Faculty Bibliography

CONTEXT: Recent studies have suggested a link between inhaled particulate matter exposure in urban areas and susceptibility to cardiovascular events; however, the precise mechanisms remain to be determined. OBJECTIVE: To test the hypothesis that subchronic exposure to environmentally relevant particulate matter, even at low concentrations, potentiates atherosclerosis and alters vasomotor tone in a susceptible disease model. DESIGN, SETTING, AND PARTICIPANTS: Between July 21, 2004, and January 12, 2005, 28 apolipoprotein E-/- (apoE-/-) mice were, based on randomized assignments, fed with normal chow or high-fat chow and exposed to concentrated ambient particles of less than 2.5 microm (PM2.5) or filtered air (FA) in Tuxedo, NY, for 6 hours per day, 5 days per week for a total of 6 months. MAIN OUTCOME MEASURES: Composite atherosclerotic plaque in the thoracic and abdominal aorta and vasomotor tone changes. RESULTS: In the high-fat chow group, the mean (SD) composite plaque area of PM2.5 vs FA was 41.5% (9.8%) vs 26.2% (8.6%), respectively (P<.001); and in the normal chow group, the composite plaque area was 19.2% (13.1%) vs 13.2% (8.1%), respectively (P = .15). Lipid content in the aortic arch measured by oil red-O staining revealed a 1.5-fold increase in mice fed the high-fat chow and exposed to PM2.5 vs FA (30.0 [8.2] vs 20.0 [7.0]; 95% confidence interval [CI], 1.21-1.83; P = .02). Vasoconstrictor responses to phenylephrine and serotonin challenge in the thoracic aorta of mice fed high-fat chow and exposed to PM2.5 were exaggerated compared with exposure to FA (mean [SE], 134.2% [5.2%] vs 100.9% [2.9%], for phenylephrine, and 156.0% [5.6%] vs 125.1% [7.5%], for serotonin; both P = .03); relaxation to the endothelium-dependent agonist acetylcholine was attenuated (mean [SE] of half-maximal dose for dilation, 8.9 [0.2] x 10(-8) vs 4.3 [0.1] x 10(-8), respectively; P = .04). Mice fed high-fat chow and exposed to PM2.5 demonstrated marked increases in macrophage infiltration, expression of the inducible isoform of nitric oxide synthase, increased generation of reactive oxygen species, and greater immunostaining for the protein nitration product 3-nitrotyrosine (all P<.001). CONCLUSION: In an apoE-/- mouse model, long-term exposure to low concentration of PM2.5 altered vasomotor tone, induced vascular inflammation, and potentiated atherosclerosis

Daily rates of cardiovascular mortality and morbidity are have been associated with daily variations in fine particulate matter (aerodynamic diameter < or = 2.5 microm, PM2.5), but little is known about the influences of the individual source-related PM2.5 categories or the temporal lags for the effects. We investigated heart rate (HR) and HR variability (HRV) data collected during a 5-month study involving 6 hr/day, 5 day/week exposures of normal (C57) mice and a murine model for atherosclerotic disease (ApoE-/-) in Sterling Forest (Tuxedo, New York, USA). The mice were exposed to concentrated ambient particles (PM2.5 concentrated 10-fold, producing an average of 113 microg/m3). Daily 6-hr PM2.5 air samples were analyzed by X-ray fluorescence, permitting attribution to major PM source categories [secondary sulfate (SS), resuspended soil (RS), residual oil (RO) combustion, and other, largely due to motor vehicle traffic]. We examined associations between these PM2.5 components and both HR and HRV for three different daily time periods: during exposure, the afternoon after exposure, and late at night. For HR there were significant transient associations for RS during exposure, and for SS in the afternoon after exposure. For HRV, there were comparable associations with RO in the afternoon after exposure and for both SS and RS late at night. The biologic bases for these associations and their temporal lags are not known but may be related to the differential solubility of the biologically active PM components at the respiratory epithelia and their access to cells that release mediators that reach the cardiovascular system. Clearly, further research to elucidate the underlying processes is needed

BACKGROUND: Individuals may develop tolerance to the induction of adverse pulmonary effects following repeated exposures to inhaled toxicants. Previously, we demonstrated that genetic background plays an important role in the development of pulmonary tolerance to inhaled zinc oxide (ZnO) in inbred mouse strains, as assessed by polymorphonuclear leukocytes (PMNs), macrophages, and total protein in bronchoalveolar lavage (BAL) phenotypes. The BALB/cByJ (CBy) and DBA/2J (D2) strains were identified as tolerant and non-tolerant, respectively. The present study was designed to identify candidate genes that control the development of pulmonary tolerance to inhaled ZnO. METHODS: Genome-wide linkage analyses were performed on a CByD2F2 mouse cohort phenotyped for BAL protein, PMNs, and macrophages following 5 consecutive days of exposure to 1.0 mg/m3 inhaled ZnO for 3 hours/day. A haplotype analysis was carried out to determine the contribution of each quantitative trait locus (QTL) and QTL combination to the overall BAL protein phenotype. Candidate genes were identified within each QTL interval using the positional candidate gene approach. RESULTS: A significant quantitative trait locus (QTL) on chromosome 1, as well as suggestive QTLs on chromosomes 4 and 5, for the BAL protein phenotype, was established. Suggestive QTLs for the BAL PMN and macrophage phenotypes were also identified on chromosomes 1 and 5, respectively. Analysis of specific haplotypes supports the combined effect of three QTLs in the overall protein phenotype. Toll-like receptor 5 (Tlr5) was identified as an interesting candidate gene within the significant QTL for BAL protein on chromosome 1. Wild-derived Tlr5-mutant MOLF/Ei mice were tolerant to BAL protein following repeated ZnO exposure. CONCLUSION: Genetic background is an important influence in the acquisition of pulmonary tolerance to BAL protein, PMNs, and macrophages following ZnO exposure. Promising candidate genes exist within the identified QTL intervals that would be good targets for additional studies, including Tlr5. The implications of tolerance to health risks in humans are numerous, and this study furthers the understanding of gene-environment interactions that are likely to be important factors from person-to-person in regulating the development of pulmonary tolerance to inhaled toxicants

This report is part of an extensive biomarker study conducted in a Chinese occupational population with benzene exposures ranging from 0.06 to 122ppm (median exposure of 3.2ppm). All urinary benzene metabolites measured in this study were significantly elevated after exposure to benzene at or above 5ppm. Among these metabolites, however, only S-phenylmercapturic acid (S-PMA) and trans,trans-muconic acid (t,t-MA) showed a significant exposure-response trend over the exposure range from 0 to 1ppm (for S-PMA, p<0.0001 and for t,t-MA, p=0.006). For benzene exposure monitoring, both S-PMA and t,t-MA were judged to be good and sensitive markers, which detected benzene exposure at around 0.1 and 1ppm, respectively. Polymorphisms of the metabolic genes, including CYP2E1, quinone oxidoreductase (NQO1), GSTT1, and myeloperoxidase (MPO), were identified and did not show significant effects on the formation of metabolites, except GSTT1 on S-PMA. The production rate of S-PMA from benzene in exposed workers with GSTT1 null alleles (24.72+/-32.48mug/g creatinine/ppm benzene) was significantly lower than that in subjects with the wild type of GSTT1 (59.84+/-47.66mug/g creatinine/ppm benzene, p<0.0001). Further regression analysis of S-PMA production rate on GSTT1 genotype with adjustment of sex, age, benzene exposure, and cotinine levels indicated that the genotype of GSTT1 plays a critical role in determining the inter-individual variations of S-PMA formation from benzene exposure. Therefore, the individual genotype of GSTT1 needs to be identified and considered while using S-PMA as a marker to estimate the personal exposure levels of benzene in future population studies

This subchronic (6-mo) inhalation study of the effects of concentrated ambient air fine particulate matter (PM2.5) in normal mice (C57) and a murine model of humans with an advanced level of aortic plaque (ApoE-/- or ApoE-/- LDLr-/-) was designed to determine the presence and extent of a variety of health-related responses. The animals were exposed for 6 h/day, 5 day/wk during the spring and summer of 2003 to concentrations that were elevated 10-fold in Tuxedo, NY, a regional background site that is upwind and approximately 50 km west-northwest of New York City. The average PM2.5 concentration during exposure was 110 microgram/m3, and the long-term average was 19.7 microg/m3. There were substantial daily variations in concentration, and we sought evidence both for the influence of peak exposures on acute responses and for the cumulative effects of the prolonged series of exposures. Acute responses were characterized in terms of: (1) short-term electrocardiographic (EKG), core body temperature, and physical activity differences between PM and sham-exposed mice; and (2) in vitro toxicity of a simultaneously collected PM2.5 sample to lung epithelial cells. Cumulative responses to PM2.5 were characterized in terms of changes in heart rate, heart-rate variability, heart-rate variance, aortic plaque density, genetic marker expression, and brain cell distributions. There were no significant changes in the normal mice. The nature and extent of the exposure-related responses that were seen in the ApoE-/- as well as ApoE-/- LDLr-/- mice are described in the articles that follow in this special issue of Inhalation Toxicology

We modified, assembled, tested, and validated the versatile aerosol concentration enrichment system (VACES) developed by Sioutas et al. (1999) for use in a subchronic experiment that involved exposure of mice in vivo and of respiratory epithelial cells in vitro to concentrated ambient particles (CAPs). Since the labor-intensive nose-only exposure regimen is not an option in a long-term experiment, a whole-body exposure mouse chamber was designed specifically for use with the VACES. The exposure system concsists of a stainless-steel (SS) tub with 32 cubicles (1 mouse per cubicle) separated by perforated SS sheets. The tops of these cubicles are covered with perforated plastic sheets to allow telemetry monitoring during the exposure. In each exposure chamber, perforated aluminum tubes are used to distribute CAPs evenly (within 2% difference) throughout the exposure chamber. The exhaust consists of perforated aluminum tubes covered with a urine shield. The modification to the original design of the VACES facilitated the operation of the system in a subchronic study. Mass flow controllers maintain a constant flow rate into the exposure chambers. For a sham control exposure, the identical system is used, except that a HEPA filter at the inlet to the VACES removes 98% of ambient particles. The entire system allow for simultaneous exposure of 64 mice to CAPs, with an equal number of sham-expose mice as controls. Telemetry receives have been modified so that 16 mice per group with electrocardiograph (EKG) transmitters can be monitored during exposure. Furthermore, a BioSampler is used to collect CAPs (one sample per day) for the in vitro exposures. In this article, the assessments of flow and particle distribution of the exposure chamber as well as the performance of the system during the subchronic exposure experiment are described

On I I September 2001, the explosion and the collapse of the World Trade Center (WTC) Twin Towers in New York City (NYC), USA, generated a massive release of dust and inhalable toxic substances to the atmosphere as a result of the pulverization of various building materials, furniture, and computers. Many concerns were raised as Particulate Matter (PM) levels in Lower Manhattan might not meet the current National Ambient Air Quality Standards (NAAQS) (65 mu g m(-3)). The current study aims to provide a first estimate of the scale of population exposures during this episode. Data collected from existing monitoring stations in September showed the occurrence of a series of high peaks Of PM2.5 registered in the Lower Manhattan area after the 11 September. An interpolation technique was used within a Geographical Information Systems (GIS) environment to estimate outdoor PM2.5 concentrations over NYC. Monthly average of 24h outdoor PM2.5 concentration of Lower Manhattan was 20.2 mu g m(-3) and did not exceed the NAAQS value. PM2.5 concentrations in indoor micro-environments were simulated by a deterministic microenvironmental model (INTAIR) and linear regression equations. Three typical population groups were identified for the NYC area - home-makers, office/shop-workers, and students/children - and their 12h nighttime and daytime exposures were estimated from 14 September until the end of September, either as mean exposure (daytime and nighttime) or as exposure weighted by residential population distribution (nighttime only). Average nighttime and daytime exposures of the Lower Manhattan population were calculated to be 37.3 and 23.6 mu g m(-3), respectively (daily average: 30.45 mu g m(-3)), in which the various group movements and activities, smoking habits of individuals, and special population movements due to access restrictions and risk avoidance behaviors were considered. Within the study period, assuming the real nighttime population distribution followed the residential population pattern, approximate one quarter of the population was exposed to 20-30 mu g m(-3) PM2.5; one half of the Lower Manhattan population was exposed to 10-20 and 30-60 mu g m(-3); around one fifth of the population was exposed to over 60 mu g m(-3) during nighttime. The results indicated that although the outdoor PM2.5 concentration was lower than the NAAQS value, personal exposure levels, which were generally higher than the outdoor PM2.5 concentration, might still be a reason of concern. (c) 2005 Elsevier Ltd. All rights reserved

Long-term exposure to fine particulate air pollution (PM2.5) has been associated increased risk of death from cardiopulmonary diseases. Cardiac function parameters have also been affected by ambient particulate matter (PM) exposure, including heart-rate variability (HRV), a measure of autonomic function that has been recognized as a well-defined, quantitative indicator of autonomic dysfunction. However, the role of HRV in ambient PM-induced cardiovascular effect is not fully understood. In an accompanying article, we report significant decreasing patterns of heart rate (HR), body temperature, and physical activity for mice lacking apoliproprotein (ApoE-/-) over 5 mo of exposure to concentrated ambient PM (CAPs), with smaller and nonsignificant change for C57 mice. In this article, we report the effects of subchronic CAPs exposure on HRV parameters that are sensitive to cardiac sympathetic and parasympathetic nerve activity. The standard deviation of normal to normal beat intervals (SDNN) and the square root of the mean squared differences of successive RR intervals (RMSSD) in the late afternoon and overnight for the ApoE-/- mice showed a gradual increase for the first 6 wk, a decline for about 12 more wk, and a slight turn upward at the end of the study period. For C57 mice, there were no chronic effect changes of SDNN or RMSSD in the late afternoon, an a slight increase after 6 wk for the overnight period. The response patterns of ApoE-/- mice indicated a perturbation of the homeostatic function in the cardiovascular system (initial enhancement and late depression of the HRV parameters). Our results complement the findings in human panel and controlled CAPs exposure studies in demonstrating that increased levels of particle pollution are able to perturb cardiac autonomic function, which may lead to adverse cardiovascular outcomes

In order to examine the biologic plausibility of adverse chronic cardiopulmonary effects in humans associated with ambient particulate matter (PM) exposure, we exposed groups of normal mice (C57) and knockout mice that develop atherosclerotic plaque (ApoE-/- and ApoE-/- LDLr-/-) for 6 h/day, 5 days/wk for 5 or 6 mo during the spring/summer of 2003 to either filtered air or 10-fold concentrated ambient particles (CAPs) in Tuxedo, NY (average PM2.5 concentration during exposure = 110 microg/m3). Some of the mice had implanted electrocardiographic monitors. We demonstrated that: (1) this complex interdisciplinary study was technically feasible in terms of daily exposure, collection of air quality monitoring data, the collection, analysis, and interpretation of continuous data on cardiac function, and the collection and analyses of tissues of the animals sacrificed at the end of the study; (2) the daily variations in CAPs were significantly associated, in ApoE-/- mice, with daily variations in cardiac functions; (3) there were significant differences between CAPs and sham-exposed ApoE-/- mice in terms of cardiac function after the end of exposure period, as well as small differences in atherosclerotic plaque density, coronary artery disease, and cell density in the substantia nigra in the brain in the ApoE-/- mice; (4) there are suggestive indications of gene expression changes for genes associated with the control of circadian rhythm in the ApoE-/- LDLr-/- double knockout (DK) mice. These various CAPs-related effects on cardiac function and the development of histological evidence of increased risk of clinically significant disease at the end of exposures in animal models of atherosclerosis provide biological plausibility for the premature mortality associated with PM2.5 exposure in human subjects and provide suggestive evidence for neurogenic disease as well