Publications by authors named "Kent E Pinkerton"

178 Publications

Impact of e-Liquid Composition, Coil Temperature, and Puff Topography on the Aerosol Chemistry of Electronic Cigarettes.

Chem Res Toxicol 2021 May 5. Epub 2021 May 5.

Department of Environmental Toxicology, University of California at Davis, Davis, California 95616, United States.

E-cigarette aerosol is a complex mixture of gases and particles with a composition that is dependent on the e-liquid formulation, puffing regimen, and device operational parameters. This work investigated mainstream aerosols from a third generation device, as a function of coil temperature (315-510 °F, or 157-266 °C), puff duration (2-4 s), and the ratio of propylene glycol (PG) to vegetable glycerin (VG) in e-liquid (100:0-0:100). Targeted and untargeted analyses using liquid chromatography high-resolution mass spectrometry, gas chromatography, in situ chemical ionization mass spectrometry, and gravimetry were used for chemical characterizations. PG and VG were found to be the major constituents (>99%) in both phases of the aerosol. Most e-cigarette components were observed to be volatile or semivolatile under the conditions tested. PG was found almost entirely in the gas phase, while VG had a sizable particle component. Nicotine was only observed in the particle phase. The production of aerosol mass and carbonyl degradation products dramatically increased with higher coil temperature and puff duration, but decreased with increasing VG fraction in the e-liquid. An exception is acrolein, which increased with increasing VG. The formation of carbonyls was dominated by the heat-induced dehydration mechanism in the temperature range studied, yet radical reactions also played an important role. The findings from this study identified open questions regarding both pathways. The vaping process consumed PG significantly faster than VG under all tested conditions, suggesting that e-liquids become more enriched in VG and the exposure to acrolein significantly increases as vaping continues. It can be estimated that a 30:70 initial ratio of PG:VG in the e-liquid becomes almost entirely VG when 60-70% of e-liquid remains during the vaping process at 375 °F (191 °C). This work underscores the need for further research on the puffing lifecycle of e-cigarettes.
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http://dx.doi.org/10.1021/acs.chemrestox.1c00070DOI Listing
May 2021

MARCKS cooperates with NKAP to activate NF-kB signaling in smoke-related lung cancer.

Theranostics 2021 19;11(9):4122-4136. Epub 2021 Feb 19.

Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine and Center for Comparative Respiratory Biology and Medicine, University of California Davis, Davis, California, USA.

Cigarette smoking is a major risk factor for lung cancer development and progression; however, the mechanism of how cigarette smoke activates signaling pathways in promoting cancer malignancy remains to be established. Herein, we aimed to determine the contribution of a signaling protein, myristoylated alanine-rich C kinase substrate (MARCKS), in smoke-mediated lung cancer. We firstly examined the levels of phosphorylated MARCKS (phospho-MARCKS) in smoke-exposed human lung cancer cells and specimens as well as non-human primate airway epithelium. Next, the MARCKS-interactome and its gene networks were identified. We also used genetic and pharmacological approaches to verify the functionality and molecular mechanism of smoke-induced phospho-MARCKS. We observed that MARCKS becomes activated in airway epithelium and lung cancer cells in response to cigarette smoke. Functional proteomics revealed MARCKS protein directly binds to NF-κB-activating protein (NKAP). Following MARCKS phosphorylation at ser159 and ser163, the MARCKS-NKAP interaction was inhibited, leading to the activation of NF-κB signaling. In a screen of two cohorts of lung cancer patients, we confirmed that phospho-MARCKS is positively correlated with phospho-NF-κB (phospho-p65), and poor survival. Surprisingly, smoke-induced phospho-MARCKS upregulated the expression of pro-inflammatory cytokines, epithelial-mesenchymal transition, and stem-like properties. Conversely, targeting of MARCKS phosphorylation with MPS peptide, a specific MARCKS phosphorylation inhibitor, suppressed smoke-mediated NF-κB signaling activity, pro-inflammatory cytokines expression, aggressiveness and stemness of lung cancer cells. Our results suggest that phospho-MARCKS is a novel NF-kB activator in smoke-mediated lung cancer progression and provide a promising molecular model for developing new anticancer strategies.
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http://dx.doi.org/10.7150/thno.53558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977464PMC
February 2021

E-Cigarettes and Cardiopulmonary Health.

Function (Oxf) 2021 8;2(2):zqab004. Epub 2021 Feb 8.

Dorothy M. Davis Heart and Lung Research Institute, Colleges of Medicine and Nursing, The Ohio State University, Columbus, OH, USA.

E-cigarettes have surged in popularity over the last few years, particularly among youth and young adults. These battery-powered devices aerosolize e-liquids, comprised of propylene glycol and vegetable glycerin, typically with nicotine, flavors, and stabilizers/humectants. Although the use of combustible cigarettes is associated with several adverse health effects including multiple pulmonary and cardiovascular diseases, the effects of e-cigarettes on both short- and long-term health have only begun to be investigated. Given the recent increase in the popularity of e-cigarettes, there is an urgent need for studies to address their potential adverse health effects, particularly as many researchers have suggested that e-cigarettes may pose less of a health risk than traditional combustible cigarettes and should be used as nicotine replacements. This report is prepared for clinicians, researchers, and other health care providers to provide the current state of knowledge on how e-cigarette use might affect cardiopulmonary health, along with research gaps to be addressed in future studies.
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http://dx.doi.org/10.1093/function/zqab004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948134PMC
February 2021

Climate Change and the Amplification of Agricultural Worker Health Risks.

J Agromedicine 2021 01 25;26(1):15-17. Epub 2021 Jan 25.

Western Center for Agricultural Health and Safety, University of California, Davis, CA, USA.

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http://dx.doi.org/10.1080/1059924X.2021.1849211DOI Listing
January 2021

Direct Observations of Silver Nanowire-Induced Frustrated Phagocytosis among NR8383 Lung Alveolar Macrophages.

J Phys Chem B 2020 12 11;124(51):11584-11592. Epub 2020 Dec 11.

Biophysics Graduate Group, University of California, Davis, California 95616, United States.

The interaction of long nanowires and living cells is directly related to nanowires' nanotoxicity and health impacts. Interactions of silver nanowires (AgNWs) and macrophage cell lines (NR8383) were investigated using laser scanning confocal microscopy and single cell compression (SCC). With high-resolution imaging and mechanics measurement of individual cells, AgNW-induced frustrated phagocytosis was clearly captured in conjunction with structural and property changes of cells. While frustrated phagocytosis is known for long microwires and long carbon nanotubes, this work reports first direct observations of frustrated phagocytosis of AgNWs among living cells in situ. In the case of partial penetration of AgNWs into NR8383 cells, confocal imaging revealed actin participation at the entry sites, whose behavior differs from microwire-induced frustrated phagocytosis. The impacts of frustrated phagocytosis on the cellular membrane and cytoskeleton were also quantified by measuring the mechanical properties using SCC. Taken collectively, this study reveals the structural and property characteristics of nanowire-induced frustrated phagocytosis, which deepens our understanding of nanowire-cell interactions and nanocytotoxicity.
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http://dx.doi.org/10.1021/acs.jpcb.0c08132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869824PMC
December 2020

Rapid Response to COVID-19 in Agriculture: A Model for Future Crises.

J Agromedicine 2020 10 8;25(4):392-395. Epub 2020 Sep 8.

Western Center for Agricultural Health and Safety, University of California, Davis , Davis, CA, USA.

The Western Center for Agricultural Health and Safety (WCAHS) at the University of California, Davis implemented a multifaceted rapid response to COVID-19 in the western United States. This paper describes the center's response from mid-March through June 30, 2020. : A comprehensive needs assessment was conducted with agricultural stakeholders. Agriculture-specific COVID-19 resources were developed and disseminated, and a farmer/employer survey was launched. : The WCAHS COVID-19 resources web page, worksite checklist, and training guide were shared on over 50 web pages nationally. As of June 30, 2020, 282 online surveys have been received. Ongoing informal discussions with agricultural stakeholders indicate a disconnect between the experiences of farmers/employers and farmworkers in relation to COVID-19 prevention at the worksite. Initial survey responses indicate that implementing social distancing is one of the greatest challenges at the worksite. Confusion over local, state, and federal guidelines and which to follow is another concern. : The WCAHS response to COVID-19, in close collaboration with agricultural stakeholders, represents a useful model for a rapid response to a public health crisis by regional centers. Key elements to its success include rapid personalized communication with a wide range of agricultural stakeholders, an actively engaged External Advisory Board, the development of industry-specific resources and information, recurring and iterative engagement with stakeholders as new COVID-19 information emerged and resources were developed, and the identification of the unique gap WCAHS was positioned to fill. The multipronged dissemination approach enhanced the reach of WCAHS COVID-19 resources.
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http://dx.doi.org/10.1080/1059924X.2020.1815618DOI Listing
October 2020

Differential lung inflammation and injury with tobacco smoke exposure in Wistar Kyoto and spontaneously hypertensive rats.

Inhal Toxicol 2020 07 11;32(8):328-341. Epub 2020 Aug 11.

Center for Health and the Environment, University of California, Davis, CA, USA.

Objective: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide and has been associated with periods of intense lung inflammation. The objective of this study was to characterize whether similar rat strains, possessing different genetic predispositions, might play a role in exacerbating the pathophysiology of COPD-like cellular and structural changes with progressive 12-week exposure to tobacco smoke (TS). Normotensive Wistar Kyoto (WKY) and spontaneously hypertensive (SH) rats were compared.

Materials And Methods: WKY and SH rats were exposed to filtered air or to tobacco smoke at a particulate concentration of 80 mg/m for 4, 8, or 12 weeks. Necropsy was performed 24 h after the last exposure to obtain cells by bronchoalveolar lavage for total cell and differential counts. Scoring of lung tissues and immunohistochemical staining for M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages were performed on paraffin-embedded lung sections.

Results And Discussion: With progressive exposure, TS-exposed SH rats demonstrated significant airspace enlargement, mucin production, and lung inflammation compared to their FA control and TS-matched WKY rats. Moreover, SH rats also demonstrated increased expression of the M1 marker in alveolar macrophages compared to FA control, as well as the M2 marker compared to controls and TS-exposed WKY rats.

Conclusion: The progressive tobacco smoke exposure contributes to persistent lung injury and inflammation that can be significantly enhanced by rat strain susceptibility in the genesis of COPD.
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http://dx.doi.org/10.1080/08958378.2020.1805052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034838PMC
July 2020

Editorial: Extreme Weather Resulting from Global Warming is an Emerging Threat to Farmworker Health and Safety.

J Agric Saf Health 2019 Oct;25(4):189-190

A warming climate has been linked to an increase in the frequency and severity of extreme weather events, including heat and cold waves, extreme precipitation, and wildfires. This increase in extreme weather results in increased risks to the health and safety of farmworkers.
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http://dx.doi.org/10.13031/jash.13555DOI Listing
October 2019

In vivo and in vitro inflammatory responses to fine particulate matter (PM) from China and California.

Toxicol Lett 2020 Aug 19;328:52-60. Epub 2020 Apr 19.

Center for Health and the Environment, University of California, Davis, USA. Electronic address:

Ambient PM was collected during the winter season from Taiyuan, Shanxi, China; Jinan, Shandong, China; and Sacramento, California, USA, and used to create PM, PM, and PM extracts, respectively. Time-lag experiments were performed to explore the in vivo and in vitro toxicity of the PM extracts. In vivo inflammatory lung responses were assessed in BALB/c mice using a single oropharyngeal aspiration (OPA) of PM extract or vehicle (CTRL) on Day 0. Necropsies were performed on Days 1, 2, and 4 post-OPA, and pulmonary effects were determined using bronchoalveolar lavage (BAL) and histopathology. On Day 1, BAL neutrophils were significantly elevated in all PM- versus CTRL-exposed mice, with PM producing the strongest response. However, histopathological scoring showed greater alveolar and perivascular effects in PM-exposed mice compared to all three other groups. By Day 4, BAL neutrophilia and tissue inflammation were resolved, similar across all groups. In vitro effects were examined in human HepG2 hepatocytes, and U937 cells following 6, 24, or 48 h of exposure to PM extract or DMSO (control). Luciferase reporter and quantitative polymerase chain reaction assays were used to determine in vitro effects on aryl hydrocarbon receptor (AhR) activation and gene transcription, respectively. Though all three PM extracts activated AhR, PM produced the greatest increases in AhR activation, and mRNA levels of cyclooxygenase-2, cytochrome P450, interleukin (IL)-8, and interleukin (IL)-1β. These effects were assumed to result from a greater abundance of polycyclic aromatic hydrocarbons (PAHs) in PM compared to PM and PM.
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http://dx.doi.org/10.1016/j.toxlet.2020.04.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641014PMC
August 2020

Application of High-Resolution Mass Spectrometry and a Theoretical Model to the Quantification of Multifunctional Carbonyls and Organic Acids in e-Cigarette Aerosol.

Environ Sci Technol 2020 05 23;54(9):5640-5650. Epub 2020 Apr 23.

Department of Environmental Toxicology, University of California Davis, Davis, California 95616, United States.

Electronic (e-) cigarette aerosol (particle and gas) is a complex mixture of chemicals, of which the profile is highly dependent on device operating parameters and e-liquid flavor formulation. The thermal degradation of the e-liquid solvents propylene glycol and glycerol often generates multifunctional carbonyls that are challenging to quantify because of unavailability of standards. We developed a theoretical method to calculate the relative electrospray ionization sensitivities of hydrazones of organic acids and carbonyls with 2,4-dinitrophenylhydrazine based on their gas-phase basicities (Δ). This method enabled quantification by high-performance liquid chromatography-high-resolution mass spectrometry HPLC-HRMS in the absence of chemical standards. Accurate mass and tandem multistage MS (MS) were used for structure identification of vaping products. We quantified five simple carbonyls, six hydroxycarbonyls, four dicarbonyls, three acids, and one phenolic carbonyl in the e-cigarette aerosol with Classic Tobacco flavor. Our results suggest that hydroxycarbonyls, such as hydroxyacetone, lactaldehyde, and dihydroxyacetone can be significant components in e-cigarette aerosols but have received less attention in the literature and have poorly understood health effects. The data support the radical-mediated e-liquid thermal degradation scheme that has been previously proposed and emphasize the need for more research on the chemistry and toxicology of the complex product formation in e-cigarette aerosols.
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http://dx.doi.org/10.1021/acs.est.9b07387DOI Listing
May 2020

Outdoor Air Pollution and New-Onset Airway Disease. An Official American Thoracic Society Workshop Report.

Ann Am Thorac Soc 2020 04;17(4):387-398

Although it is well accepted that air pollution exposure exacerbates preexisting airway disease, it has not been firmly established that long-term pollution exposure increases the risk of new-onset asthma or chronic obstruction pulmonary disease (COPD). This Workshop brought together experts on mechanistic, epidemiological, and clinical aspects of airway disease to review current knowledge regarding whether air pollution is a causal factor in the development of asthma and/or COPD. Speakers presented recent evidence in their respective areas of expertise related to air pollution and new airway disease incidence, followed by interactive discussions. A writing committee summarized their collective findings. The Epidemiology Group found that long-term exposure to air pollution, especially metrics of traffic-related air pollution such as nitrogen dioxide and black carbon, is associated with onset of childhood asthma. However, the evidence for a causal role in adult-onset asthma or COPD remains insufficient. The Mechanistic Group concluded that air pollution exposure can cause airway remodeling, which can lead to asthma or COPD, as well as asthma-like phenotypes that worsen with long-term exposure to air pollution, especially fine particulate matter and ozone. The Clinical Group concluded that air pollution is a plausible contributor to the onset of both asthma and COPD. Available evidence indicates that long-term exposure to air pollution is a cause of childhood asthma, but the evidence for a similar determination for adult asthma or COPD remains insufficient. Further research is needed to elucidate the exact biological mechanism underlying incident childhood asthma, and the specific air pollutant that causes it.
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http://dx.doi.org/10.1513/AnnalsATS.202001-046STDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175976PMC
April 2020

Engineered metal oxide nanomaterials inhibit corneal epithelial wound healing and .

NanoImpact 2020 Jan 6;17. Epub 2019 Dec 6.

Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California - Davis, Davis, CA, 95616, USA.

Ocular exposure to metal oxide engineered nanomaterials (ENMs) is common as exemplified by zinc oxide (ZnO), a major constituent of sunscreens and cosmetics. The ocular surface that includes the transparent cornea and its protective tear film are common sites of exposure for metal ENMs. Despite the frequency of exposure of the ocular surface, there is a knowledge gap regarding the effects of metal oxide ENMs on the cornea in health and disease. Therefore, we studied the effects of metal oxide ENMs on the cornea in the presence or absence of injury. Cell viability of immortalized human corneal epithelial (hTCEpi) cells was assessed following treatment with 11 metal oxide ENMs with a concentration ranging from 0.5 to 250 μg/mL for 24 hours. An epithelial wound healing assay with a monolayer of hTCEpi cells was then performed using 11 metal oxide ENMs at select concentrations based on data from the viability assays. Subsequently, based on the results, testing of precorneal tear film (PTF) quantity and stability as well as a corneal epithelial wound healing were tested in the presence or absence ZnO or vanadium pentoxide (VO) at a concentration of 50 μg/mL. We found that WO, ZnO, VO and CuO ENMs significantly reduced hTCEpi cell viability in comparison to vehicle control or the other metal oxide ENMs tested. Furthermore, ZnO and VO ENMs also significantly decreased hTCEpi cell migration. Although ZnO and VO did not alter PTF parameters of rabbits , corneal epithelial wound healing was significantly delayed by topical ZnO while VO did not alter wound healing. Finally, hyperspectral images confirmed penetration of ZnO and VO through all corneal layers and into the iris stroma. Considering the marked epithelial toxicity and corneal penetration of ZnO, further investigations on the impact of this ENM on the eye are warranted.
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http://dx.doi.org/10.1016/j.impact.2019.100198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062360PMC
January 2020

Wildfire Smoke Exposure: Awareness and Safety Responses in the Agricultural Workplace.

J Agromedicine 2020 07 11;25(3):330-338. Epub 2020 Feb 11.

Western Center for Agricultural Health and Safety, University of California, Davis , Davis, CA, USA.

: The study examines how wildfire smoke exposure may impact health and safety in the agricultural workplace. : Semi-structured interviews were conducted with agricultural employers and focus group discussions were held with farmworkers in three regions of California. : Agricultural employers had varying knowledge about and experience responding to poor air quality due to wildfire smoke. Respirators or masks were not mentioned as a potential protective measure when describing their safety practices. Farmworkers reported experiencing poor air quality due to wildfire smoke, although knowledge of safety precautions varied. Farmworkers reported employer and supervisors' attitudes toward safety as having the greatest impact on the implementation of workplace safety measures. : Adapting health promotion and workplace safety strategies to meet the multiple vulnerabilities and diverse needs of farmworkers is critical to successful implementation of workplace protection and safety measures. Given limited familiarity with the topic, wildfire smoke exposure resources are needed to assist employers and supervisors in their compliance with a new wildfire smoke safety regulation in California. To the best of our knowledge, this is the first study to explore agricultural employer and farmworker perceptions of the health and safety impacts of wildfire smoke and workplace exposure.
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http://dx.doi.org/10.1080/1059924X.2020.1725699DOI Listing
July 2020

Long-Term Sequelae of Smoking and Cessation in Spontaneously Hypertensive Rats.

Toxicol Pathol 2020 04 24;48(3):422-436. Epub 2019 Dec 24.

Center for Health and the Environment, University of California, Davis, CA, USA.

Smoking is a major risk factor for heart attack, stroke, and lung cancer. Tobacco smoke (TS) causes bronchitis, emphysema, persistent cough, and dyspnea. Smoking cessation minimizes risks of TS-related disease. To determine whether smoking cessation could reverse TS-induced pulmonary changes, 10-week-old male spontaneously hypertensive rats were exposed to TS or filtered air (FA) for 39 weeks and allowed to live out their normal lifespan. Significantly ( ≤ .05) decreased survival was noted by 21 months in TS versus FA rats. In TS rats, persistent peribronchiolar, perivascular, alveolar, and subpleural inflammation were observed with pervasive infiltration of pigmented foamy macrophages and plausible intra-alveolar fibrosis and osseous metaplasia. Alveolar airspace was significantly ( ≤ .05) increased in TS versus FA rats as was the volume of stored epithelial mucosubstances in the left central axial airway. Increased mucin contributes to airflow obstruction and increased lung infection risks. Findings suggest TS-induced changes do not attenuate with smoking cessation but result in irreversible damage similar to chronic obstructive pulmonary disease. The observed persistent pulmonary changes mirror common TS effects such as chest congestion, sputum production, and shortness of breath long after smoking cessation and represent important targets for treatment of former smokers.
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http://dx.doi.org/10.1177/0192623319893312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113118PMC
April 2020

Respiratory Health Effects of Exposure to Ambient Particulate Matter and Bioaerosols.

Compr Physiol 2019 12 18;10(1):1-20. Epub 2019 Dec 18.

Center for Health and the Environment, John Muir Institute of the Environment, University of California, Davis, California, USA.

Researchers have been studying the respiratory health effects of ambient air pollution for more than 70 years. While air pollution as a whole can include gaseous, solid, and liquid constituents, this article focuses only on the solid and liquid fractions, termed particulate matter (PM). Although PM may contain anthropogenic, geogenic, and/or biogenic fractions, in this article, particles that originate from microbial, fungal, animal, or plant sources are distinguished from PM as bioaerosols. Many advances have been made toward understanding which particle and exposure characteristics most influence deposition and clearance processes in the respiratory tract. These characteristics include particle size, shape, charge, and composition as well as the exposure concentration and dose rate. Exposure to particles has been directly associated with the exacerbation and, under certain circumstances, onset of respiratory disease. The circumstances of exposure leading to disease are dependent on stressors such as human activity level and changing particle composition in the environment. Historically, researchers assumed that bioaerosols were too large to be inhaled into the deep lung, and thus, not applicable for study in conjunction with PM (the 2.5-μm and below size fraction that can reach the deep lung); however, this concept is beginning to be challenged. While there is extensive research on the health effects of PM and bioaerosols independent of each other, only limited work has been performed on their coexposure. Studying these two particle types as dual stressors to the respiratory system may aid in more thoroughly understanding the etiology of respiratory injury and disease. © 2020 American Physiological Society. Compr Physiol 10:1-20, 2020.
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http://dx.doi.org/10.1002/cphy.c180040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553137PMC
December 2019

Cardiopulmonary Health Effects of Airborne Particulate Matter: Correlating Animal Toxicology to Human Epidemiology.

Toxicol Pathol 2019 12 23;47(8):954-961. Epub 2019 Oct 23.

Center for Health and the Environment, University of California, Davis, USA.

The effects of particulate matter (PM) on cardiopulmonary health have been studied extensively over the past three decades. Particulate matter is the primary criteria air pollutant most commonly associated with adverse health effects on the cardiovascular and respiratory systems. The mechanisms by which PM exerts its effects are thought to be due to a variety of factors which may include, but are not limited to, concentration, duration of exposure, and age of exposed persons. Adverse effects of PM are strongly driven by their physicochemical properties, sites of deposition, and interactions with cells of the respiratory and cardiovascular systems. The direct translocation of particles, as well as neural and local inflammatory events, are primary drivers for the observed cardiopulmonary health effects. In this review, toxicological studies in animals, and clinical and epidemiological studies in humans are examined to demonstrate the importance of using all three approaches to better define potential mechanisms driving health outcomes upon exposure to airborne PM of diverse physicochemical compositions.
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http://dx.doi.org/10.1177/0192623319879091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911013PMC
December 2019

Alveolar macrophage reaction to PM of hazy day in vitro: Evaluation methods and mitochondrial screening to determine mechanisms of biological effect.

Ecotoxicol Environ Saf 2019 Jun 11;174:566-573. Epub 2019 Mar 11.

Department of Chemistry, Inha University, Incheon 402751, Republic of Korea.

Hazy weather in China has recently become a major public health concern due to high levels of atmospheric fine particulate matter (PM) with a large amount of polycyclic aromatic hydrocarbon (PAHs). In this study, the mass concentration of PAHs in hazy PM in urban Taiyuan city, China was determined and toxicities of different dosage of the hazy PM on rat alveolar macrophages (AMs) were examined. It was found that the hazy PM, bounded with many species of PAHs (CHR, BbF, BaP, BaA, and etc.), significantly increased cellular malondialdehyde (MDA) content followed by the decreasing in superoxide (SOD) and glutathione peroxidase (GPx) in AMs. They induced mitochondrial changes in ultrastructure as evidenced by mitochondrial swelling and cristae disorganization, and a dose-dependent decrease in mitochondrial profile density. Also, the mRNA expression levels of mitochondrial fusion-related genes were modified. The Mfn1 and Mfn2 which are essential for mitochondrial fusion increased significantly in hazy PM-treated group compared to the control in a dose-dependent manner, OPA1 was significantly increased at the highest PM dose delivered. These findings suggested that exposure to hazy PM could activate oxidative stress pathways in AMs, resulting in abnormal mitochondrial morphology and fusion/fission frequency. Possibly, the toxic effects were mostly attributed to the high burden of varied PAHs in hazy PM.
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http://dx.doi.org/10.1016/j.ecoenv.2019.02.093DOI Listing
June 2019

Age-dependent pulmonary reactivity to house dust mite allergen: a model of adult-onset asthma?

Am J Physiol Lung Cell Mol Physiol 2019 05 6;316(5):L757-L763. Epub 2019 Mar 6.

Center for Health and the Environment, University of California , Davis, California.

Asthma is a heterogeneous disease differentiated by factors like allergen sensitivity, inflammation, sex, and age at onset. The mouse model is widely used to study the early-life development of allergic asthma. However, age-dependent allergen responses later in life remain relatively understudied and lack a widely accepted model. To differentiate age-dependent responses to the ubiquitous house dust mite (HDM), 3- and 9-mo-old female C57BL/6 mice were randomized into two groups each and exposed to HDM or phosphate-buffered saline (control) via intranasal instillation for sensitization and challenge phases. At 24 h after challenge, all mice underwent pulmonary function testing and methacholine challenge. Bronchoalveolar lavage fluid (BALF) was collected for assessment of cell differentials, and right lung lobes were fixed, sectioned, and stained for histopathology and immunohistochemistry. Both age groups demonstrated strong inflammatory/allergic responses to HDM exposure. However, only 9-mo-old HDM-exposed mice demonstrated significant airway hyperresponsiveness compared with age-matched controls. These HDM-exposed mice also had ) statistically significant increases in tissue bronchiolitis, perivasculitis, and BALF neutrophilia relative to their younger counterparts and ) significantly increased extent of immunostaining compared with all other groups. This study presents a potential model for adult-onset asthma, focusing specifically on the atopic, perimenopausal female phenotype. Our findings suggest that lung function declines with age and that the inflammatory profile of this adult subgroup is a mixed, rather than a simple, atopic, Th2 response. This model may enhance our understanding of how age influences the development of asthmic-like symptoms in older subgroups.
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http://dx.doi.org/10.1152/ajplung.00468.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589581PMC
May 2019

Exposure to Secondhand Smoke and Arrhythmogenic Cardiac Alternans in a Mouse Model.

Environ Health Perspect 2018 12;126(12):127001

Department of Pharmacology, University of California, Davis, Davis, California, USA.

Background: Epidemiological evidence suggests that a majority of deaths attributed to secondhand smoke (SHS) exposure are cardiovascular related. However, to our knowledge, the impact of SHS on cardiac electrophysiology, [Formula: see text] handling, and arrhythmia risk has not been studied.

Objectives: The purpose of this study was to investigate the impact of an environmentally relevant concentration of SHS on cardiac electrophysiology and indicators of arrhythmia.

Methods: Male C57BL/6 mice were exposed to SHS [total suspended particles (THS): [Formula: see text], nicotine: [Formula: see text], carbon monoxide: [Formula: see text], or filtered air (FA) for 4, 8, or 12 wk ([Formula: see text]]. Hearts were excised and Langendorff perfused for dual optical mapping with voltage- and [Formula: see text]-sensitive dyes.

Results: At slow pacing rates, SHS exposure did not alter baseline electrophysiological parameters. With increasing pacing frequency, action potential duration (APD), and intracellular [Formula: see text] alternans magnitude progressively increased in all groups. At 4 and 8 wk, there were no statistical differences in APD or [Formula: see text] alternans magnitude between SHS and FA groups. At 12 wk, both APD and [Formula: see text] alternans magnitude were significantly increased in the SHS compared to FA group ([Formula: see text]). SHS exposure did not impact the time constant of [Formula: see text] transient decay ([Formula: see text]) at any exposure time point. At 12 wk exposure, the recovery of [Formula: see text] transient amplitude with premature stimuli was slightly (but nonsignificantly) delayed in SHS compared to FA hearts, suggesting that [Formula: see text] release via ryanodine receptors may be impaired.

Conclusions: In male mice, chronic exposure to SHS at levels relevant to social situations in humans increased their susceptibility to cardiac alternans, a known precursor to ventricular arrhythmia. https://doi.org/10.1289/EHP3664.
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http://dx.doi.org/10.1289/EHP3664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6371715PMC
December 2018

Effects of aging and environmental tobacco smoke exposure on ocular and plasma circulatory microRNAs in the Rhesus macaque.

Mol Vis 2018 24;24:633-646. Epub 2018 Sep 24.

Department of Ophthalmology & Vision Science, School of Medicine, University of California, Davis, Davis, CA.

Purpose: To identify changes induced by environmental tobacco smoke (ETS) in circulatory microRNA (miRNA) in plasma and ocular fluids of the Rhesus macaque and compare these changes to normal age-related changes. Tobacco smoke has been identified as the leading environmental risk factor for age-related macular degeneration (AMD).

Methods: All Rhesus macaques were housed at the California National Primate Research Center (CNPRC), University of California, Davis. Four groups of animals were used: Group 1 (1-3 years old), Group 2 (19-28 years old), Group 3 (10-16 years old), and Group 4 (middle aged, 9-14 years old). Group 4 was exposed to smoke for 1 month. Ocular fluids and plasma samples were collected, miRNAs isolated, and expression data obtained using Affymetrix miRNA GeneTitan Array Plates 4.0. Bioinformatics analysis was done on the Affymetrix Expression Console (EC), Transcriptome Analysis Software (TAS) using ANOVA for candidate miRNA selection, followed by Ingenuity Pathway Analysis (IPA).

Results: The expression of circulatory miRNAs showed statistically significant changes with age and ETS. In the plasma samples, 45 miRNAs were strongly upregulated (fold change >±1.5, p<0.05) upon ETS exposure. In the vitreous, three miRNAs were statistically significantly downregulated with ETS, and two of them (miR-6794 and miR-6790) were also statistically significantly downregulated with age. Some retinal layers exhibited a thinning trend measured with optical coherence tomography (OCT) imaging. The pathways activated were IL-17A, VEGF, and recruitment of eosinophils, Th2 lymphocytes, and macrophages.

Conclusions: ETS exposure of Rhesus macaques resulted in statistically significant changes in the expression of the circulatory miRNAs, distinct from those affected by aging. The pathways activated appear to be common for ETS and AMD pathogenesis. These data will be used to develop an animal model of early dry AMD.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161805PMC
November 2018

Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice.

Science 2018 09;361(6409)

Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.

Cancer cells from a primary tumor can disseminate to other tissues, remaining dormant and clinically undetectable for many years. Little is known about the cues that cause these dormant cells to awaken, resume proliferating, and develop into metastases. Studying mouse models, we found that sustained lung inflammation caused by tobacco smoke exposure or nasal instillation of lipopolysaccharide converted disseminated, dormant cancer cells to aggressively growing metastases. Sustained inflammation induced the formation of neutrophil extracellular traps (NETs), and these were required for awakening dormant cancer. Mechanistic analysis revealed that two NET-associated proteases, neutrophil elastase and matrix metalloproteinase 9, sequentially cleaved laminin. The proteolytically remodeled laminin induced proliferation of dormant cancer cells by activating integrin α3β1 signaling. Antibodies against NET-remodeled laminin prevented awakening of dormant cells. Therapies aimed at preventing dormant cell awakening could potentially prolong the survival of cancer patients.
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http://dx.doi.org/10.1126/science.aao4227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777850PMC
September 2018

Exposure to tobacco smoke increases bone loss in spontaneously hypertensive rats.

Inhal Toxicol 2018 05 26;30(6):229-238. Epub 2018 Sep 26.

a Department of Endocrinology , First Affiliated Hospital of Xi'an Jiaotong University , Xi'an , China.

Purpose: To define if exposure to tobacco smoke (TS) could induce reduction of bone mass and impairment of bone architecture, features observed in osteoporosis in normotensive rats and the influence of TS exposure on the osteoporotic features exhibited in the spontaneously hypertensive (SH) rats.

Methods: Normotensive Wistar Kyoto (WKY) and SH rats were exposed to filtered air or TS for 8 weeks, then their proximal femurs were extracted for micro-computed tomography (micro-CT) assessment, histological and immune-histological examinations to quantify the adverse influence of TS exposure on the bone mass and density, as well as bone architecture.

Results: We found that TS exposure not only induced significant decreases in bone mineral density (BMD), bone volume (BV), cortical and trabecular thickness (Ct.Th and Tb.Th), trabecular surface area (Tb.Ar), expression of hypoxia-inducible factor-1α (HIF-1α) in the trabecular marrow, delayed ossification of cartilage, as well as statistical increases in trabecular separation (Tb.SP) and the number of trabecular marrow adipocytes in both WKY and SH rats, but also exacerbated multiple features of osteoporosis exhibited in SH rats, including decreased BMD, Ct.Th, Tb.Ar, HIF-1α expression, delayed cartilage ossification, and increased Tb.SP.

Conclusions: Our results show that TS exposure can reduce bone mass and impair bone architecture and exacerbate multiple features of osteoporosis exhibited in SH rats.
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http://dx.doi.org/10.1080/08958378.2018.1506838DOI Listing
May 2018

Ambient particulate matter enhances the pulmonary allergic immune response to house dust mite in a BALB/c mouse model by augmenting Th2- and Th17-immune responses.

Physiol Rep 2018 09;6(18):e13827

Center for Health and the Environment, University of California, Davis, California.

Ambient particulate matter (PM) exacerbates airway inflammation and hyper-reactivity in asthmatic patients. Studies show that PM has adjuvant-like properties that enhance the allergic inflammatory response; however, the mechanisms through which PM enhances these processes remain elusive. The objective of the study was to examine how ambient PM enhances the allergic immune response. Eight-week-old BALB/c mice were sensitized with house dust mite (HDM) or HDM and ambient particulate matter (PM, 2.5 μm; Sacramento, CA) to assess how PM modulates the development of adaptive immune responses against allergens. Both groups were challenged with HDM only. Bronchoalveolar lavage (BAL) was analyzed for extent of airway inflammation. Lung tissue was used for histological analysis, mucosubstance quantification, and heme oxygenase-1 (HO-1) localization/quantification. Gene expression was analyzed in whole lung to characterize immune markers of inflammation: cytokines, chemokines, antioxidant enzymes, and transcription factors. Cytokine and chemokine protein levels were quantified in whole lung to confirm gene expression patterns. Compared to HDM-only sensitization, exposure to PM during HDM sensitization led to significant immune cell recruitment into the airway subepithelium, IgE gene expression, mucosubstance production, and Th2-associated cytokine expression. HO-1 levels were not significantly different between the treatment groups. Gene expression profiles suggest that polycyclic aromatic hydrocarbon (PAH) content in PM activated the aryl hydrocarbon receptor (AhR) and enhanced Th17-responses in the mice that received HDM and PM compared to mice that received HDM-only. The findings suggest that PM enhances allergic sensitization via enhancement of Th2-mediated inflammation and that AhR activation by PAHs in PM promotes Th17-immune responses.
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http://dx.doi.org/10.14814/phy2.13827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6144457PMC
September 2018

Harmful Interruptions: Impact of Smoking Patterns on Tumorigenesis and Emphysema.

Am J Respir Cell Mol Biol 2018 08;59(2):133-134

1 Center for Health and the Environment University of California, Davis Davis, California.

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http://dx.doi.org/10.1165/rcmb.2018-0151EDDOI Listing
August 2018

TH17-Induced Neutrophils Enhance the Pulmonary Allergic Response Following BALB/c Exposure to House Dust Mite Allergen and Fine Particulate Matter From California and China.

Toxicol Sci 2018 08;164(2):627-643

Center for Health and the Environment.

Asthma is a global and increasingly prevalent disease. According to the World Health Organization, approximately 235 million people suffer from asthma. Studies suggest that fine particulate matter (PM2.5) can induce innate immune responses, promote allergic sensitization, and exacerbate asthmatic symptoms and airway hyper-responsiveness. Recently, severe asthma and allergic sensitization have been associated with T-helper cell type 17 (TH17) activation. Few studies have investigated the links between PM2.5 exposure, allergic sensitization, asthma, and TH17 activation. This study aimed to determine whether (1) low-dose extracts of PM2.5 from California (PMCA) or China (PMCH) enhance allergic sensitization in mice following exposure to house dust mite (HDM) allergen; (2) eosinophilic or neutrophilic inflammatory responses result from PM and HDM exposure; and (3) TH17-associated cytokines are increased in the lung following exposure to PM and/or HDM. Ten-week-old male BALB/c mice (n = 6-10/group) were intranasally instilled with phosphate-buffered saline (PBS), PM+PBS, HDM, or PM+HDM, on days 1, 3, and 5 (sensitization experiments), and PBS or HDM on days 12-14 (challenge experiments). Pulmonary function, bronchoalveolar lavage cell differentials, plasma immunoglobulin (Ig) protein levels, and lung tissue pathology, cyto-/chemo-kine proteins, and gene expression were assessed on day 15. Results indicated low-dose PM2.5 extracts can enhance allergic sensitization and TH17-associated responses. Although PMCA+HDM significantly decreased pulmonary function, and significantly increased neutrophils, Igs, and TH17-related protein and gene levels compared with HDM, there were no significant differences between HDM and PMCH+HDM treatments. This may result from greater copper and oxidized organic content in PMCA versus PMCH.
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http://dx.doi.org/10.1093/toxsci/kfy127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061684PMC
August 2018

Ambient particulate matter activates the aryl hydrocarbon receptor in dendritic cells and enhances Th17 polarization.

Toxicol Lett 2018 Aug 22;292:85-96. Epub 2018 Apr 22.

Center for Health and the Environment, University of California, Davis, 95616, USA; Department of Environmental Toxicology, University of California, Davis, 95616, USA. Electronic address:

The objective of this study was to explore the role of the aryl hydrocarbon receptor (AhR) in ambient particulate matter (PM)-mediated activation of dendritic cells (DCs) and Th17-immune responses in vitro. To assess the potential role of the AhR in PM-mediated activation of DCs, co-stimulation, and cytokine expression, bone marrow (BM)-derived macrophages and DCs from C57BL/6 wildtype or AhR knockout (AhR) mice were treated with PM. Th17 differentiation was assessed via co-cultures of wildtype or AhR BMDCs with autologous naive T cells. PM significantly induced AhR DNA binding activity to dioxin responsive elements (DRE) and expression of the AhR repressor (AhRR), cytochrome P450 (CYP) 1A1, and CYP1B1, indicating activation of the AhR. In activated (OVA sensitized) BMDCs, PM induced interleukin (IL)-1β, CD80, CD86, and MHC class II, suggesting enhanced DC activation, co-stimulation, and antigen presentation; responses that were abolished in AhR deficient DCs. DC-T cell co-cultures treated with PM and lipopolysaccharide (LPS) led to elevated IL-17A and IL-22 expression at the mRNA level, which is mediated by the AhR. PM-treated DCs were essential in endowing T cells with a Th17-phenotype, which was associated with enhanced expression of MHC class II and cyclooxygenase (COX)-2. In conclusion, PM enhances DC activation that primes naive T cell differentiation towards a Th17-like phenotype in an AhR-dependent manner.
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http://dx.doi.org/10.1016/j.toxlet.2018.04.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5971007PMC
August 2018

Realizing the Paris Climate Agreement to Improve Cardiopulmonary Health. Where Science Meets Policy.

Ann Am Thorac Soc 2018 07;15(7):791-798

10 Department of Environmental Medicine, New York University School of Medicine, New York, New York.

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http://dx.doi.org/10.1513/AnnalsATS.201803-203PSDOI Listing
July 2018

Nonhuman Primate Models of Respiratory Disease: Past, Present, and Future.

ILAR J 2017 12;58(2):269-280

Department of Anatomy, Physiology & Cell Biology, UC Davis School of Veterinary Medicine, University of California, Davis, California.

The respiratory system consists of an integrated network of organs and structures that primarily function for gas exchange. In mammals, oxygen and carbon dioxide are transmitted through a complex respiratory tract, consisting of the nasal passages, pharynx, larynx, and lung. Exposure to ambient air throughout the lifespan imposes vulnerability of the respiratory system to environmental challenges that can contribute toward development of disease. The importance of the respiratory system to human health is supported by statistics from the Centers for Disease Control and Prevention; in 2015, chronic lower respiratory diseases were the third leading cause of death in the United States. In light of the significant mortality associated with respiratory conditions that afflict all ages of the human population, this review will focus on basic and preclinical research conducted in nonhuman primate models of respiratory disease. In comparison with other laboratory animals, the nonhuman primate lung most closely resembles the human lung in structure, physiology, and mucosal immune mechanisms. Studies defining the influence of inhaled microbes, pollutants, or allergens on the nonhuman primate lung have provided insight on disease pathogenesis, with the potential for elucidation of molecular targets leading to new treatment modalities. Vaccine trials in nonhuman primates have been crucial for confirmation of safety and protective efficacy against infectious diseases of the lung in a laboratory animal model that recapitulates pathology observed in humans. In looking to the future, nonhuman primate models of respiratory diseases will continue to be instrumental for translating biomedical research for improvement of human health.
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http://dx.doi.org/10.1093/ilar/ilx030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886323PMC
December 2017

Perinatal exposure to environmental tobacco smoke is associated with changes in DNA methylation that precede the adult onset of lung disease in a mouse model.

Inhal Toxicol 2017 08;29(10):435-442

a Department of Biomedical and Pharmaceutical Sciences , University of Montana , Missoula , MT , USA.

Prenatal and early-life environmental tobacco smoke (ETS) exposure can induce epigenetic alterations associated with inflammation and respiratory disease. The objective of this study was to address the long-term epigenetic consequences of perinatal ETS exposure on latent respiratory disease risk, which are still largely unknown. C57BL/6 mice were exposed to prenatal and early-life ETS; offspring lung pathology, global DNA, and gene-specific methylation were measured at two adult ages. Significant alterations in global DNA methylation and promoter methylation of IFN-γ and Thy-1 were found in ETS-exposed offspring at 10-12 and 20 weeks of age. These sustained epigenetic alterations preceded the onset of significant pulmonary pathologies observed at 20 weeks of age. This study suggests that perinatal ETS exposure induces persistent epigenetic alterations in global DNA, as well as IFN-γ and Thy-1 promoter methylation that precede the adult onset of fibrotic lung pathology. These epigenetic findings could represent potential biomarkers of latent respiratory disease risk.
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http://dx.doi.org/10.1080/08958378.2017.1392655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6114174PMC
August 2017