantly increased percentage changes relative to the OVA alone group in terms of airway hyperresponsiveness (AHR) and inflammatory cells, levels of IL-5 and thymus and activation regulated chemokine (TARC) in bronchoalveolar lavage (BAL) fluid than did Nrf2^+/+ mice. Lung tissues of Nrf2^−/− mice after DEP exposure showed inflammatory cell infiltrates, and increased PAS staining-positive mucus cell hyperplasia. In contrast, the percentage changes relative to the OVA group in the reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio in whole blood was higher in Nrf2^+/+ mice than in Nrf2^−/− mice. By using Nrf2^−/− mice, it was shown for the first time that relatively low-dose DEP exposure induces oxidant stress, and that host anti-oxidant responses play a key role in the development of DEP-induced exacerbation of allergic airway inflammation.     

Major grass pollen allergen Lol p 1 binds to diesel exhaust particles: implications for asthma and air pollution

Background Grass pollen allergens are known to be present in the atmosphere in a range of particle sizes from whole pollen grains (approx. 20 to 55 μim in diameter) to smaller size fractions < 2.5 μ (fine particles, PM2.5). These latter particles are within the respirable range and include allergen-containing starch granules released from within the grains into the atmosphere when grass pollen ruptures in rainfall and are associated with epidemics of thunderstorm asthma during the grass pollen season. The question arises whether grass pollen allergens can interact with other sources of fine particles, particularly those present during episodes of air pollution. Objective We propose the hypothesis that free grass pollen allergen molecules, derived from dead or burst grains and dispersed in microdroplets of water in aerosols, can bind to fine particles in polluted air. Methods We used diesel exhaust carbon particles (DECP) derived from the exhaust of a stationary diesel engine, natural highly purified Lol p 1, immunogold labelling with specific monoclonal antibodies and a high voltage transmission electron -microscopic imaging technique Results DECP are visualized as small carbon spheres, each 30–60 nm in diameter, forming fractal aggregates about 1–2μ in diameter. Here we test our hypothesis and show by in vitro experiments that the major grass pollen allergen, Lol p I. binds to one defined class of fine particles, DECP. Conclusion DECP are in the respirable size range, can bind to the major grass pollen allergen Lol p I under in vitro conditions and represent a possible mechanism by which allergens can become concentrated in polluted air and thus trigger attacks of asthma.     

The influence of genetic polymorphisms in XRCC3 and ADH5 genes on the frequency of genotoxicity biomarkers in workers exposed to formaldehyde

The International Agency for Research on Cancer classified formaldehyde as carcinogenic to humans because there is “sufficient epidemiological evidence that it causes nasopharyngeal cancer in humans”. Genes involved in DNA repair and maintenance of genome integrity are critically involved in protecting against mutations that lead to cancer and/or inherited genetic disease. Association studies have recently provided evidence for a link between DNA repair polymorphisms and micronucleus (MN) induction. We used the cytokinesis‐block micronucleus (CBMN assay) in peripheral lymphocytes and MN test in buccal cells to investigate the effects of XRCC3 Thr241Met, ADH5 Val309Ile, and Asp353Glu polymorphisms on the frequency of genotoxicity biomarkers in individuals occupationally exposed to formaldehyde (n = 54) and unexposed workers (n = 82). XRCC3 participates in DNA double‐strand break/recombination repair, while ADH5 is an important component of cellular metabolism for the elimination of formaldehyde. Exposed workers had significantly higher frequencies (P < 0.01) than controls for all genotoxicity biomarkers evaluated in this study. Moreover, there were significant associations between XRCC3 genotypes and nuclear buds, namely XRCC3 Met/Met (OR = 3.975, CI 1.053–14.998, P = 0.042) and XRCC3 Thr/Met (OR = 5.632, CI 1.673–18.961, P = 0.005) in comparison with XRCC3 Thr/Thr. ADH5 polymorphisms did not show significant effects. This study highlights the importance of integrating genotoxicity biomarkers and genetic polymorphisms in human biomonitoring studies. Environ. Mol. Mutagen. 54:213–221, 2013. © 2013 Wiley Periodicals, Inc.     

Effect of topical fluticasone propionate on the mucosal allergic response induced by ragweed allergen and diesel exhaust particle challenge

Glucocorticoids block the local allergic response in a variety of ways. However, studies have also shown that glucocorticoids increase in vitro IgE synthesis and that treatment with corticosteroids may result in elevated serum IgE concentrations. The ability of topical glucocorticoids to modulate the mucosal IgE response has not been elucidated. We studied the effect of topical steroid (fluticasone propionate) treatment on the local allergic antibody response induced by challenge with either allergen or diesel exhaust particles (DEP). A parallel group study was performed with ragweed-allergic subjects, each subject serving as his/her own control. Nasal provocation challenges were performed on three groups. One group received ragweed allergen, another diesel exhaust particles, and the third saline. The study was repeated following 1 week of treatment with intranasal fluticasone propionate. Each group received the same challenge as before. The concentrations of total immunoglobulins (IgE, IgG, IgA, and IgM), anti-ragweed antibody, IgE- and IgA-secreting cells, epsilon (epsilon) mRNA, and cytokine mRNAs (IL-2, -4, -5, -6, TNF-alpha, INF-gamma) were measured in nasal lavages performed before and at various time points after challenge. Treatment with fluticasone propionate for 7 days caused a decrease in the concentrations of nasal IgE protein, IgE-producing cells, total epsilon mRNA, and all the cytokine mRNAs tested. Furthermore, treatment with fluticasone propionate inhibited the production of allergen-specific IgE and cytokine mRNAs following challenge with ragweed antigen. However, fluticasone treatment did not significantly inhibit the enhancement of mucosal IgE production or cytokine mRNAs observed following nasal challenge with DEP. These results indicate that 1-week treatment with topical fluticasone propionate was effective in blocking local effects of allergen exposure but was unable to inhibit the adjuvant-like effect of DEP.     

Gas,dust, and fumes exposure is associated with mite sensitization and with asthma in mite‐sensitized adults

Occupational exposure to gas, dust, and fumes (GDF) increases the risk of asthma and eczema. We investigated the role of sensitization in the association between GDF and allergic conditions. A population‐based sample of 788 adults from the West Sweden Asthma Study completed questionnaires and skin prick tests. After adjustment for confounders, GDF exposure was associated with a doubled risk of sensitization to mites, but not with other allergens. Mite sensitization also modified the effect of GDF on asthma. In mite‐sensitized subjects, GDF was associated with physician‐diagnosed asthma, adjusted OR 2.9 (1.2–7.2), and with wheeze, OR 2.4 (1.1–5.3). In non‐mite‐sensitized subjects, the corresponding ORs were 1.1 (0.5–2.6) and 0.6 (0.3–1.3). GDF was independently associated with eczema regardless of mite sensitization, but not with rhinitis. These novel findings suggest that components of GDF may act as adjuvants that facilitate sensitization to mites and that mite‐sensitized individuals may be especially susceptible to inhalant occupational exposures.     

Occupational exposure to trichloroethylene and serum concentrations of IL‐6, IL‐10, and TNF‐alpha

To evaluate the immunotoxicity of trichloroethylene (TCE), we conducted a cross‐sectional molecular epidemiology study in China of workers exposed to TCE. We measured serum levels of IL‐6, IL‐10, and TNF‐α, which play a critical role in regulating various components of the immune system, in 71 exposed workers and 78 unexposed control workers. Repeated personal exposure measurements were taken in workers before blood collection using 3 M organic vapor monitoring badges. Compared to unexposed workers, the serum concentration of IL‐10 in workers exposed to TCE was decreased by 70% (P = 0.001) after adjusting for potential confounders. Further, the magnitude of decline in IL‐10 was >60% and statistically significant in workers exposed to <12 ppm as well as in workers with exposures ≥ 12 ppm of TCE, compared to unexposed workers. No significant differences in levels of IL‐6 or TNF‐α were observed among workers exposed to TCE compared to unexposed controls. Given that IL‐10 plays an important role in immunologic processes, including mediating the Th1/Th2 balance, our findings provide additional evidence that TCE is immunotoxic in humans. Environ. Mol. Mutagen. 54:450–454, 2013. © 2013 Wiley Periodicals, Inc.     

阳山县医务人员艾滋病职业暴露知识与锐器刺伤状况调查

目的了解阳山县医务人员对艾滋病职业暴露知识的知晓程度和医护过程中锐器刺伤暴露情况。方法采用整群抽样方法选择阳山县3间县级医院及5间乡镇卫生院,于2008年9月对其572名医务人员进行问卷调查。结果572名医务人员艾滋病职业暴露相关知识总体知晓率为59.03%,其中对艾滋病的传播途径知晓率最高为98.78%;不同医院级别、职业、职称和科室之间医务人员以及是否曾参加过相关培训者掌握艾滋病职业暴露相关知识的程度有不同（P〈0.05）;37.24%的调查对象承认在医疗护理过程中曾经被针具利器刺破皮肤经历,不同职业、职称和科室之间医务人员职业暴露发生率不同（P〈0.05）。结论阳山县医务人员对艾滋病职业暴露相关知识掌握较差,发生锐器刺伤等的职业暴露率较高,有必要加强培训,提高医务人员艾滋病职业暴露相关知识和自我防护能力。     

Differences between cytokine release from bronchial epithelial cells of asthmatic patients and non-asthmatic subjects: effect of exposure to diesel exhaust particles

BACKGROUND: Recent evidence suggests that the airways of asthmatics are more susceptible to adverse effects of air pollutants than the airways of non-asthmatics, but the underlying mechanisms are not clear. METHODS: We have cultured bronchial epithelial cells (HBEC) from biopsies of atopic mild asthmatic patients and non-atopic non-asthmatic subjects, and investigated constitutive and diesel exhaust particles (DEP)-induced release of several pro-inflammatory mediators. RESULTS: HBEC of asthmatic patients constitutively released significantly greater amounts of IL-8, GM-CSF and sICAM-1 than HBEC of non-asthmatic subjects. RANTES was only released by HBEC of asthmatic patients. Incubation of the asthmatic cultures with 10 micrograms/ml DEP significantly increased the release of IL-8, GM-CSF and sICAM-1 after 24 h. In contrast, only the higher concentrations of 50-100 micrograms/ml DEP significantly increased the release of IL-8 and GM-CSF from HBEC of non-asthmatics. CONCLUSIONS: These results suggest that the increased sensitivity of the airways of asthmatics to air pollutants such as DEP may, at least in part, be a consequence of greater constitutive and pollutant-induced release of specific pro-inflammatory mediators from their bronchial epithelial cells.     

Effects of occupational exposure to carbon black on peripheral white blood cell counts and lymphocyte subsets

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

BER gene polymorphisms (OGG1 Ser326Cys and XRCC1 Arg194Trp) and modulation of DNA damage due to pesticides exposure

The susceptibility of individuals to the genotoxic effect of pesticides can be modulated by genetic variations in the xenobiotic detoxification and DNA repair processes. This study evaluates if the two BER polymorphisms (XRCC1Arg194Trp and OGG1Ser326Cys) or the combined genotypes of these polymorphisms with PON1Gln192Arg could modify individual susceptibility to pesticide exposure in vineyard workers, as measured by micronucleus formation and DNA damage induction in peripheral leukocytes. The study population comprised 108 agricultural workers exposed to pesticides and 65 nonexposed. Our results demonstrate that individuals with the variant allele (OGG1Cys) showed higher DNA damage, detected by the comet assay, in relation to individuals carrying the wild‐type OGG1Ser allele. Considering the combined influence of metabolizing PON1 and the DNA repair OGG1 genes, we observed significantly higher DNA damage in the comet assay in the exposed group when a less efficient OGG1Cys allele was acting independently of the PON1 genotype, reinforcing the importance of the OGG1 repair enzyme in the response to DNA damage by pesticide exposure. The association of the PONGln/Gln genotype with higher MN frequency suggests that the PON1 genotype is a major determinant of genotoxic risk in individuals exposed to pesticides. Analysis of the compared effect of XRCC1 and PON1 genotypes in the exposed group suggested that, among the poorly metabolizing PON1Gln/Gln individuals, the XRCC1Arg/Trp genotype has a protective effect with respect to MN formation. These results indicate that enhanced XRCC1 function may provide some protection from the enhanced genotoxic risk associated with inefficient xenobiotic detoxification in the studied population. Environ. Mol. Mutagen. 52:20–27, 2011. © 2010 Wiley‐Liss, Inc.     

Chromosome aberration,sister-chromatid exchange,proliferative rate index,and serum thiocyanate concentration in smokers exposed to low-dose benzene

Cytogenetical endpoints, i.e., chromosome aberration (CA), sister-chromatid exchange (SCE), and proliferative rate indexes (PRI), were measured in peripheral blood lymphocytes (PBL) of 42 workers exposed occupationally to low-dose benzene, and of 42 controls. The role of smoking habit as a confounding factor of genotoxic effects caused by occupational low-dose benzene exposure was also studied. The benzene concentrations in the ambient air samples varied from 3 to 20 mg/m³ (mean: 7 mg/m³). The continuous low-dose benzene exposure significantly increased the CA and SCE frequencies, but did not influence PRI. Smoking levels were characterized by subjective accounts and by serum thiocyanate concentrations (SCN). CA and SCE were not significantly increased in smokers compared to nonsmokers, but the differences were expressed to a greater extent in the case of measurement of SCN concentrations. Determination of SCN proved to be more objective in the assessment of genotoxic effects of smoking as a confounding factor of occupational low-dose benzene exposure. © 1994 Wiley-Liss, Inc.     

Asthma and exposure to cleaning products – a European Academy of Allergy and Clinical Immunology task force consensus statement

Professional and domestic cleaning is associated with work‐related asthma (WRA). This position paper reviews the literature linking exposure to cleaning products and the risk of asthma and focuses on prevention. Increased risk of asthma has been shown in many epidemiological and surveillance studies, and several case reports describe the relationship between exposure to one or more cleaning agents and WRA. Cleaning sprays, bleach, ammonia, disinfectants, mixing products, and specific job tasks have been identified as specific causes and/or triggers of asthma. Because research conclusions and policy suggestions have remained unheeded by manufactures, vendors, and commercial cleaning companies, it is time for a multifaceted intervention. Possible preventive measures encompass the following: substitution of cleaning sprays, bleach, and ammonia; minimizing the use of disinfectants; avoidance of mixing products; use of respiratory protective devices; and worker education. Moreover, we suggest the education of unions, consumer, and public interest groups to encourage safer products. In addition, information activities for the general population with the purpose of improving the knowledge of professional and domestic cleaners regarding risks and available preventive measures and to promote strict collaboration between scientific communities and safety and health agencies are urgently needed.     

Induction of germline-length mutations at the minisatellites PC-1 and PC-2 in male mice exposed to polychlorinated biphenyls and diesel exhaust emissions

PC-1 and PC-2 are hypervariable mouse minisatellites. The rates of spontaneous germline-length mutation have been shown to vary between different mouse strains. PC-1 is composed of GGCAG repeat units and PC-2 of GGCAGGA. Minisatellites frequently mutate by gaining or losing repeat units. Such length mutations in mini- and microsatellites have been associated with human disease and may therefore be an important endpoint in genetic toxicity testing. Carcinogenic activity of many chemicals is associated with their ability to induce heritable mutations. Since minisatellites are highly prone to mutate to new lengths, which can be assayed by Southern analysis, we used this method to detect heritable genetic effects in mice. Male mice exposed to diesel exhausts and/or polychlorinted biphenyls (PCB) were investigated for effects on the germline mutation frequenallele lengths in parents and offspring. For PC-1 significantly higher mutation frequencies were found in males treated with diesel exhausts + PCB (6 of 35 alleles) and with PCB alone (6 of 51 alleles) as compared to the males in the control group (0 of 43 alleles). The mutation frequency in the diesel exhaust group was not significantly increased (2 of 43 alleles). For PC-2 the only mutation found occurred in the PCB group (1 of 51 alleles). This in vivo study demonstrates—for the first time—chemically induced minisatellite mutations in the germline. Environ. Mol. Mutagen. 30:254–259, 1997 © 1997 Wiley-Liss, Inc.     

Abnormalities in the male reproductive system after exposure to diesel and biodiesel blend

Altering the fuel source from petroleum‐based ultralow sulfur diesel to biodiesel and its blends is considered by many to be a sustainable choice for controlling exposures to particulate material. As the exhaust of biodiesel/diesel blends is composed of a combination of combustion products of polycyclic aromatic hydrocarbons and fatty acid methyl esters, we hypothesize that 50% biodiesel/diesel blend (BD50) exposure could induce harmful outcomes because of its ability to trigger oxidative damage. Here, adverse effects were compared in murine male reproductive organs after pharyngeal aspiration with particles generated by engine fueled with BD50 or neat petroleum diesel (D100). When compared with D100, exposure to BD50 significantly altered sperm integrity, including concentration, motility, and morphological abnormalities, as well as increasing testosterone levels in testes during the time course postexposure. Serum level of luteinizing hormone was significantly depleted only after BD50 exposure. Moreover, we observed that exposure to BD50 significantly increased sperm DNA fragmentation and the upregulation of inflammatory cytokines in the serum and testes on Day 7 postexposure when compared with D100. Histological evaluation of testes sections from BD50 exposure indicated more noticeable interstitial edema, degenerating spermatocytes, and dystrophic seminiferous tubules with arrested spermatogenesis. Significant differences in the level of oxidative stress assessed by accumulation of lipid peroxidation products and depletion of glutathione were detected on exposure to respirable BD50 and D100. Taken together, these results indicate that exposure of mice to inhalable BD50 caused more pronounced adverse effects on male reproductive function than diesel. Environ. Mol. Mutagen. 56:265–276, 2015. © 2014 Wiley Periodicals, Inc.