E-Cigarette Toxicology.

Since the spread of tobacco from the Americas hundreds of years ago, tobacco cigarettes and, more recently, alternative tobacco products have become global products of nicotine addiction. Within the evolving alternative tobacco product space, electronic cigarette (e-cigarette) vaping has surpassed conventional cigarette smoking among adolescents and young adults in the United States and beyond. This review describes the experimental and clinical evidence of e-cigarette toxicity and deleterious health effects. Adverse health effects related to e-cigarette aerosols are influenced by several factors, including e-liquid components, physical device factors, chemical changes related to heating, and health of the e-cigarette user (e.g., asthmatic). Federal, state, and local regulations have attempted to govern e-cigarette flavors, manufacturing, distribution, and availability, particularly to underaged youths. However, the evolving e-cigarette landscape continues to impede timely toxicological studies and hinder progress made toward our understanding of the long-term health consequence of e-cigarettes.

World Trade Center dust induces nasal and neurological tissue injury while propagating reduced olfaction capabilities and increased anxiety behaviors.

Objective: Previous in vitro and in vivo World Trade Center particulate matter (WTCPM) exposure studies have provided evidence of exposure-driven oxidative/nitrative stress and inflammation on respiratory tract and aortic tissues. What remains to be fully understood are secondary organ impacts due to WTCPM exposure. This study was designed to test if WTC particle-induced nasal and neurologic tissue injury may result in unforeseen functional and behavioral outcomes.Material and Methods: WTCPM was intranasally administered in mice, evaluating genotypic, histopathologic, and olfaction latency endpoints.Results: WTCPM exposure was found to incite neurologic injury and olfaction latency in intranasally (IN) exposed mice. Single high-dose and repeat low-dose nasal cavity insults from WTCPM dust resulted in significant olfaction delays and enduring olfaction deficits. Anxiety-dependent behaviors also occurred in mice experiencing olfaction loss including significant body weight loss, increased incidence and time spent in hind stretch postures, as well as increased stationary time and decreased exploratory time. Additionally, WTCPM exposure resulted in increased whole brain wet/dry ratios and wet whole brain to body mass ratios that were correlated with exposure and increased exposure dose (p<0.05).Discussion: The potential molecular drivers of WTCPM-driven tissue injury and olfaction latency may be linked to oxidative/nitrative stress and inflammatory cascades in both upper respiratory nasal and brain tissues.Conclusion: Cumulatively, these data provide evidence of WTCPM exposure in relation to tissue damage related to oxidative stress-driven inflammation identified in the nasal cavity, propagated to olfactory bulb tissues and, potentially, over extended periods, to other CNS tissues.

Electronic-cigarette smoke induces lung adenocarcinoma and bladder urothelial hyperplasia in mice.

Electronic-cigarettes (E-cigs) are marketed as a safe alternative to tobacco to deliver the stimulant nicotine, and their use is gaining in popularity, particularly among the younger population. We recently showed that mice exposed to short-term (12 wk) E-cig smoke (ECS) sustained extensive DNA damage in lungs, heart, and bladder mucosa and diminished DNA repair in lungs. Nicotine and its nitrosation product, nicotine-derived nitrosamine ketone, cause the same deleterious effects in human lung epithelial and bladder urothelial cells. These findings raise the possibility that ECS is a lung and bladder carcinogen in addition to nicotine. Given the fact that E-cig use has become popular in the past decade, epidemiological data on the relationship between ECS and human cancer may not be known for a decade to come. In this study, the carcinogenicity of ECS was tested in mice. We found that mice exposed to ECS for 54 wk developed lung adenocarcinomas (9 of 40 mice, 22.5%) and bladder urothelial hyperplasia (23 of 40 mice, 57.5%). These lesions were extremely rare in mice exposed to vehicle control or filtered air. Current observations that ECS induces lung adenocarcinomas and bladder urothelial hyperplasia, combined with our previous findings that ECS induces DNA damage in the lungs and bladder and inhibits DNA repair in lung tissues, implicate ECS as a lung and potential bladder carcinogen in mice. While it is well established that tobacco smoke poses a huge threat to human health, whether ECS poses any threat to humans is not yet known and warrants careful investigation.

Ambient fine particulate matter exposure disrupts placental autophagy and fetal development in gestational mice.

Recent studies have shown that some adverse pregnancy outcomes, especially intrauterine growth restriction (IUGR), are associated with gestational exposure to ambient fine particulate matter (PM2.5). However, potential mechanism remains to be elucidated. In the present study, pregnant C57BL/6 mice were randomly assigned to be exposed to either filtered air or ambient PM2.5 in the gestation period via a concentrated whole-body exposure system. We found that gestational PM2.5 exposure exerted no effect on implantation, preterm delivery, as well as fetal resorption and death. However, in utero fetal exposure to PM2.5 showed a significant reduction in body weight and crown-rump length on GD13 and GD18. Meanwhile, maternal blood sinusoid in placenta was markedly reduced along with abnormal expression of placental nutrient transporters and growth hormone in dams exposed to PM2.5. Additional tests showed gestational PM2.5 exposure decreased autophagy-related protein levels and inhibited autophagy flux mainly on GD15. Correspondingly, AMPK/mTOR signaling pathway, a critical negative regulator of autophagy, was activated in placenta on GD15 by PM2.5 exposure as well. These findings provide evidences that placental developmental disorder caused by autophagy inhibition might be an important mechanism for the growth restriction caused by PM2.5 exposure.

E-cigarette smoke damages DNA and reduces repair activity in mouse lung, heart, and bladder as well as in human lung and bladder cells.

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.

Aldehydes are the predominant forces inducing DNA damage and inhibiting DNA repair in tobacco smoke carcinogenesis.

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.

World Trade Center Dust induces airway inflammation while promoting aortic endothelial dysfunction.

Respiratory ailments have plagued occupational and public health communities exposed to World Trade Center (WTC) dust since the September 11, 2001 attack on the Twin Towers in Lower Manhattan. We proposed that these ailments were proposed to be induced by inhalation exposure to WTC particulate matter (WTCPM), that was released during the collapse of the buildings and its subsequent resuspension during cleanup. We investigated this hypothesis using both an in vitro and an in vivo mouse intranasal (IN) exposure models to identify the inflammatory potential of WTCPM with specific emphasis on respiratory and endothelial tissue responses. The in vitro exposure studies found WTCPM exposure to be positively correlated with cytotoxicity and increased NO2- production in both BEAS-2B pulmonary epithelial cells and THP-1 macrophage cells. The in vivo C57BL/6 mouse studies found significant increases in inflammatory markers including increases in polymorphonuclear neutrophil (PMN) influx into nasal and bronchoalveolar lavage fluids (NLF and BALF), as well as increased levels of total protein and cytokine/chemokines levels. Concurrently, NLF, BALF, and serum NO2- levels exhibited significant homeostatic temporal deviations as well as temporal myograohic aortic dysfunction in myography studies. Respiratory exposure to- and evidence -based retention of- WTCPM may have contributed to chronic systemic effects in exposed mice that r resembled to observed effects in WTCPM-exposed human populations. Collectively, these findings are reflective of WTCPM exposure and its effect(s) on respiratory and aortic tissues, highlighting potential dysfunctional pathways that may precipitate inflammatory events, while simultaneously altering homeostatic balances. The tight interplay between these balances, when chronically altered, may contribute to- or result in- chronically diseased pathological states.

Toxicity of particles emitted by fireworks.

BACKGROUND: Particle matter (PM) has been associated with increased morbidity and mortality rates across the world. This study was designed to test the hypotheses that pyrotechnic firework displays introduce significant amounts of toxic metals into the atmosphere and are hazardous to human health. Size-selective emissions from 10 different fireworks displays were collected during particle generation in a dynamic, stainless steel chamber and tested for toxicity in cells. A subset of 2 particle types were tested in vivo in mice. At doses that did not produce cytotoxicity in an LDH assay, in vitro reactive oxygen species (ROS) formation was measured in bronchial epithelial airway (BEAS-2B) and human pulmonary microvascular endothelial (HPMEC-ST1.6R) cell lines treated with size-fractionated particles from the emissions of fireworks. RESULTS: Significant increases in ROS, in both cell types, were dependent upon the type of firework but not particle size. The in vitro ROS activity was correlated with lung inflammation produced in groups of mice treated by oropharyngeal aspiration with 0, 50, or 100 µg fireworks PM10/mouse. Trace metal analyses of the PM10 samples showed significant differences in metal content among fireworks type. Interestingly, the PM10 sample for the fireworks type producing the greatest in vitro ROS response in BEAS-2B cells contained ~ 40,000 and ~ 12,000 ppm of lead and copper, respectively. This sample also produced the greatest inflammatory response (i.e., increased neutrophils in bronchoalveolar lavage fluid) in mice. CONCLUSIONS: These findings demonstrate that pyrotechnic display particles can produce adverse effects in mammalian cells and lungs, thus suggesting that further research is needed to expand our understanding of the contribution of metal content to the adverse health effects of fireworks particles. This information will lead to the manufacture of safer fireworks.

Sex-dependent effects of ambient PM2.5 pollution on insulin sensitivity and hepatic lipid metabolism in mice.

BACKGROUND & AIMS: Emerging evidence supports ambient fine particulate matter (PM2.5) exposure is associated with insulin resistance (IR) and hepatic lipid accumulation. In this study, we aimed to evaluate the sex-dependent vulnerability in response to PM2.5 exposure and investigate the underlying mechanism by which PM2.5 modulates hepatic lipid metabolism. METHODS: Both male and female C57BL/6 mice were randomly assigned to ambient PM2.5 or filtered air for 24 weeks via a whole body exposure system. High-coverage quantitative lipidomics approaches and liquid chromatography-mass spectrometry techniques were performed to measure hepatic metabolites and hormones in plasma. Metabolic studies, histological analyses, as well as gene expression levels and molecular signal transduction analysis were applied to examine the effects and mechanisms by which PM2.5 exposure-induced metabolic disorder. RESULTS: Female mice were more susceptible than their male counterparts to ambient PM2.5 exposure-induced IR and hepatic lipid accumulation. The hepatic lipid profile was changed in response to ambient PM2.5 exposure. Levels of hepatic triacylglycerols (TAGs), free fatty acids (FFAs) and cholesterol were only increased in female mice from PM group compared to control group. Plasmalogens were dysregulated in the liver from PM2.5-exposed mice as well. In addition, exposure to PM2.5 led to enhanced hepatic ApoB and microsomal triglyceride transport protein expression in female mice. Finally, PM2.5 exposure inhibited hypothalamus-pituitary-adrenal (HPA) axis and decreased glucocorticoids levels, which may contribute to the vulnerability in PM2.5-induced metabolic dysfunction. CONCLUSIONS: Ambient PM2.5 exposure inhibited HPA axis and demonstrated sex-associated differences in its effects on IR and disorder of hepatic lipid metabolism. These findings provide new mechanistic evidence of hormone regulation in air pollution-mediated metabolic abnormalities of lipids and more personalized care should be considered in terms of sex-specific risk factors.

Impact on rats from acute intratracheal inhalation exposures to WTC dusts.

Background: Studies have revealed the increased incidence of health disorders in First Responders (FR) who were at Ground Zero over the initial 72 hr after the World Trade Center (WTC) collapses. Previous studies in rats exposed to WTC dusts using exposure scenarios that mimicked FR mouthbreathing showed exposure led to altered expression of genes whose products could be involved in lung ailments. Nevertheless, it was uncertain if repeated exposures (as occurred in earliest days post-disaster) might have given rise to long-term changes in the lungs/other organs, in white blood cell (WBC) profiles, and/or systemic expression of select (mostly immune-related) proteins.Methods: To examine this, rats were exposed on 2 consecutive days (2 hr/d, intratracheal inhalation) to WTC dusts and then examined over a 1-yr period thereafter. At select times post-exposure, organ (lung, heart, liver, kidney, spleen) weights, WBC profiles, and blood levels of a variety of proteins were evaluated.Results: The study showed that over the 1-yr period, there were nominal effects on organ weights (absolute, index) as a result of the dust exposures. There were significant changes (relative to in naïve rats) in WBC profiles, with exposed rats having increased monocyte-macrophage and decreased lymphocyte percentages. The study also found that dust exposure led to significant systemic increases in many proteins, including MCP-1, RANTES, MMP-9, RAGE, and Galectin-3.Conclusions: These results provide further support for our longstanding hypothesis that the WTC dusts could potentially have acted as direct inducers of many of the health effects that have been seen in the exposed FR.

Complementary biobank of rodent tissue samples to study the effect of World Trade Center exposure on cancer development.

World Trade Center (WTC) responders were exposed to mixture of dust, smoke, chemicals and carcinogens. New York University (NYU) and Mount Sinai have recreated WTC exposure in rodents to observe the resulting systemic and local biological responses. These experiments aid in the interpretation of epidemiological observations and are useful for understanding the carcinogenesis process in the exposed human WTC cohort. Here we describe the implementation of a tissue bank system for the rodents experimentally exposed to WTC dust. NYU samples were experimentally exposed to WTC dust via intratracheal inhalation that mimicked conditions in the immediate aftermath of the disaster. Tissue from Mount Sinai was derived from genetically modified mice exposed to WTC dust via nasal instillation. All processed tissues include annotations of the experimental design, WTC dust concentration/dose, exposure route and duration, genetic background of the rodent, and method of tissue isolation/storage. A biobank of tissue from rodents exposed to WTC dust has been compiled representing an important resource for the scientific community. The biobank remains available as a scientific resource for future research through established mechanisms for samples request and utilization. Studies using the WTC tissue bank would benefit from confirming their findings in corresponding tissues from organs of animals experimentally exposed to WTC dust. Studies on rodent tissues will advance the understanding of the biology of the tumors developed by WTC responders and ultimately impact the modalities of treatment, and the probability of success and survival of WTC cancer patients.

Bituminous coal combustion and Xuan Wei Lung cancer: a review of the epidemiology, intervention, carcinogens, and carcinogenesis.

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.

Five-year lung cancer mortality risk analysis and topography in Xuan Wei: a spatiotemporal correlation analysis.

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.

Genetic determinants of susceptibility to silver nanoparticle-induced acute lung inflammation in mice.

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.

Environmental stressors and cardio-metabolic disease: part II-mechanistic insights.

Environmental factors can act as facilitators of chronic non-communicable diseases. Ambient noise and air pollution collectively outrank all other environmental risk factors in importance, contributing to over 75% of the disease and disability burden associated with known environmental risk factors. In the first part of this review, we discussed the global burden and epidemiologic evidence supporting the importance of these novel risk factors as facilitators of cardiometabolic disease. In this part, we will discuss pathophysiological mechanisms responsible for noise and air pollution-mediated effects. Akin to traditional cardiovascular risk factors, a considerable body of evidence suggests that these environmental agents induce low-grade inflammation, oxidative stress, vascular dysfunction, and autonomic nervous system imbalance, thereby facilitating the development of diseases such as hypertension and diabetes. Through their impact on traditional risk factors and via additional novel mechanisms, environmental risk factors may have much larger impact on cardiovascular events than currently appreciated. In the second part of this review, we discuss deficiencies and gaps in knowledge and opportunities for new research.

Environmental stressors and cardio-metabolic disease: part I-epidemiologic evidence supporting a role for noise and air pollution and effects of mitigation strategies.

Traffic noise and air pollution together represent the two most important environmental risk factors in urbanized societies. The first of this two-part review discusses the epidemiologic evidence in support of the existence of an association between these risk factors with cardiovascular and metabolic disease. While independent effects of these risk factors have now clearly been shown, recent studies also suggest that the two exposures may interact with each other and with traditional risk factors such as hypertension and type 2 diabetes. From a societal and policy perspective, the health effects of both air pollution and traffic noise are observed for exposures well below the thresholds currently accepted as being safe. Current gaps in knowledge, effects of intervention and their impact on cardiovascular disease, will be discussed in the last section of this review. Increased awareness of the societal burden posed by these novel risk factors and acknowledgement in traditional risk factor guidelines may intensify the efforts required for effective legislation to reduce air pollution and noise.

CD36-dependent 7-ketocholesterol accumulation in macrophages mediates progression of atherosclerosis in response to chronic air pollution exposure.

RATIONALE: Air pollution exposure has been shown to potentiate plaque progression in humans and animals. Our previous studies have suggested a role for oxidized lipids in mediating adverse vascular effect of air pollution. However, the types of oxidized lipids formed in response to air pollutants and how this occurs and their relevance to atherosclerosis are not fully understood. OBJECTIVE: To investigate the mechanisms by which particulate matter <2.5 µm (PM2.5) induces progression of atherosclerosis. METHODS AND RESULTS: Atherosclerosis-prone ApoE(-/-) or LDLR(-/-) mice were exposed to filtered air or concentrated ambient PM2.5 using a versatile aerosol concentrator enrichment system for 6 months. PM2.5 increased 7-ketocholesterol (7-KCh), an oxidatively modified form of cholesterol, in plasma intermediate density lipoprotein/low-density lipoprotein fraction and in aortic plaque concomitant with progression of atherosclerosis and increased CD36 expression in plaque macrophages from PM2.5-exposed mice. Macrophages isolated from PM2.5-exposed mice displayed increased uptake of oxidized lipids without alterations in their efflux capacity. Consistent with these finding, CD36-positive macrophages displayed a heightened capacity for oxidized lipid uptake. Deficiency of CD36 on hematopoietic cells diminished the effect of air pollution on 7-KCh accumulation, foam cell formation, and atherosclerosis. CONCLUSIONS: Our results suggest a potential role for CD36-mediated abnormal accumulations of oxidized lipids, such as 7-KCh, in air pollution-induced atherosclerosis progression.

Aerosolized Silver Nanoparticles in the Rat Lung and Pulmonary Responses over Time.

Silver nanoparticle (Ag NP) production methods are being developed and refined to produce more uniform Ag NPs through chemical reactions involving silver salt solutions, solvents, and capping agents to control particle formation. These chemical reactants are often present as contaminants and/or coatings on the Ag NPs, which could alter their interactions in vivo. To determine pulmonary effects of citrate-coated Ag NPs, Sprague-Dawley rats were exposed once nose-only to aerosolized Ag NPs (20 nm [C20] or 110 nm [C110] Ag NPs) for 6 hr. Bronchoalveolar lavage fluid (BALF) and lung tissues were obtained at 1, 7, 21, and 56 days postexposure for analyses. Inhalation of Ag NPs, versus citrate buffer control, produced significant inflammatory and cytotoxic responses that were measured in BALF cells and supernatant. At day 7, total cells, protein, and lactate dehydrogenase were significantly elevated in BALF, and peak histopathology was noted after C20 or C110 exposure versus control. At day 21, BALF polymorphonuclear cells and tissue inflammation were significantly greater after C20 versus C110 exposure. By day 56, inflammation was resolved in Ag NP-exposed animals. Overall, results suggest delayed, short-lived inflammatory and cytotoxic effects following C20 or C110 inhalation and potential for greater responses following C20 exposure.

Exposure to fine airborne particulate matters induces hepatic fibrosis in murine models.

BACKGROUND & AIMS: Hepatic fibrosis, featured by the accumulation of excessive extracellular matrix in liver tissue, is associated with metabolic disease and cancer. Inhalation exposure to airborne particulate matter in fine ranges (PM2.5) correlates with pulmonary dysfunction, cardiovascular disease, and metabolic syndrome. In this study, we investigated the effect and mechanism of PM2.5 exposure on hepatic fibrogenesis. METHODS: Both inhalation exposure of mice and in vitro exposure of specialized cells to PM2.5 were performed to elucidate the effect of PM2.5 exposure on hepatic fibrosis. Histological examinations, gene expression analyses, and genetic animal models were utilized to determine the effect and mechanism by which PM2.5 exposure promotes hepatic fibrosis. RESULTS: Inhalation exposure to concentrated ambient PM2.5 induces hepatic fibrosis in mice under the normal chow or high-fat diet. Mice after PM2.5 exposure displayed increased expression of collagens in liver tissues. Exposure to PM2.5 led to activation of the transforming growth factor ß-SMAD3 signaling, suppression of peroxisome proliferator-activated receptor γ, and expression of collagens in hepatic stellate cells. NADPH oxidase plays a critical role in PM2.5-induced liver fibrogenesis. CONCLUSIONS: Exposure to PM2.5 exerts discernible effects on promoting hepatic fibrogenesis. NADPH oxidase mediates the effects of PM2.5 exposure on promoting hepatic fibrosis.

Malignant human cell transformation of Marcellus Shale gas drilling flow back water.

The rapid development of high-volume horizontal hydraulic fracturing for mining natural gas from shale has posed potential impacts on human health and biodiversity. The produced flow back waters after hydraulic stimulation are known to carry high levels of saline and total dissolved solids. To understand the toxicity and potential carcinogenic effects of these wastewaters, flow back waters from five Marcellus hydraulic fracturing oil and gas wells were analyzed. The physicochemical nature of these samples was analyzed by inductively coupled plasma mass spectrometry and scanning electron microscopy/energy dispersive X-ray spectroscopy. A cytotoxicity study using colony formation as the endpoint was carried out to define the LC50 values of test samples using human bronchial epithelial cells (BEAS-2B). The BEAS-2B cell transformation assay was employed to assess the carcinogenic potential of the samples. Barium and strontium were among the most abundant metals in these samples and the same metals were found to be elevated in BEAS-2B cells after long-term treatment. BEAS-2B cells treated for 6weeks with flow back waters produced colony formation in soft agar that was concentration dependent. In addition, flow back water-transformed BEAS-2B cells show better migration capability when compared to control cells. This study provides information needed to assess the potential health impact of post-hydraulic fracturing flow back waters from Marcellus Shale natural gas mining.