Faculty Bibliography

Fine ambient particulate matter (PM2.5) is able to induce sympathetic activation and inflammation in the brain. However, direct evidence demonstrating an essential role of sympathetic activation in PM2.5-associated disease progression is lacking. We assess the contribution of α2B-adrenergic receptor (Adra2b) in air pollution-associated hypertension and behavioral changes in this study. Wild-type mice and Adra2b-transgenic mice overexpressing Adra2b in the brain (Adra2bTg) were exposed to concentrated PM2.5 or filtered air for 3 months via a versatile aerosol concentrator exposure system. Mice were fed with a high salt diet (4.0% NaCl) for 1 week at week 11 of exposure to induce blood pressure elevation. Intra-arterial blood pressure was monitored by radio-telemetry and behavior changes were assessed by open field, light-dark, and prepulse inhibition tests. PM2.5 exposure increased Adra2b in the brain of wild-type mice. Adra2b overexpression enhanced the anxiety-like behavior and high salt diet-induced blood pressure elevation in response to air pollution but not filtered air exposure. Adra2b overexpression induced upregulation of inflammatory genes such as TLR2, TLR4, and IL-6 in the brain exposed to PM2.5. In addition, there were increased frequencies of activated effector T cells and increased expression of oxidative stress-related genes, such as SOD1, NQO1, Nrf2, and Gclm in Adra2bTg mice compared with wild-type mice. Our results provide new evidence of distinct behavioral changes consistent with anxiety and blood pressure elevation in response to high salt intake and air pollution exposure, highlighting the importance of centrally expressed Adra2b in the vulnerability to air pollution exposure.

Indoor air pollution from bituminous coal combustion has been linked to the extremely high lung cancer rates of nonsmoking women in Xuan Wei County, Yunnan Province, China. Venting the smoke outdoors by installing chimneys was found to be effective at reducing the lung cancer risk in a cohort study of 21,232 farmers in central Xuan Wei. However, the lung cancer mortality rates in all 1.2 million residents of Xuan Wei have been increasing dramatically over the last four decades. It was higher than that in Yunnan Province and China overall, with significant heterogeneities in the geographic patterns of Xuan Wei. Intervention measures targeting certain types of coal or certain carcinogenic components in coal smoke need to be explored. To inform targeted intervention policies, it is essential to pinpoint the specific substance (particulate matter, organic extract, PAHs, free radicals, crystalline silica, and inorganic matter) that might account for the carcinogenicity of bituminous coal smoke. Exploring the underlying carcinogenesis mechanisms would also contribute to the intervention and control of the lung cancer epidemic in Xuan Wei, China. Here we review the suspected carcinogens and carcinogenesis mechanisms and discuss future research directions towards a better understanding of the etiology of lung cancer in Xuan Wei, China.

BACKGROUND:In Xuan Wei, China, the lung cancer mortality rate is rising significantly more than that of the nation overall. However, it remains unclear 1) if improved diagnosis can just partially explain this observation and how other local risk factors may be correlated with the lung cancer mortality rate and 2) how the lung cancer mortality rates differ within Xuan Wei and how these spatiotemporal patterns are linked with local risk factors. To increase etiological knowledge, this study evaluated the spatial and temporal distributions of the health effects (the lung cancer mortality rates) from 2011 to 2015. METHODS:Four steps of spatial analysis were applied, as follows: 1) hotspot analysis to determine the geographical patterns of lung cancer mortality, 2) spatially-weighted sum to identify areas with higher health risks, 3) bivariate statistical analysis to assess the overall correlation between coal mines and lung cancer mortality, and 4) geographically-weighted regression to test for correlations among different towns within Xuan Wei. RESULTS:Women had higher lung cancer mortality rates than those in men, with an increasing trend in both sexes over time. The incidence rates in Laibin Town were the highest in Xuan Wei every year. Over the 5-year study period, the lung cancer mortality was increasingly concentrated in Laibin, Shuanglong, and Longchang, where the smoky coal mines are most concentrated. The population-level health risks from the coal mine in Xuan Wei were mapped and divided into five types of risk areas (Type I - Type IV). Correlation analysis revealed that there was no significant correlation between lung cancer mortality as a whole and coal mine distribution during the 5-year study period. However, the geographically-weighted regression revealed a stronger correlation in medium (Type III) and second-lowest (Type IV) health risks. CONCLUSIONS:Xuan Wei lung cancer mortality has increased continuously since the third national retrospective surveys on the causes of death by the Ministry of Health of the People's Republic of China (2004-2005), especially for local women and residents over 35 years of age. Geographically, lung cancer in Xuan Wei showed unique spatiotemporal clustering. The local lung cancer mortality was significantly correlated with the smoky coal mine geographically. Some specific towns (Laibin, Shuanglong, and Longchang) within Xuan Wei manifested high correlations between lung cancer mortality and coal mines. The effects of coal mines on lung cancer mortality rates also spread geographically outward from these areas. Public health concern regarding lung cancer in Xuan Wei should prioritize higher-risk towns surrounded by smoking coal mines. Intervention strategies for particular toxic coal types require further studies on their chemical characteristics and mechanisms of carcinogenesis. Additional studies are also warranted to systematically examine the local environmental health risks related to coal industries and combustion air pollution and eventually to conduct early screening of lung cancer for local people who are more exposed to smoky coal in high-risk areas.

BACKGROUND:The popularity of electronic cigarettes (E-cigarettes) has risen considerably. Several studies have suggested that nicotine may affect insulin resistance, however, the impact of E-cigarette exposure on insulin resistance, an early measure of cardiometabolic risk, is not known. METHODS AND RESULTS/RESULTS:Using experimental animals and human data obtained from 3,989 participants of the United States National Health and Nutrition Examination Survey (NHANES), respectively, we assessed the association between E-cigarette and conventional cigarette exposures and insulin resistance, as modelled using the homeostatic model assessment of insulin resistance (HOMA-IR) and glucose tolerance tests (GTT). C57BL6/J mice (on standard chow diet) exposed to E-cigarette aerosol or mainstream cigarette smoke (MCS) for 12 weeks showed HOMA-IR and GTT levels comparable with filtered air-exposed controls. In the NHANES cohort, there was no significant association between defined tobacco product use categories (non-users; sole E-cigarette users; cigarette smokers and dual users) and insulin resistance. Compared with non-users of e-cigarettes/conventional cigarettes, sole E-cigarette users showed no significant difference in HOMA-IR or GTT levels following adjustment for age, sex, race, physical activity, alcohol use and BMI. CONCLUSION/CONCLUSIONS:E-cigarettes do not appear to be linked with insulin resistance. Our findings may inform future studies assessing potential cardiometabolic harms associated with E-cigarette use.

Tobacco smoke (TS) contains numerous cancer-causing agents, with polycyclic aromatic hydrocarbons (PAHs) and nitrosamines being most frequently cited as the major TS human cancer agents. Many lines of evidence seriously question this conclusion. To resolve this issue, we determined DNA adducts induced by the three major TS carcinogens: benzo(a)pyrene (BP), 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanoe (NNK), and aldehydes in humans and mice. In mice, TS induces abundant aldehyde-induced γ-hydroxy-propano-deoxyguanosine (γ-OH-PdG) and α-methyl-γ-OH-PdG adducts in the lung and bladder, but not in the heart and liver. TS does not induce the BP- and NNK-DNA adducts in lung, heart, liver, and bladder. TS also reduces DNA repair activity and the abundance of repair proteins, XPC and OGG1/2, in lung tissues. These TS effects were greatly reduced by diet with polyphenols. We found that γ-OH-PdG and α-methyl-γ-OH-PdG are the major adducts formed in tobacco smokers' buccal cells as well as the normal lung tissues of tobacco-smoking lung cancer patients, but not in lung tissues of nonsmokers. However, the levels of BP- and NNK-DNA adducts are the same in lung tissues of smokers and nonsmokers. We found that while BP and NNK can induce BPDE-dG and O⁶-methyl-dG adducts in human lung and bladder epithelial cells, these inductions can be inhibited by acrolein. Acrolein also can reduce DNA repair activity and repair proteins. We propose a TS carcinogenesis paradigm. Aldehydes are major TS carcinogens exerting dominant effect: Aldehydes induce mutagenic PdG adducts, impair DNA repair functions, and inhibit many procarcinogens in TS from becoming DNA-damaging agents.

E-cigarette smoke delivers stimulant nicotine as aerosol without tobacco or the burning process. It contains neither carcinogenic incomplete combustion byproducts nor tobacco nitrosamines, the nicotine nitrosation products. E-cigarettes are promoted as safe and have gained significant popularity. In this study, instead of detecting nitrosamines, we directly measured DNA damage induced by nitrosamines in different organs of E-cigarette smoke-exposed mice. We found mutagenic O6-methyldeoxyguanosines and γ-hydroxy-1,N2 -propano-deoxyguanosines in the lung, bladder, and heart. DNA-repair activity and repair proteins XPC and OGG1/2 are significantly reduced in the lung. We found that nicotine and its metabolite, nicotine-derived nitrosamine ketone, can induce the same effects and enhance mutational susceptibility and tumorigenic transformation of cultured human bronchial epithelial and urothelial cells. These results indicate that nicotine nitrosation occurs in vivo in mice and that E-cigarette smoke is carcinogenic to the murine lung and bladder and harmful to the murine heart. It is therefore possible that E-cigarette smoke may contribute to lung and bladder cancer, as well as heart disease, in humans.

Electronic cigarettes (e-cigarette) have emerged as a popular electronic nicotine delivery system (ENDS) in the last decade. Despite the absence of combustion products and toxins such as carbon monoxide (CO) and tobacco-specific nitrosamines (TSNA), carbonyls including short-chain, toxic aldehydes have been detected in e-cigarette-derived aerosols up to levels found in tobacco smoke. Given the health concerns regarding exposures to toxic aldehydes, understanding both aldehyde generation in e-cigarette and e-cigarette exposure is critical. Thus, we measured aldehydes generated in aerosols derived from propylene glycol (PG):vegetable glycerin (VG) mixtures and from commercial e-liquids with flavorants using a state-of-the-art carbonyl trap and mass spectrometry. To track e-cigarette exposure in mice, we measured urinary metabolites of 4 aldehydes using ULPC-MS/MS or GC-MS. Aldehyde levels, regardless of abundance (saturated: formaldehyde, acetaldehyde > unsaturated: acrolein, crotonaldehyde), were dependent on the PG:VG ratio and the presence of flavorants. The metabolites of 3 aldehydes - formate, acetate and 3-hydroxypropyl mercapturic acid (3-HPMA; acrolein metabolite) -- were increased in urine after e-cigarette aerosol and mainstream cigarette smoke (MCS) exposures, but the crotonaldehyde metabolite (3-hydroxy-1-methylpropylmercapturic acid, HPMMA) was increased only after MCS exposure. Interestingly, exposure to menthol-flavored e-cigarette aerosol increased the levels of urinary 3-HPMA and sum of nicotine exposure (nicotine, cotinine, trans-3'-hydroxycotinine) relative to exposure to a Classic Tobacco-flavored e-cigarette aerosol. Comparing these findings with aerosols of other ENDS and by measuring aldehyde-derived metabolites in human urine following exposure to e-cigarette aerosols will further our understanding of the relationship between ENDS use, aldehyde exposure and health risk.

Air pollution is associated with the increased risk of metabolic syndrome. In this study, we performed inhalation exposure of mice fed normal chow or a high-fat diet to airborne fine particulate matters (PM2.5), and then investigated the complex effects and mechanisms of inhalation exposure to PM2.5 on hepatic steatosis, a precursor or manifestation of metabolic syndrome. Our studies demonstrated that inhalation exposure of mice fed normal chow to concentrated ambient PM2.5 repressed hepatic transcriptional regulators involved in fatty acid oxidation and lipolysis, and thus promoted hepatic steatosis. However, PM2.5 exposure relieved hepatic steatosis in high-fat diet-induced obese mice. Further investigation revealed that inhalation exposure to PM2.5 induced hepatic autophagy in mouse livers in a manner depending on the MyD88-mediated inflammatory pathway. The counteractive effect of PM2.5 exposure on high-fat diet-induced hepatic steatosis was mediated through PM2.5-induced hepatic autophagy. The findings from this study not only defined the effects and mechanisms of PM2.5 exposure in metabolic disorders, but also revealed the pleotrophic acts of an environmental stressor in a complex stress system relevant to public health.

Silver nanoparticles (AgNPs) are employed in a variety of consumer products; however, in vivo rodent studies indicate that AgNPs can cause lung inflammation and toxicity in a strain- and particle type-dependent manner, but mechanisms of susceptibility remain unclear. The aim of this study was to assess the variation in AgNP-induced lung inflammation and toxicity across multiple inbred mouse strains and to use genome-wide association (GWA) mapping to identify potential candidate susceptibility genes. Mice received doses of 0.25 mg/kg of either 20-nm citrate-coated AgNPs or citrate buffer using oropharyngeal aspiration. Neutrophils in bronchoalveolar lavage fluid (BALF) served as markers of inflammation. We found significant strain- and treatment-dependent variation in neutrophils in BALF. GWA mapping identified 10 significant single-nucleotide polymorphisms (false discovery rate, 15%) in 4 quantitative trait loci on mouse chromosomes 1, 4, 15, and 18, and Nedd4l (neural precursor cell expressed developmentally downregulated gene 4-like; chromosome 18), Ano6 (anocatmin 6; chromosome 15), and Rnf220 (Ring finger protein 220; chromosome 4) were considered candidate genes. Quantitative RT-PCR revealed significant inverse associations between mRNA levels of these genes and neutrophil influx. Nedd4l, Ano6, and Rnf220 are candidate susceptibility genes for AgNP-induced lung inflammation that warrant additional exploration in future studies.-Scoville, D. K., Botta, D., Galdanes, K., Schmuck, S. C., White, C. C., Stapleton, P. L., Bammler, T. K., MacDonald, J. W., Altemeier, W. A., Hernandez, M., Kleeberger, S. R., Chen, L.-C., Gordon, T., Kavanagh, T. J. Genetic determinants of susceptibility to silver nanoparticle-induced acute lung inflammation in mice.

This study's aim was to investigate the post-effect of an air quality improvement on systemic inflammation and circulating microparticles in asthmatic patients during, and 2 months after, the Beijing Olympics 2008. We measured the levels of circulating inflammatory cytokines and microparticles in the peripheral blood from asthma patients and healthy controls during (phase 1), and 2 months after (phase 2) the Beijing 2008 Olympic Games. The concentrations of circulating cytokines (including TNFalpha, IL-6, IL-8, and IL-10) were still seen reduced in phase 2 when compared with those in phase 1. The number of circulating endothelial cell-derived microparticles was significantly lower during the phase 2 than that during phase 1 in asthma patients. The level of plasma lipopolysaccharide-binding protein (LBP) was significantly decreased in asthmatics in phase 2. The level of norepinephrine was significantly higher in phase 2 than that in phase 1 in plasma from both asthma patients and healthy subjects. There were no significant differences in the gene profile for the toll-like receptor (TLR) signaling from peripheral blood mononuclear cells. In vitro, microvesicles from patients with asthma impaired the relaxation to bradykinin and contraction to acetylcholine, whereas microparticles from healthy subjects did not. These data suggested that reduction in systemic pro-inflammatory responses and circulating LBP and increased level of norepinephrine in asthma patients persisted even after 2 months of the air pollution intervention. These changes were independent of the TLR signaling pathway. Circulating microparticles might be associated with airway smooth muscle dysfunction.