Faculty Bibliography

BACKGROUND: Occupational exposure to nickel (Ni) is associated with an increased risk of lung and nasal cancers. Ni compounds exhibit weak mutagenic activity, alter the cell's epigenetic homeostasis, and activate signaling pathways. However, changes in gene expression associated with Ni exposure have only been investigated in vitro. This study was conducted in a Chinese population to determine whether occupational exposure to Ni was associated with differential gene expression profiles in the peripheral blood mononuclear cells (PBMC) of Ni-refinery workers when compared with referents. METHODS: Eight Ni-refinery workers and ten referents were selected. PBMC RNA was extracted and gene expression profiling was conducted using Affymetrix exon arrays. Differentially expressed genes (DEG) between both groups were identified in a global analysis. RESULTS: There were a total of 2,756 DEGs in the Ni-refinery workers relative to the referents [false discovery rate (FDR) adjusted P < 0.05] with 770 upregulated genes and 1,986 downregulated genes. DNA repair and epigenetic genes were significantly overrepresented (P < 0.0002) among the DEGs. Of 31 DNA repair genes, 29 were repressed in the Ni-refinery workers and 2 were overexpressed. Of the 16 epigenetic genes, 12 were repressed in the Ni-refinery workers and 4 were overexpressed. CONCLUSIONS: The results of this study indicate that occupational exposure to Ni is associated with alterations in gene expression profiles in PBMCs of subjects. Impact: Gene expression may be useful in identifying patterns of deregulation that precede clinical identification of Ni-induced cancers. Cancer Epidemiol Biomarkers Prev; 22(2); 261-9. (c)2012 AACR.

Exposure to ambient fine particulate matter (PM2.5) increases risks for cardiovascular disorders (CVD). However, the mechanisms and components responsible for the effects are poorly understood. Based on our previous murine exposure studies, a translational pilot study was conducted in female residents of Jinchang and Zhangye, China, to test the hypothesis that specific chemical component of PM2.5 is responsible for PM2.5 associated CVD. Daily ambient and personal exposures to PM2.5 and 35 elements were measured in the two cities. A total of 60 healthy nonsmoking adult women residents were recruited for measurements of inflammation biomarkers. In addition, circulating endothelial progenitor cells (CEPCs) were also measured in 20 subjects. The ambient levels of PM2.5 were comparable between Jinchang and Zhangye (47.4 and 54.5microg/m(3), respectively). However, the levels of nickel, copper, arsenic, and selenium in Jinchang were 82, 26, 12, and 6 fold higher than Zhangye, respectively. The levels of C-reactive protein (3.44+/-3.46 vs. 1.55+/-1.13), interleukin-6 (1.65+/-1.17 vs. 1.09+/-0.60), and vascular endothelial growth factor (117.6+/-217.0 vs. 22.7+/-21.3) were significantly higher in Jinchang. Furthermore, all phenotypes of CEPCs were significantly lower in subjects recruited from Jinchang than those from Zhangye. These results suggest that specific metals may be important components responsible for PM2.5-induced cardiovascular effects and that the reduced capacity of endothelial repair may play a critical role.

Many studies have linked ambient fine particulate matter (aerodynamic diameters less than 2.5mum, PM(2.5)) air pollution to increased morbidity and mortality of cardiovascular diseases in the general population, but the biologic mechanisms of these associations are yet to be elucidated. In this study, we aimed to evaluate the relationship between daily variations in exposure to PM(2.5) and inflammatory responses in mice during and for 2 months after the Beijing Olympic Games. Male C57BL/6 mice were exposed to Beijing PM(2.5) or filtered air (FA) in 2008 during the 2 months of Beijing Olympic and Paralympic Games, and for 2 months after the end of the Games. During the Games, circulating monocyte chemoattractant protein 1 and interleukin 6 were increased significantly in the PM(2.5) exposure group, when compared with the FA control group, although there were no significant inter-group differences in tumor necrosis factor-alpha or interferon-gamma, or in macrophages, neutrophils or lymphocytes in the spleen or thymus between these 2 groups. However, macrophages were significantly increased in the lung and visceral fat with increasing PM(2.5). After the Olympic Games, there were no significant PM(2.5)-associated differences for macrophages, neutrophils or lymphocytes in the thymus, but macrophages were significantly elevated in the lung, spleen, subcutaneous and visceral fat with increasing PM(2.5), and the numbers of macrophages were even higher after than those during the Games. Moreover, the number of neutrophils was markedly higher in the spleen for the PM(2.5)-exposed- than the FA-group. These data suggest that short-term increases in exposure to ambient PM(2.5) leads to increased systemic inflammatory responses, primarily macrophages and neutrophils in the lung, spleen, and visceral adipose tissue. Short-term air quality improvements were significantly associated with reduced overall inflammatory responses.

The precise mechanisms by which nickel and arsenic compounds exert their carcinogenic properties are not completely understood. In recent years, alterations of epigenetic mechanisms have been implicated in the carcinogenesis of compounds of these two metals. In vitro exposure to certain nickel or arsenic compounds induces changes in both DNA methylation patterns, as well as, in the levels of posttranslational modifications of histone tails. Changes in DNA methylation patterns have been reported in human subjects exposed to arsenic. Here we review our recent reports on the alterations in global levels of posttranslational histone modifications in peripheral blood mononuclear cells (PBMCs) of subjects with occupational exposure to nickel and subjects exposed to arsenic in their drinking water. Occupational exposure to nickel was associated with an increase in H3K4me3 and decrease in H3K9me2. A global increase in H3K9me2 and decrease in H3K9ac was found in subjects exposed to arsenic. Additionally, exposure to arsenic resulted in opposite changes in a number of histone modifications in males when compared with females in the arsenic population. The results of these two studies suggest that exposure to nickel or arsenic compounds, and possibly other carcinogenic metal compounds, can induce changes in global levels of posttranslational histone modifications in peripheral blood mononuclear cells.

Background: Occupational exposure to nickel is associated with an increased risk for lung and nasal cancers. Nickel compounds exhibit weak mutagenic activity, cause gene amplification, and disrupt cellular epigenetic homeostasis. However, the nickel-induced changes in global histone modification levels have only been tested in vitro. Objective: This study was conducted in a Chinese population to determine whether occupational exposure to nickel is associated with alterations of global histone modification levels and to evaluate the inter-and intra-individual variance of global histone modification levels. Method: 45 subjects with occupational exposure to nickel and 75 referents were recruited. Urinary nickel and global H3K4 trimethylation (H3K4me3), H3K9 acetylation (H3K9ac), and H3K9 dimethylation (H3K9me2) levels were measured in peripheral blood mononuclear cells (PBMCs) of subjects. Results: H3K4me3 was elevated (0.25%+/-0.11%, 0.15%+/-0.04%, p=0.0004) and H3K9me2 was decreased (0.11%+/-0.05%, 0.15%+/-0.04%, p=0.003) in Ni-exposed subjects. H3K4me3 was positively (r=0.4, p=0.0008) and H3K9ac was negatively (r=0.1, p=0.01) associated with urinary nickel. Inter-individual variances of H3K4me3, H3K9ac, and H3K9me2 were larger relative to intra-individual variance in both groups, resulting in reliability coefficients, estimate of consistency of a set of measurements, of 0.75, 0.74, and 0.97 for H3K4me3, H3K9ac, and H3K9me2, respectively, for referent subjects. Reliability coefficients of 0.60, 0.67, and 0.79 were found for H3K4me3, H3K9ac, and H3K9me2, respectively, for Ni-exposed subjects. Conclusion: The results of this study indicate that occupational exposure to nickel is associated with alterations of global histone modification levels and that measurements of global levels of histone modifications are relatively stable over time in human PBMCs

INTRODUCTION: Particulate matter (PM), specifically nickel (Ni) found on or in PM, has been associated with an increased risk of mortality in human population studies and significant increases in vascular inflammation, generation of reactive oxygen species, altered vasomotor tone, and potentiated atherosclerosis in murine exposures. Recently, murine inhalation of Ni nanoparticles have been shown to cause pulmonary inflammation that affects cardiovascular tissue and potentiates atherosclerosis. These adverse cardiovascular outcomes may be due to the effects of Ni on endothelial progenitor cells (EPCs), endogenous semi-pluripotent stem cells that aid in endothelial repair. Thus, we hypothesize that Ni nanoparticle exposures decrease cell count and cause impairments in function that may ultimately have significant effects on various cardiovascular diseases, such as, atherosclerosis. METHODS: Experiments involving inhaled Ni nanoparticle exposures (2 days/5 h/day at approximately 1200 microg/m(3), 3 days/5 h/day at approximately 700 microg/m(3), and 5 days/5 h/day at approximately 100 microg/m(3)), were performed in order to quantify bone marrow resident EPCs using flow cytometry in C57BL/6 mice. Plasma levels of human stromal cell-derived factor 1alpha (SDF-1alpha) and vascular endothelial growth factor (VEGF) were assessed by enzyme-linked immunosorbent assay and in vitro functional assessments of cultured EPCs were conducted. RESULTS AND CONCLUSIONS: Significant EPC count differences between exposure and control groups for Ni nanoparticle exposures were observed. Differences in EPC tube formation and chemotaxis were also observed for the Ni nanoparticle exposed group. Plasma VEGF and SDF-1alpha differences were not statistically significant. In conclusion, this study shows that inhalation of Ni nanoparticles results in functionally impaired EPCs and reduced number in the bone marrow, which may lead to enhanced progression of atherosclerosis

The World Trade Center (WTC) collapse on September 11, 2001 released copious amounts of particulate matter (PM) into the atmosphere of New York City. Follow-up studies on persons exposed to the dusts have revealed a severely increased rate for asthma and other respiratory illnesses. There have only been a few studies that have sought to discern the possible mechanisms underlying these untoward pathologies. In one study, an increased cytokine release was detected in cells exposed to WTC fine dusts (PM. fraction or WTC.). However, the mechanism(s) for these increases has yet to be fully defined. Because activation of the mitogen-activated protein kinase (MAPK) signaling pathways is known to cause cytokine induction, the current study was undertaken to analyze the possible involvement of these pathways in any increased cytokine formation by lung epithelial cells (as BEAS-2B cells) exposed to WTC.. Our results showed that exposure to WTC. for 5 hr increased interleukin-6 (IL-6) mRNA expression in BEAS-2B cells, as well as its protein levels in the culture media, in a dose-dependent manner. Besides IL-6, cytokine multiplex analyses revealed that formation of IL-8 and -10 was also elevated by the exposure. Both extracellular signal-regulated kinase (ERK) and p38, but not c-Jun N-terminal protein kinase, signaling pathways were found to be activated in cells exposed to WTC.. Inactivation of ERK signaling pathways by PD98059 effectively blocked IL-6, -8, and -10 induction by WTC.; the p38 kinase inhibitor SB203580 significantly decreased induction of IL-8 and -10. Together, our data demonstrated activation of MAPK signaling pathway(s) likely played an important role in the WTC.-induced formation of several inflammatory (and, subsequently, anti-inflammatory) cytokines. The results are important in that they help to define one mechanism via which the WTC dusts may have acted to cause the documented increases in asthma and other inflammation-associated respiratory dysfunctions in the individuals exposed to the dusts released from the WTC collapse

Although cigarette smoking continues to occur worldwide, there are few methods available to assess a person's retrospective exposure to mainstream smoke. The tobacco of cigarettes contains trace quantities of radioactive (210)Pb and (210)Po, which are volatilized and inhaled when a cigarette is smoked. It was hypothesized that urinary (210)Pb and (210)Po activity concentrations could be used as biomarkers of exposure to mainstream tobacco smoke. Human subjects (n = 250) were recruited from Beijing, China, and reported their smoking habits. Each subject provided a 24-hour urine sample, which was assayed for its (210)Pb and (210)Po activity concentrations. Although the urinary (210)Po activity from smoking was very low compared with background levels, the urinary (210)Pb activity correlated with the number of cigarettes smoked per day (CPD; rho = 0.38, P < 0.001) and the urinary cotinine concentration (rho = 0.52, P < 0.001). In a linear regression model, a 1-unit increase in CPD was associated with an increase of 0.13 mBq in urinary (210)Pb activity. In a logistic regression model, a 1-unit increase in urinary (210)Pb activity was associated with an estimated 25% increase in the odds of being a smoker. These data were modeled using the respiratory, gastrointestinal, and biokinetic models of the International Commission on Radiological Protection. When the final model was applied for a long-term smoker (20 CPD) that suddenly quits, the predicted urinary activity decreased to 50% of the steady-state activity in about 90 days. Based on this half-time estimate and the regression results, urinary (210)Pb can be used to assess the probability of having smoked in the past months. Cancer Epidemiol Biomarkers Prev; 19(2); 338-50

Particulate matter (PM) is a ubiquitous environmental pollutant that has been associated with increased risk of cardiopulmonary mortality and morbidity in urban communities. An increasing body of evidence suggests that inflammation induced by PM may play an important role in the development of cardiovascular diseases. However, airway epithelial cell lines, instead of vascular endothelial cells, are commonly used to investigate the effects of PM with respect to cardiovascular effects. Thus, the present study was conducted using primary human vascular endothelial cells (HMVEC-LB1), human white blood cells (WBC), and their cocultures to evaluate their inflammatory responses to various PM exposures. Enzyme-linked immunosorbent assay (ELISA) kits were used to measure the concentrations of interleukin (IL)-6, soluble intercellular adhesion marker (sICAM-1), and soluble vascular cell adhesion marker (sVCAM-1) in HMVEC-LB1, WBC, and their cocultures after exposure to size-fractionated PM. Pretreatment of cells with inhibitors was performed in order to examine pathways involved in PM-induced cellular responses. IL-6 levels increased significantly in HMVEC-LB1 cells exposed to PM in both a time- and concentration-dependent manner. However, particle exposure for up to 24 h failed to induce any detectable production of sICAM-1 or sVCAM-1 in HMVEC-LB1 cells. IL-6 production in response to size-fractioned PM exposures failed to show evidence of relative importance of particle sizes in their abilities to induce proinflammatory responses. Lastly, cocultures with WBC significantly enhanced particle induced IL-6 release in HMVEC-LB1 cells in a synergistic manner. The present study suggests that HMVEC-LB1 cells can be successfully used as an in vitro model to examine effects of PM exposure