111 results on '"Madden MC"'
Search Results
2. Cancer biology. Cell proliferation in nasal respiratory epithelium of people exposed to urban pollution.
- Author
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Calderón-Garcidueñas, L, Rodriguez-Alcaraz, A, Garcia, R, Barragan, G, Villarreal-Calderón, A, and Madden, MC
- Abstract
The nasal passages are a common portal of entry and are a prime site for toxicant-induced pathology. Sustained increases in regenerative cell proliferation can be a significant driving force in chemical carcinogenesis. The atmosphere in Mexico City contains a complex mixture of air pollutants and its residents are exposed chronically and sequentially to numerous toxicants and potential carcinogens. We were concerned that exposure to Mexico City's atmosphere might induce cytotoxicity and increase nasal respiratory epithelial cell proliferation. Nasal biopsies were obtained for DNA cell cycle analysis from 195 volunteers. The control population consisted of 16 adults and 27 children that were residents in a Caribbean island with low pollution. The exposed Mexico City population consisted of 109 adults and 43 children. Sixty-one of the adult subjects were newly arrived in Mexico City and were followed for 25 days from their arrival. Control children, control adult and exposed Mexico City children all had similar percentages of cells in the replicative DNA synthesis phase (S phase) of the cell cycle (%S). A significant increase in %S in nasal epithelial cells was seen in exposed adult residents in Mexico City biopsied at three different dates compared with control adults. Newly arrived adults exhibited a control level of cell turnover at day 2 after coming to the city. However, at days 7, 14 and 25 they exhibited significant increases in %S. These data demonstrate an increased and sustained nasal cell turnover rate in the adult population observable in as little as 1 week of residence in Mexico City. This increase in cell proliferation is in agreement with other reports of induced pathological changes in the nasal passages of Mexico City dwellers. These observations suggest an increased potential risk factor of developing nasal neoplasms for residents of large cities with heavy pollution. [ABSTRACT FROM PUBLISHER]
- Published
- 1999
3. Prostacyclin expression by a continuous human cell line derived from vascular endothelium
- Author
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Suggs, JE, Madden, MC, Friedman, M, and Edgell, CJ
- Abstract
Prostacyclin is primarily an endothelial cell product. It contributes to the important role of endothelium in maintaining the fluidity of blood by inhibiting platelet aggregation and by promoting vasodilation. Endothelial cells in culture tend to senesce, and the level of prostacyclin expression decreases. A permanent human cell line, EA.hy 926, derived from a fusion of primary endothelial cells with cells of a less differentiated line, has been found to sustain basal and stimulated levels of prostacyclin synthesis.
- Published
- 1986
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4. E-Cigarette Liquids and Aldehyde Flavoring Agents Inhibit CYP2A6 Activity in Lung Epithelial Cells.
- Author
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Winters BR, Clapp PW, Simmons SO, Kochar TK, Jaspers I, and Madden MC
- Abstract
Certain e-liquids and aromatic aldehyde flavoring agents were previously identified as inhibitors of microsomal recombinant CYP2A6, the primary nicotine-metabolizing enzyme. However, due to their reactive nature, aldehydes may react with cellular components before reaching CYP2A6 in the endoplasmic reticulum. To determine whether e-liquid flavoring agents inhibited CYP2A6 in a cellular system, we investigated their effects on CYP2A6 using BEAS-2B cells transduced to overexpress CYP2A6. We demonstrated that two e-liquids and three aldehyde flavoring agents (cinnamaldehyde, benzaldehyde, and ethyl vanillin) exhibited dose-dependent inhibition of cellular CYP2A6., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)
- Published
- 2023
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5. Exhaled breath condensate biomarkers in critically ill, mechanically ventilated patients.
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Davis MD, Winters BR, Madden MC, Pleil JD, Sessler CN, Wallace MAG, Ward-Caviness CK, and Montpetit AJ
- Subjects
- Acute Disease, Adult, Breath Tests, Humans, Interleukin-1beta metabolism, Linear Models, Male, Middle Aged, Pneumonia diagnosis, Sepsis metabolism, Thorax diagnostic imaging, Treatment Outcome, Tumor Necrosis Factor-alpha metabolism, Biomarkers analysis, Critical Illness, Exhalation, Respiration, Artificial
- Abstract
Pneumonia is a significant risk for critically ill, mechanically ventilated (CIMV) patients. Diagnosis of pneumonia generally requires a combination of clinician-guided diagnoses and clinical scoring systems. Exhaled breath condensate (EBC) can be safely collected non-invasively from CIMV patients. Hundreds of biomarkers in EBC are associated with acute disease states, including pneumonia. We evaluated cytokines in EBC from CIMV patients and hypothesized that these biomarkers would correlate with disease severity in pneumonia, sepsis, and death. EBC IL-2 levels were associated with chest radiograph severity scores (odds ratio = 1.68; 95% confidence interval = 1.09-2.60; P = 0.02). EBC TNF-α levels were also associated with pneumonia (odds ratio = 3.20; 95% confidence interval = 1.19-8.65; P = 0.02). The techniques and results from this study may be useful for all mechanically ventilated patients.
- Published
- 2020
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6. Ozone Reacts With Carbon Black to Produce a Fulvic Acid-Like Substance and Increase an Inflammatory Effect.
- Author
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Ghio AJ, Gonzalez DH, Paulson SE, Soukup JM, Dailey LA, Madden MC, Mahler B, Elmore SA, Schladweiler MC, and Kodavanti UP
- Subjects
- Animals, Benzopyrans, Humans, Male, Particulate Matter toxicity, Rats, Soot toxicity, Air Pollutants toxicity, Ozone toxicity
- Abstract
Exposure to ambient ozone has been associated with increased human mortality. Ozone exposure can introduce oxygen-containing functional groups in particulate matter (PM) effecting a greater capacity of the particle for metal complexation and inflammatory effect. We tested the postulate that (1) a fulvic acid-like substance can be produced through a reaction of a carbonaceous particle with high concentrations of ozone and (2) such a fulvic acid-like substance included in the PM can initiate inflammatory effects following exposure of respiratory epithelial (BEAS-2B) cells and an animal model (male Wistar Kyoto rats). Carbon black (CB) was exposed for 72 hours to either filtered air (CB-Air) or approximately 100 ppm ozone (CB-O
3 ). Carbon black exposure to high levels of ozone produced water-soluble, fluorescent organic material. Iron import by BEAS-2B cells at 4 and 24 hours was not induced by incubations with CB-Air but was increased following coexposures of CB-O3 with ferric ammonium citrate. In contrast to CB-Air, exposure of BEAS-2B cells and rats to CB-O3 for 24 hours increased expression of pro-inflammatory cytokines and lung injury, respectively. It is concluded that inflammatory effects of carbonaceous particles on cells can potentially result from (1) an inclusion of a fulvic acid-like substance after reaction with ozone and (2) changes in iron homeostasis following such exposure.- Published
- 2020
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7. Impact of E-Cigarette Liquid Flavoring Agents on Activity of Microsomal Recombinant CYP2A6, the Primary Nicotine-Metabolizing Enzyme.
- Author
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Winters BR, Kochar TK, Clapp PW, Jaspers I, and Madden MC
- Subjects
- Cytochrome P-450 CYP2A6 metabolism, Cytochrome P-450 Enzyme Inhibitors analysis, Dose-Response Relationship, Drug, Flavoring Agents analysis, Humans, Mass Spectrometry, Microsomes drug effects, Microsomes metabolism, Molecular Conformation, Nicotine metabolism, Recombinant Proteins metabolism, Cytochrome P-450 CYP2A6 antagonists & inhibitors, Cytochrome P-450 Enzyme Inhibitors pharmacology, Electronic Nicotine Delivery Systems, Flavoring Agents pharmacology, Nicotine antagonists & inhibitors, Vaping
- Abstract
Nicotine is the primary psychoactive chemical in both traditional and electronic cigarettes (e-cigarettes). Nicotine levels in both traditional cigarettes and e-cigarettes are an important concern for public health. Nicotine exposure due to e-cigarette use is of importance primarily due to the addictive potential of nicotine, but there is also concern for nicotine poisoning in e-cigarette users. Nicotine concentrations in e-liquids vary widely. Additionally, there is significant genetic variability in the rate of metabolism of nicotine due to polymorphisms of CYP2A6, the enzyme responsible for the metabolism of approximately 80% of nicotine. Recent studies have shown CYP2A6 activity is also reduced by aromatic aldehydes such as those added to e-liquids as flavoring agents, which may increase nicotine serum concentrations. However, the impacts of flavored e-liquids on CYP2A6 activity are unknown. In this study, we investigated the impact of three flavored e-liquids on microsomal recombinant CYP2A6. Microsomal recombinant CYP2A6 was challenged at e-liquid concentrations ranging up to 0.125% (v/v) and monitored for metabolic activity using a probe molecule approach. Two e-liquids exhibited dose-dependent inhibition of CYP2A6 activity. Mass spectrometry was conducted to identify flavoring agents in flavored e-liquids that inhibited CYP2A6. Microsomal recombinant CYP2A6 was subsequently exposed to flavoring agents at concentrations ranging from 0.03 μM to 500 μM. Cinnamaldehyde and benzaldehyde were found to be the most potent inhibitors of microsomal CYP2A6 of the flavoring agents tested, with identified IC
50 values of 1.1 μM and 3.0 μM, respectively. These data indicate certain aromatic aldehyde flavoring agents are potent inhibitors of CYP2A6, which may reduce nicotine metabolism in vivo. These findings indicate an urgent need to evaluate the effects of flavoring agents in e-cigarette liquids on the pharmacokinetics of nicotine in vivo.- Published
- 2020
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8. Oleic acid and derivatives affect human endothelial cell mitochondrial function and vasoactive mediator production.
- Author
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Bass VL, Soukup JM, Ghio AJ, and Madden MC
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- Air Pollutants toxicity, Cyclooxygenase 2 genetics, Dinoprost biosynthesis, Gene Expression drug effects, Human Umbilical Vein Endothelial Cells drug effects, Human Umbilical Vein Endothelial Cells physiology, Humans, Intercellular Adhesion Molecule-1 genetics, Iron metabolism, Ricinoleic Acids toxicity, Vasomotor System physiology, Human Umbilical Vein Endothelial Cells ultrastructure, Mitochondria drug effects, Mitochondria physiology, Oleic Acid toxicity, Vasomotor System drug effects
- Abstract
Background: Inhalation of common air pollutants such as diesel and biodiesel combustion products can induce vascular changes in humans which may contribute to increased mortality and morbidity associated with fine particulate matter exposures. Diesel, biodiesel, and other combustion byproducts contain fatty acid components capable of entering the body through particulate matter inhalation. Fatty acids can also be endogenously released into circulation following a systemic stress response to some inhaled pollutants such as ozone. When in the circulation, bioactive fatty acids may interact with cells lining the blood vessels, potentially inducing endothelial dysfunction. To examine whether fatty acids could potentially be involved in human vascular responses to air pollutants, we determined the effects of fatty acids and derivatives on important vascular cell functions., Methods: Human umbilical vein endothelial cells (HUVEC) were exposed in vitro to oleic acid (OA) or OA metabolites for 4-48 h. Cytotoxicity, vasodilator production (by ELISA measurement), mitochondrial function (using Sea Horse assays), and iron metabolism (inferred by ICP-OES measurements) were examined, with standard statistical testing (ANOVA, t-tests) employed., Results: Dose-dependent cytotoxicity was noted at 24 h, with 12-hydroxy OA more potent than OA. Mitochondrial stress testing showed that 12-hydroxy OA and OA induce mitochondrial dysfunction. Analysis of soluble mediator release from HUVEC showed a dose-dependent increase in prostaglandin F
2α , a lipid involved in control of vascular tone, at 24 h (85% above controls) after OA-BSA exposure. RT-PCR analysis revealed OA did not induce changes in gene expression at noncytotoxic concentrations in exposed HUVEC, but 12-OH OA did alter ICAM and COX2 gene expression., Conclusions: Together, these data demonstrate that FA may be capable of inducing cytotoxic effects and altering expression of mediators of vascular function following inhalation exposure, and may be implicated in air pollutant-induced deaths and hospitalizations. (267 of max 350 words).- Published
- 2020
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9. Air pollutants disrupt iron homeostasis to impact oxidant generation, biological effects, and tissue injury.
- Author
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Ghio AJ, Soukup JM, Dailey LA, and Madden MC
- Subjects
- Homeostasis, Iron, Iron Chelating Agents, Oxidants, Particulate Matter toxicity, Air Pollutants toxicity
- Abstract
Air pollutants cause changes in iron homeostasis through: 1) a capacity of the pollutant, or a metabolite(s), to complex/chelate iron from pivotal sites in the cell or 2) an ability of the pollutant to displace iron from pivotal sites in the cell. Through either pathway of disruption in iron homeostasis, metal previously employed in essential cell processes is sequestered after air pollutant exposure. An absolute or functional cell iron deficiency results. If enough iron is lost or is otherwise not available within the cell, cell death ensues. However, prior to death, exposed cells will attempt to reverse the loss of requisite metal. This response of the cell includes increased expression of metal importers (e.g. divalent metal transporter 1). Oxidant generation after exposure to air pollutants includes superoxide production which functions in ferrireduction necessary for cell iron import. Activation of kinases and phosphatases and transcription factors and increased release of pro-inflammatory mediators also result from a cell iron deficiency, absolute or functional, after exposure to air pollutants. Finally, air pollutant exposure culminates in the development of inflammation and fibrosis which is a tissue response to the iron deficiency challenging cell survival. Following the response of increased expression of importers and ferrireduction, activation of kinases and phosphatases and transcription factors, release of pro-inflammatory mediators, and inflammation and fibrosis, cell iron is altered, and a new metal homeostasis is established. This new metal homeostasis includes increased total iron concentrations in cells with metal now at levels sufficient to meet requirements for continued function., (Published by Elsevier Inc.)
- Published
- 2020
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10. A Fulvic Acid-like Substance Participates in the Pro-inflammatory Effects of Cigarette Smoke and Wood Smoke Particles.
- Author
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Gonzalez DH, Soukup JM, Madden MC, Hays M, Berntsen J, Paulson SE, and Ghio AJ
- Subjects
- Cells, Cultured, Epithelial Cells drug effects, Epithelial Cells metabolism, Humans, Inflammation metabolism, Interleukin-3 metabolism, Interleukin-8 metabolism, Benzopyrans analysis, Benzopyrans toxicity, Cigarette Smoking, Inflammation chemically induced, Smoke adverse effects, Tobacco Smoke Pollution analysis, Wood chemistry
- Abstract
We tested the postulates that (1) a fulvic acid (FA)-like substance is included in cigarette smoke and wood smoke particles (WSP) and (2) cell exposure to this substance results in a disruption of iron homeostasis, associated with a deficiency of the metal and an inflammatory response. The fluorescence excitation-emission matrix spectra of the water-soluble components of cigarette smoke condensate and WSP (Cig-WS and Wood-WS) approximated those for the standard reference materials, Suwanee River and Nordic fulvic acids (SRFA and NFA). Fourier transform infrared spectra for the FA fraction of cigarette smoke and WSP (Cig-FA and Wood-FA), SRFA, and NFA also revealed significant similarities (O-H bond in alcohols, phenols, and carboxylates, C═O in ketones, aldehydes, and carboxylates, and a significant carboxylate content). After exposure to Cig-WS and Wood-WS and the FA standards, iron was imported by respiratory epithelial cells, reflecting a functional iron deficiency. The release of pro-inflammatory mediators interleukin (IL)-8 and IL-6 by respiratory epithelial cells also increased following exposures to Cig-WS, Wood-WS, SRFA, and NFA. Co-exposure of the respiratory epithelial cells with iron decreased supernatant concentrations of the ILs relative to exposures to Cig-WS, Wood-WS, SRFA, and NFA alone. It is concluded that (1) a FA-like substance is included in cigarette smoke and WSP and (2) respiratory epithelial cell exposure to this substance results in a disruption of iron homeostasis associated with both a cell deficiency of the metal and an inflammatory response.
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- 2020
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11. How do cancer-sniffing dogs sort biological samples? Exploring case-control samples with non-targeted LC-Orbitrap, GC-MS, and immunochemistry methods.
- Author
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Pleil JD, Wallace MAG, McCord J, Madden MC, Sobus J, and Ferguson G
- Subjects
- Aerosols, Animals, Case-Control Studies, Chromatography, Liquid, Cytokines metabolism, Discriminant Analysis, Dogs, Exhalation, Humans, Least-Squares Analysis, Breath Tests methods, Gas Chromatography-Mass Spectrometry methods, Immunochemistry methods, Neoplasms diagnosis
- Abstract
Early identification of disease onset is regarded as an important factor for successful medical intervention. However, cancer and other long-term latency diseases are rare and may take years to manifest clinically. As such, there are no gold standards with which to immediately validate proposed preclinical screening methodologies. There is evidence that dogs can sort samples reproducibly into yes/no categories based on case-control training, but the basis of their decisions is unknown. Because dogs are sniffing air, the distinguishing chemicals must be either in the gas-phase or attached to aerosols and/or airborne particles. Recent biomonitoring research has shown how to extract and analyze semi- and non-volatile compounds from human breath in exhaled condensates and aerosols. Further research has shown that exhaled aerosols can be directly collected on standard hospital-style olefin polypropylene masks and that these masks can be used as a simple sampling scheme for canine screening. In this article, detailed liquid chromatography-high resolution mass spectrometry (LC-HR-MS) with Orbitrap instrumentation and gas chromatography-mass spectrometry (GC-MS) analyses were performed on two sets of masks sorted by consensus of a four-dog cohort as either cancer or control. Specifically, after sorting by the dogs, sample masks were cut into multiple sections and extracted for LC-MS and GC-MS non-targeted analyses. Extracts were also analyzed for human cytokines, confirming the presence of human aerosol content above levels in blank masks. In preliminary evaluations, 345 and 44 high quality chemical features were detected by LC-MS and GC-MS analyses, respectively. These features were used to develop provisional orthogonal projection to latent structures-discriminant analysis (OPLS-DA) models to determine if the samples classified as cancer (case) or non-cancer (control) by the dogs could be separated into the same groups using analytical instrumentation. While the OPLS-DA model for the LC-HR-MS data was able to separate the two groups with statistical significance, although weak explanatory power, the GC-MS model was not found to be significant. These results suggest that the dogs may rely on the less volatile compounds from breath aerosol that were analyzed by LC-HR-MS than the more volatile compounds observed by GC-MS to sort mask samples into groups. These results provide justification for more expansive studies in the future that aim to characterize specific chemical features, and the role(s) of these features in maintaining homeostatic biological processes.
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- 2019
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12. Identifying organic compounds in exhaled breath aerosol: Non-invasive sampling from respirator surfaces and disposable hospital masks.
- Author
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Geer Wallace MA, Pleil JD, and Madden MC
- Abstract
Exhaled breath aerosol (EBA) is an important non-invasive biological medium for detecting exogenous environmental contaminants and endogenous metabolites present in the pulmonary tract. Currently, EBA is typically captured as a constituent of the mainstream clinical tool referred to as exhaled breath condensate (EBC). This article describes a simpler, completely non-invasive method for collecting EBA directly from different forms of hard-surface plastic respirator masks and disposable hospital paper breathing masks without first collecting EBC. The new EBA methodology bypasses the complex EBC procedures that require specialized collection gear, dry ice or other coolant, in-field sample processing, and refrigerated transport to the laboratory. Herein, mask samples collected from different types of plastic respirators and paper hospital masks worn by volunteers in the laboratory were analyzed using high resolution-liquid chromatography-mass spectrometry (HR-LC-MS) and immunochemistry. The results of immunochemistry analysis revealed that cytokines were collected above background on both plastic respirator surfaces and paper hospital masks, confirming the presence of human biological constituents. Non-targeted HR-LC-MS analyses demonstrated that larger exogenous molecules such as plasticizers, pesticides, and consumer product chemicals as well as endogenous biochemicals, including cytokines and fatty acids were also detected on mask surfaces. These results suggest that mask sampling is a viable technique for EBA collection to assess potential inhalation exposures and endogenous indicators of health state., Competing Interests: CONFLICT OF INTEREST The authors declare no conflicts of interest.
- Published
- 2019
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13. Quartz Disrupts Iron Homeostasis in Alveolar Macrophages To Impact a Pro-Inflammatory Effect.
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Ghio AJ, Soukup JM, Stonehuerner J, Tong H, Richards J, Gilmour MI, Madden MC, Shen Z, and Kantrow SP
- Subjects
- Acetophenones pharmacology, Animals, Cell Line, Tumor, Cytokines metabolism, Enzyme Inhibitors pharmacology, Ferric Compounds pharmacology, Ferritins metabolism, Humans, Male, Mice, Inbred C57BL, Mice, Knockout, NADPH Oxidase 2 genetics, NADPH Oxidases antagonists & inhibitors, Oxidative Stress drug effects, Quaternary Ammonium Compounds pharmacology, Homeostasis drug effects, Inflammation chemically induced, Iron metabolism, Macrophages, Alveolar drug effects, Quartz toxicity
- Abstract
The biological response of bronchial epithelial cells to particles is associated with a sequestration of cell metal by the particle surface and a subsequent disruption in host iron homeostasis. The macrophage is the cell type resident in the respiratory tract that is most likely to make initial contact with inhaled particles. We tested the postulates that (1) silica, a prototypical particle, disrupts iron homeostasis in alveolar macrophages (AMs); and (2) the altered iron homeostasis results in both an oxidative stress and pro-inflammatory effects. Human AMs (1.0 × 10
6 /mL) demonstrated an increased import of iron following particle exposure with nonheme iron concentrations of 0.57 ± 0.03, 1.72 ± 0.09, 0.88 ± 0.09, and 3.21 ± 0.11 ppm in cells exposed for 4 h to media, 500 μM ferric ammonium citrate (FAC), 100 μg/mL silica, and both silica and FAC, respectively. Intracellular ferritin concentrations and iron release were similarly increased after AM exposure to FAC and silica. Silica increased oxidant generation by AMs measured using both dichlorofluorescein diacetate fluorescence and reduction of nitroblue tetrazolium salt. Concentrations of interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor-α in macrophage supernatant increased following 100 μg/mL silica exposure for 24 h. Treatment of AMs with 500 μM FAC decreased both oxidant generation and cytokine release associated with silica exposure, supporting a dependence of these effects on sequestration of cell metal by the particle surface. We conclude that (1) silica exposure disrupts iron homeostasis resulting in increased import, accumulation, and release of the metal; and (2) the altered iron homeostasis following silica exposure impacts oxidant generation and pro-inflammatory effects.- Published
- 2019
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14. 12-hydroxy oleic acid impairs endothelium-dependent vasorelaxation.
- Author
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Bass VL, Snow S, Soukup J, Schladweiler M, Ghio A, Kodavanti U, and Madden MC
- Subjects
- Animals, Male, Myography, Rats, Rats, Inbred WKY, Endothelium drug effects, Oleic Acid adverse effects, Particulate Matter adverse effects, Ricinoleic Acids adverse effects, Vasodilation drug effects
- Abstract
Diesel and biodiesel emissions exposures reduce vascular responsiveness in vivo, but the components of PM responsible for this effect are poorly understood. Fatty acids (FAs) represent a significant fraction of the compounds that make up organic combustion by-products, and may be involved in vascular responses following inhalation. It was hypothesized that vascular tissue exposed to a model FA might impair responses to vasoactive agonists ex vivo. Rat aortic rings were exposed to oleic acid or 12-hydroxy oleic acid and responses determined by myography. 12-Hydroxy oleic acid was found to significantly reduce endothelium-dependent vasodilation at sub-cytotoxic concentrations. This approach demonstrates the potential for FAs, especially oxidized forms, to play a role in the vascular responses observed following air pollution exposure.
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- 2019
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15. Iron concentration in exhaled breath condensate decreases in ever-smokers and COPD patients.
- Author
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Ghio AJ, Soukup JM, McGee J, Madden MC, and Esther CR
- Subjects
- Aged, Female, Humans, Male, Middle Aged, Pulmonary Disease, Chronic Obstructive diagnosis, Zinc analysis, Breath Tests methods, Exhalation, Iron analysis, Pulmonary Disease, Chronic Obstructive metabolism, Smokers
- Abstract
Investigation employing bronchoalveolar lavage supports both increased and decreased iron concentrations in the epithelial lining fluid (ELF) of smokers. Exhaled breath condensate (EBC) is an alternative approach to sampling the ELF. We evaluated for an association between iron homeostasis and both smoking and a diagnosis of chronic obstructive pulmonary disease (COPD) by measuring metal concentrations in EBC samples from non-smoker controls, smoker controls, and individuals diagnosed with COPD. The total number of EBC specimens was 194. EBC iron and zinc concentrations (mean ± standard error) in the total study population were 0.610 ± 0.025 and 40.73 ± 1.79 ppb respectively. In linear regressions, total cigarette smoking in pack years showed a significant (negative) relationship with EBC iron concentration but not with EBC zinc concentration. Iron concentrations in EBC from GOLD stage II, III, and IV patients were all significantly decreased relative to those from non-smoker and smoker controls. In contrast to iron, zinc concentrations in EBC were not significantly different than those from non-smoker and smoker controls. It is concluded that smoking decreases EBC iron concentrations and patients diagnosed with COPD have significantly lower EBC iron concentrations. These results likely reflect an increased burden of cigarette smoke particles in the lower respiratory tract of ever-smokers and patients with COPD and the capacity of components in this particle to complex iron.
- Published
- 2018
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16. The toxicology of air pollution predicts its epidemiology.
- Author
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Ghio AJ, Soukup JM, and Madden MC
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- Diabetes Mellitus epidemiology, Female, Humans, Humic Substances adverse effects, Ozone chemistry, Particulate Matter adverse effects, Pregnancy, Pulmonary Disease, Chronic Obstructive epidemiology, Tobacco Smoke Pollution adverse effects, Air Pollution adverse effects, Cardiovascular Diseases epidemiology, Cerebrovascular Disorders epidemiology, Environmental Exposure adverse effects, Lung Diseases epidemiology
- Abstract
The epidemiologic investigation has successively delineated associations of air pollution exposure with non-malignant and malignant lung disease, cardiovascular disease, cerebrovascular disease, pregnancy outcomes, perinatal effects and other extra-pulmonary disease including diabetes. Defining these relationships between air pollution exposure and human health closely parallels results of an earlier epidemiologic investigation into cigarette smoking and environmental tobacco smoke (ETS), two other particle-related exposures. Humic-like substances (HULIS) have been identified as a chemical component common to cigarette smoke and air pollution particles. Toxicology studies provide evidence that a disruption of iron homeostasis with sequestration of host metal by HULIS is a fundamental mechanistic pathway through which biological effects are initiated by cigarette smoke and air pollution particles. As a result of a common chemical component and a shared mechanistic pathway, it should be possible to extrapolate from the epidemiology of cigarette smoking and ETS to predict associations of air pollution exposure with human disease, which are currently unrecognized. Accordingly, it is anticipated that the forthcoming epidemiologic investigation will demonstrate relationships of air pollution with COPD causation, peripheral vascular disease, hypertension, renal disease, digestive disease, loss of bone mass/risk of fractures, dental disease, eye disease, fertility problems, and extrapulmonary malignancies.
- Published
- 2018
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17. Review: Endogenously Produced Volatiles for In Vitro Toxicity Testing Using Cell Lines.
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Winters BR, Pleil JD, Boyer JC, Nylander-French LA, Wallace MAG, and Madden MC
- Abstract
Due to the ∼86,000 chemicals registered under the Toxic Substances Control Act and increasing ethical concerns regarding animal testing, it is not economically or technically feasible to screen every registered chemical for toxicity using animal-based toxicity assays. To address this challenge, regulatory agencies are investigating high-throughput screening in vitro methods to increase speed of toxicity testing, while reducing the overall cost. One approach for rapid toxicity testing currently being investigated is monitoring of volatile emissions produced by cell lines in culture. Such a metabolomics approach would measure gaseous emissions from a cell line and determine if such gaseous metabolites are altered upon exposure to a xenobiotic. Herein, we describe the history and rationale of monitoring endogenously produced volatiles for identification of pathologic conditions, as well as emerging applications in toxicity testing for such an approach., Competing Interests: The authors declare that no competing financial interests exist.
- Published
- 2018
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18. Human lung injury following exposure to humic substances and humic-like substances.
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Ghio AJ and Madden MC
- Subjects
- Aerosols, Humans, Lung drug effects, Lung Diseases etiology, Lung Injury chemically induced, Lung Injury etiology, Smoking adverse effects, Air Pollutants toxicity, Environmental Exposure, Humic Substances adverse effects, Lung Diseases chemically induced
- Abstract
Among the myriad particles the human respiratory tract is exposed to, a significant number are distinctive in that they include humic substances (HS) and humic-like substances (HULIS) as organic components. HS are heterogeneous, amorphous, organic materials which are ubiquitous occurring in all terrestrial and aqueous environments. HULIS are a complex class of organic, macromolecular compounds initially extracted from atmospheric aerosol particles which share some features with HS including an aromatic, polyacidic nature. As a result of having a variety of oxygen-containing functional groups, both HS and HULIS complex metal cations, especially iron. Following particle uptake by cells resident in the lung, host iron will be sequestered by HS- and HULIS-containing particles initiating pathways of inflammation and subsequent fibrosis. It is proposed that (1) human exposures to HS and HULIS of respirable size (<10 µm diameter) are associated with inflammatory and fibrotic lung disease and (2) following retention of particles which include HS and HULIS, the mechanism of cell and tissue injury involves complexation of host iron. Human inflammatory and fibrotic lung injuries following HS and HULIS exposures may include coal workers' pneumoconiosis, sarcoidosis, and idiopathic pulmonary fibrosis as well as diseases associated with cigarette smoking and exposures to emission and ambient air pollution particles.
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- 2018
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19. Transition and post-transition metals in exhaled breath condensate.
- Author
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Ghio AJ, Madden MC, and Esther CR
- Subjects
- Environmental Exposure analysis, Humans, Lung Diseases diagnosis, Occupational Exposure analysis, Breath Tests methods, Exhalation, Metals analysis, Transition Elements analysis
- Abstract
Water vapor in expired air, as well as dispersed non-volatile components, condense onto a cooler surface after exiting the respiratory tract. This exhaled breath condensate (EBC) provides a dilute sampling of the epithelial lining fluid. Accordingly, the collection of EBC imparts a capacity to provide biomarkers of injury preceding clinical disease. Concentrations of transition and post-transition metals in EBC are included among these endpoints. Iron and zinc are the metals with the highest concentration and are measurable in all EBC samples from healthy subjects; other metals are most frequently either at or below the level of detection in this group. Gender, age, and smoking can impact EBC metal concentrations in healthy subjects. EBC metal concentrations among patients diagnosed with particular lung diseases (e.g. asthma, chronic obstructive disease, and interstitial lung disease) have been of research interest but no definite pattern of involvement has been delineated. Studies of occupationally exposed workers confirm significant exposure to specific metals, but such EBC metal measurements frequently provide evidence redundant with environmental sampling. Measurements of metal concentrations in EBC remain a research tool into metal homeostasis in the respiratory tract and participation of metals in disease pathogenesis. The quantification of metal concentrations in EBC is currently not reliable for clinical use in either supporting or determining any diagnosis. Issues that must be addressed prior to the use of EBC metal measurements include the establishment of both standardized collection and measurement techniques.
- Published
- 2018
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20. Exhaled breath aerosol (EBA): the simplest non-invasive medium for public health and occupational exposure biomonitoring.
- Author
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Pleil JD, Wallace MAG, and Madden MC
- Published
- 2018
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21. Standardization of the collection of exhaled breath condensate and exhaled breath aerosol using a feedback regulated sampling device.
- Author
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Winters BR, Pleil JD, Angrish MM, Stiegel MA, Risby TH, and Madden MC
- Subjects
- Adult, Biomarkers analysis, Humans, Hydrogen-Ion Concentration, Reference Standards, Aerosols analysis, Breath Tests instrumentation, Breath Tests methods, Exhalation, Feedback
- Abstract
Exhaled breath condensate (EBC) and associated exhaled breath aerosols (EBA) are valuable non-invasive biological media used for the quantification of biomarkers. EBC contains exhaled water vapor, soluble gas-phase (polar) organic compounds, ionic species, plus other species including semi- and non-volatile organic compounds, proteins, cell fragments, DNA, dissolved inorganic compounds, ions, and microbiota (bacteria and viruses) dissolved in the co-collected EBA. EBC is collected from subjects who breathe 'normally' through a chilled tube assembly for approximately 10 min and is then harvested into small vials for analysis. Aerosol filters without the chilled tube assembly are also used to separately collect EBA. Unlike typical gas-phase breath samples used for environmental and clinical applications, the constituents of EBC and EBA are not easily characterized by total volume or carbon dioxide (CO
2 ) concentration, because the gas-phase is vented. Furthermore, EBC and associated EBA are greatly affected by breathing protocol, more specifically, depth of inhalation and expelled breath velocity. We have tested a new instrument developed by Loccioni Gruppa Humancare (Ancona, Italy) for implementation of EBC collection from human subjects to assess EBC collection parameters. The instrument is the first EBC collection device that provides instantaneous visual feedback to the subjects to control breathing patterns. In this report we describe the operation of the instrument, and present an overview of performance and analytical applications.- Published
- 2017
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22. Linking physiological parameters to perturbations in the human exposome: Environmental exposures modify blood pressure and lung function via inflammatory cytokine pathway.
- Author
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Stiegel MA, Pleil JD, Sobus JR, Stevens T, and Madden MC
- Subjects
- Adult, Aged, Aged, 80 and over, Environmental Monitoring, Female, Humans, Male, Middle Aged, Biomarkers metabolism, Blood Pressure drug effects, Cytokines metabolism, Environmental Exposure adverse effects, Lung Injury etiology, Ozone toxicity, Vehicle Emissions toxicity
- Abstract
Human biomonitoring is an indispensable tool for evaluating the systemic effects derived from external stressors including environmental pollutants, chemicals from consumer products, and pharmaceuticals. The aim of this study was to explore consequences of environmental exposures to diesel exhaust (DE) and ozone (O
3 ) and ultimately to interpret these parameters from the perspective of in vitro to in vivo extrapolation. In particular, the objective was to use cytokine expression at the cellular level as a biomarker for physiological systemic responses such as blood pressure and lung function at the systemic level. The values obtained could ultimately link in vivo behavior to simpler in vitro experiments where cytokines are a measured parameter. Human exposures to combinations of DE and O3 and the response correlations between forced exhaled volume in 1 second (FEV1 ), forced vital capacity (FVC), systolic and diastolic blood pressure (SBP and DBP, respectively), and 10 inflammatory cytokines in blood (interleukins 1β, 2, 4, 5, 8, 10, 12p70 and 13, IFN-γ, and TNF-α) were determined in 15 healthy human volunteers. Results across all exposures revealed that certain individuals displayed greater inflammatory responses compared to the group and, generally, there was more between-person variation in the responses. Evidence indicates that individuals are more stable within themselves and are more likely to exhibit responses independent of one another. Data suggest that in vitro findings may ultimately be implemented to elucidate underlying adverse outcome pathways (AOP) for linking high-throughput toxicity tests to physiological in vivo responses. Further, this investigation supports assessing subjects based upon individual responses as a complement to standard longitudinal (pre vs. post) intervention grouping strategies. Ultimately, it may become possible to predict a physiological (systemic) response based upon cellular-level (in vitro) observations.- Published
- 2017
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23. A paler shade of green? The toxicology of biodiesel emissions: Recent findings from studies with this alternative fuel.
- Author
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Madden MC
- Subjects
- Air Pollutants analysis, Air Pollution analysis, Animals, Biofuels analysis, Humans, Inhalation Exposure, Lung drug effects, Models, Animal, Petroleum analysis, Petroleum toxicity, Rapeseed Oil, Skin drug effects, Vehicle Emissions analysis, Air Pollutants toxicity, Biofuels toxicity, Plant Oils chemistry, Vehicle Emissions toxicity
- Abstract
Background: Biodiesel produced primarily from plants and algal feedstocks is believed to have advantages for production and use compared to petroleum and to some other fuel sources. There is some speculation that exposure to biodiesel combustion emissions may not induce biological responses or health effects or at a minimum reduce the effects relative to other fuels. In evaluating the overall environmental and health effects of biodiesel production to end use scenario, empirical data or modeling data based on such data are needed., Scope of Review: This manuscript examines the available toxicology reports examining combustion derived biodiesel emissions since approximately 2007, when our last review of the topic occurred. Toxicity derived from other end uses of biodiesel - e.g., spills, dermal absorption, etc. - are not examined. Findings from biodiesel emissions are roughly divided into three areas: whole non-human animal model exposures; in vitro exposures of mammalian and bacterial cells (used for mutation studies primarily); and human exposures in controlled or other exposure fashions., Major Conclusions: Overall, these more current studies clearly demonstrate that biodiesel combustion emission exposure- to either 100% biodiesel or a blend in petroleum diesel- can induce biological effects. There are reports that show biodiesel exposure generally induces more effects or a greater magnitude of effect than petroleum diesel, however there are also a similar number of reports showing the opposite trend. It is unclear whether effects induced by exposure to a blend are greater than exposure to 100% biodiesel. Taken together, the evidence suggest biodiesel emissions can have some similar effects as diesel emissions on inflammatory, vascular, mutagenic, and other responses., General Significance: While acute biodiesel exposures can show toxicity with a variety of endpoints, the potential effects on human health need further validation. Additionally there are few or no findings to date on whether biodiesel emissions can induce effects or even a weaker response that petroleum diesel with repeated exposure scenarios such as in an occupational setting. This article is part of a Special Issue entitled Air Pollution, edited by Wenjun Ding, Andrew J. Ghio and Weidong Wu., (Copyright © 2016. Published by Elsevier B.V.)
- Published
- 2016
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24. Ozone Exposure Increases Circulating Stress Hormones and Lipid Metabolites in Humans.
- Author
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Miller DB, Ghio AJ, Karoly ED, Bell LN, Snow SJ, Madden MC, Soukup J, Cascio WE, Gilmour MI, and Kodavanti UP
- Subjects
- Adult, Biomarkers blood, Cross-Over Studies, Fatty Acids, Nonesterified blood, Female, Glycerol blood, Humans, Male, Metabolomics methods, Monoglycerides blood, Young Adult, Corticosterone blood, Hydrocortisone blood, Lipid Metabolism, Lipids blood, Ozone blood, Ozone pharmacology
- Abstract
Rationale: Air pollution has been associated with increased prevalence of type 2 diabetes; however, the mechanisms remain unknown. We have shown that acute ozone exposure in rats induces release of stress hormones, hyperglycemia, leptinemia, and glucose intolerance that are associated with global changes in peripheral glucose, lipid, and amino acid metabolism., Objectives: To examine ozone-induced metabolic derangement in humans using serum metabolomic assessment, establish human-to-rodent coherence, and identify novel nonprotein biomarkers., Methods: Serum samples were obtained from a crossover clinical study that included two clinic visits (n = 24 each) where each subject was blindly exposed in the morning to either filtered air or 0.3 parts per million ozone for 2 hours during 15-minute on-off exercise. Serum samples collected within 1 hour after exposure were assessed for changes in metabolites using a metabolomic approach., Measurements and Main Results: Metabolomic analysis revealed that ozone exposure markedly increased serum cortisol and corticosterone together with increases in monoacylglycerol, glycerol, and medium- and long-chain free fatty acids, reflective of lipid mobilization and catabolism. Additionally, ozone exposure increased serum lysolipids, potentially originating from membrane lipid breakdown. Ozone exposure also increased circulating mitochondrial β-oxidation-derived metabolites, such as acylcarnitines, together with increases in the ketone body 3-hydroxybutyrate. These changes suggested saturation of β-oxidation by ozone in exercising humans., Conclusions: As in rodents, acute ozone exposure increased stress hormones and globally altered peripheral lipid metabolism in humans, likely through activation of a neurohormonally mediated stress response pathway. The metabolomic assessment revealed new biomarkers and allowed for establishment of rodent-to-human coherence. Clinical trial registered with www.clinicaltrials.gov (NCT 01492517).
- Published
- 2016
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25. Inflammatory Cytokines and White Blood Cell Counts Response to Environmental Levels of Diesel Exhaust and Ozone Inhalation Exposures.
- Author
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Stiegel MA, Pleil JD, Sobus JR, and Madden MC
- Subjects
- Adolescent, Adult, Female, Humans, Leukocyte Count, Male, Middle Aged, Young Adult, Air Pollutants adverse effects, Cytokines metabolism, Environmental Exposure adverse effects, Inflammation Mediators metabolism, Inhalation Exposure adverse effects, Ozone adverse effects, Vehicle Emissions
- Abstract
Epidemiological observations of urban inhalation exposures to diesel exhaust (DE) and ozone (O3) have shown pre-clinical cardiopulmonary responses in humans. Identifying the key biological mechanisms that initiate these health bioindicators is difficult due to variability in environmental exposure in time and from person to person. Previously, environmentally controlled human exposure chambers have been used to study DE and O3 dose-response patterns separately, but investigation of co-exposures has not been performed under controlled conditions. Because a mixture is a more realistic exposure scenario for the general public, in this study we investigate the relationships of urban levels of urban-level DE exposure (300 μg/m3), O3 (0.3 ppm), DE + O3 co-exposure, and innate immune system responses. Fifteen healthy human volunteers were studied for changes in ten inflammatory cytokines (interleukins 1β, 2, 4, 5, 8, 10, 12p70 and 13, IFN-γ, and TNF-α) and counts of three white blood cell types (lymphocytes, monocytes, and neutrophils) following controlled exposures to DE, O3, and DE+O3. The results show subtle cytokines responses to the diesel-only and ozone-only exposures, and that a more complex (possibly synergistic) relationship exists in the combination of these two exposures with suppression of IL-5, IL-12p70, IFN-γ, and TNF-α that persists up to 22-hours for IFN-γ and TNF-α. The white blood cell differential counts showed significant monocyte and lymphocyte decreases and neutrophil increases following the DE + O3 exposure; lymphocytes and neutrophils changes also persist for at least 22-hours. Because human studies must be conducted under strict safety protocols at environmental levels, these effects are subtle and are generally only seen with detailed statistical analysis. This study indicates that the observed associations between environmental exposures and cardiopulmonary effects are possibly mediated by inflammatory response mechanisms.
- Published
- 2016
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26. Taxonomic applicability of inflammatory cytokines in adverse outcome pathway (AOP) development.
- Author
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Angrish MM, Pleil JD, Stiegel MA, Madden MC, Moser VC, and Herr DW
- Subjects
- Animals, Biomarkers blood, Biomarkers metabolism, Biomarkers urine, Carbaryl toxicity, Cytokines blood, Cytokines metabolism, Cytokines urine, Female, High-Throughput Screening Assays instrumentation, Humans, Male, Mice, Ozone toxicity, Pyrazoles toxicity, Toxicity Tests instrumentation, Vehicle Emissions toxicity, Air Pollutants toxicity, Cytokines immunology, High-Throughput Screening Assays methods, Insecticides toxicity, Toxicity Tests methods
- Abstract
Cytokines, low-molecular-weight messenger proteins that act as intercellular immunomodulatory signals, have become a mainstream preclinical marker for assessing the systemic inflammatory response to external stressors. The challenge is to quantitate from healthy subjects cytokine levels that are below or at baseline and relate those dynamic and complex cytokine signatures of exposures with the inflammatory and repair pathways. Thus, highly sensitive, specific, and precise analytical and statistical methods are critically important. Investigators at the U.S. Environmental Protection Agency (EPA) have implemented advanced technologies and developed statistics for evaluating panels of inflammatory cytokines in human blood, exhaled breath condensate, urine samples, and murine biological media. Advanced multiplex, bead-based, and automated analytical platforms provided sufficient sensitivity, precision, and accuracy over the traditional enzyme-linked immunosorbent assay (ELISA). Thus, baseline cytokine levels can be quantified from healthy human subjects and animals and compared to an in vivo exposure response from an environmental chemical. Specifically, patterns of cytokine responses in humans exposed to environmental levels of ozone and diesel exhaust, and in rodents exposed to selected pesticides (such as fipronil and carbaryl), were used as case studies to generally assess the taxonomic applicability of cytokine responses. The findings in this study may aid in the application of measureable cytokine markers in future adverse outcome pathway (AOP)-based toxicity testing. Data from human and animal studies were coalesced and the possibility of using cytokines as key events (KE) to bridge species responses to external stressors in an AOP-based framework was explored.
- Published
- 2016
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27. Immunochemistry for high-throughput screening of human exhaled breath condensate (EBC) media: implementation of automated Quanterix SIMOA instrumentation.
- Author
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Pleil JD, Angrish MM, and Madden MC
- Subjects
- Adult, Automation, Calibration, Culture Media, Humans, Interleukin-6 metabolism, Least-Squares Analysis, Linear Models, Tumor Necrosis Factor-alpha metabolism, Young Adult, Breath Tests instrumentation, Breath Tests methods, Exhalation, High-Throughput Screening Assays instrumentation, Immunochemistry methods
- Abstract
Immunochemistry is an important clinical tool for indicating biological pathways leading towards disease. Standard enzyme-linked immunosorbent assays (ELISA) are labor intensive and lack sensitivity at low-level concentrations. Here we report on emerging technology implementing fully-automated ELISA capable of molecular level detection and describe application to exhaled breath condensate (EBC) samples. The Quanterix SIMOA HD-1 analyzer was evaluated for analytical performance for inflammatory cytokines (IL-6, TNF-α, IL-1β and IL-8). The system was challenged with human EBC representing the most dilute and analytically difficult of the biological media. Calibrations from synthetic samples and spiked EBC showed excellent linearity at trace levels (r(2) > 0.99). Sensitivities varied by analyte, but were robust from ~0.006 (IL-6) to ~0.01 (TNF-α) pg ml(-1). All analytes demonstrated response suppression when diluted with deionized water and so assay buffer diluent was found to be a better choice. Analytical runs required ~45 min setup time for loading samples, reagents, calibrants, etc., after which the instrument performs without further intervention for up to 288 separate samples. Currently, available kits are limited to single-plex analyses and so sample volumes require adjustments. Sample dilutions should be made with assay diluent to avoid response suppression. Automation performs seamlessly and data are automatically analyzed and reported in spreadsheet format. The internal 5-parameter logistic (pl) calibration model should be supplemented with a linear regression spline at the very lowest analyte levels, (<1.3 pg ml(-1)). The implementation of the automated Quanterix platform was successfully demonstrated using EBC, which poses the greatest challenge to ELISA due to limited sample volumes and low protein levels.
- Published
- 2015
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28. Probe molecule (PrM) approach in adverse outcome pathway (AOP) based high-throughput screening (HTS): in vivo discovery for developing in vitro target methods.
- Author
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Angrish MM, Madden MC, and Pleil JD
- Subjects
- Animals, Humans, In Vitro Techniques, Models, Chemical, Drug Discovery, High-Throughput Screening Assays, Molecular Probes
- Abstract
Efficient and accurate adverse outcome pathway (AOP) based high-throughput screening (HTS) methods use a systems biology based approach to computationally model in vitro cellular and molecular data for rapid chemical prioritization; however, not all HTS assays are grounded by relevant in vivo exposure data. The challenge is to develop HTS assays with unambiguous quantitative links between in vitro responses and corresponding in vivo effects, which is complicated by metabolically insufficient systems, in vitro to in vivo extrapolation (IVIVE), cross-species comparisons, and other inherent issues correlating IVIVE findings. This article introduces the concept of ultrasensitive gas phase probe molecules (PrMs) to help bridge the current HTS assay IVIVE gap. The PrM concept assesses metabolic pathways that have already been well-defined from intact human or mammalian models. Specifically, the idea is to introduce a gas phase probe molecule into a system, observe normal steady state, add chemicals of interest, and quantitatively measure (from headspace gas) effects on PrM metabolism that can be directly linked back to a well-defined and corresponding in vivo effect. As an example, we developed the pharmacokinetic (PK) parameters and differential equations to estimate methyl tertiary butyl ether (MTBE) metabolism to tertiary butyl alcohol (TBA) via cytochrome (CYP) 2A6 in the liver from human empirical data. Because MTBE metabolic pathways are well characterized from in vivo data, we can use it as a PrM to explore direct and indirect chemical effects on CYP pathways. The PrM concept could be easily applied to in vitro and alternative models of disease and phenotype, and even test for volatile chemicals while avoiding liquid handling robotics. Furthermore, a PrM can be designed for any chemical with known empirical human exposure data and used to assess chemicals for which no information exists. Herein, we propose an elegant gas phase probe molecule-based approach to in vitro toxicity testing.
- Published
- 2015
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29. Interaction effects of temperature and ozone on lung function and markers of systemic inflammation, coagulation, and fibrinolysis: a crossover study of healthy young volunteers.
- Author
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Kahle JJ, Neas LM, Devlin RB, Case MW, Schmitt MT, Madden MC, and Diaz-Sanchez D
- Subjects
- Adult, Air Pollutants toxicity, Biomarkers analysis, Cross-Over Studies, Female, Fibrin Fibrinogen Degradation Products drug effects, Forced Expiratory Volume, Humans, Inflammation metabolism, Male, Respiratory Physiological Phenomena, Blood Coagulation, Fibrinolysis, Ozone adverse effects, Temperature
- Abstract
Background: Trends in climate suggest that extreme weather events such as heat waves will become more common. High levels of the gaseous pollutant ozone are associated with elevated temperatures. Ozone has been associated with respiratory diseases as well as cardiovascular morbidity and mortality and can reduce lung function and alter systemic markers of fibrinolysis. The interaction between ozone and temperature is unclear., Methods: Sixteen healthy volunteers were exposed in a randomized crossover study to 0.3 ppm ozone and clean air for 2 hr at moderate (22°C) temperature and again at an elevated temperature (32.5°C). In each case lung function was performed and blood taken before and immediately after exposure and the next morning., Results: Ozone exposure at 22°C resulted in a decrease in markers of fibrinolysis the next day. There was a 51.8% net decrease in PAI-1 (plasminogen activator inhibitor-1), a 12.1% net decrease in plasminogen, and a 17.8% net increase in D-dimer. These significantly differed from the response at 32.5°C, where there was a 44.9% (p = 0.002) and a 27.9% (p = 0.001) increase in PAI-1 and plasminogen, respectively, and a 12.5% (p = 0.042) decrease in D-dimer. In contrast, decrements in lung function following ozone exposure were comparable at both moderate and elevated temperatures (forced expiratory volume in 1 sec, -12.4% vs. -7.5%, p > 0.05). No changes in systemic markers of inflammation were observed for either temperature., Conclusion: Ozone-induced systemic but not respiratory effects varied according to temperature. Our study suggests that at moderate temperature ozone may activate the fibrinolytic pathway, while at elevated temperature ozone may impair it. These findings provide a biological basis for the interaction between temperature and ozone on mortality observed in some epidemiologic studies.
- Published
- 2015
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30. Analysis of inflammatory cytokines in human blood, breath condensate, and urine using a multiplex immunoassay platform.
- Author
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Stiegel MA, Pleil JD, Sobus JR, Morgan MK, and Madden MC
- Subjects
- Adult, Calibration, Cytokines urine, Exhalation, Humans, Middle Aged, Reference Standards, Reference Values, Sensitivity and Specificity, Young Adult, Cytokines blood
- Abstract
A change in the expression of cytokines in human biological media indicates an inflammatory response to external stressors and reflects an early step along the adverse outcome pathway (AOP) for various health endpoints. To characterize and interpret this inflammatory response, methodology was developed for measuring a suite of 10 different cytokines in human blood, exhaled breath condensate (EBC), and urine using an electrochemiluminescent multiplex Th1/Th2 cytokine immunoassay platform. Measurement distributions and correlations for eight interleukins (IL) (1β, 2, 4, 5, 8, 10, 12p70 and 13), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) were evaluated using 90 blood plasma, 77 EBC, and 400 urine samples collected from nominally healthy adults subjects in North Carolina in 2008-2012. The in vivo results show that there is sufficient sensitivity for characterizing all 10 cytokines at levels of 0.05-0.10 ρg/ml with a dynamic range up to 100 ng/ml across all three of these biological media. The measured in vivo results also show that the duplicate analysis of blood, EBC and urine samples have average estimated fold ranges of 2.21, 3.49, and 2.50, respectively, which are similar to the mean estimated fold range (2.88) for the lowest concentration (0.610 ρg/ml) from a series of spiked control samples; the cytokine method can be used for all three biological media. Nine out of the 10 cytokines measured in EBC were highly correlated within one another with Spearman ρ coefficients ranging from 0.679 to 0.852, while the cytokines measured in blood had a mix of negative and positive correlations, ranging from -0.620 to 0.836. Almost all correlations between EBC and blood were positive. This work also represents the first successful within- and between-person evaluation of ultra trace-level inflammatory markers in blood, EBC, and urine.
- Published
- 2015
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31. Comparative toxicity and mutagenicity of soy-biodiesel and petroleum-diesel emissions: overview of studies from the U.S. EPA, Research Triangle Park, NC.
- Author
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Madden MC
- Subjects
- Animals, Humans, North Carolina, United States, Biofuels toxicity, Mutagens toxicity, Petroleum toxicity, Glycine max toxicity, United States Environmental Protection Agency standards, Vehicle Emissions toxicity
- Abstract
Biodiesel use as a fuel is increasing globally as an alternate to petroleum sources. To comprehensively assess the effects of the use of biodiesel as an energy source, end stage uses of biodiesel such as the effects of inhalation of combusted products on human health must be incorporated. To date, few reports concerning the toxicological effects of the emissions of combusted biodiesel or blends of biodiesel on surrogates of health effects have been published. The relative toxicity of the combusted biodiesel emissions compared to petroleum diesel emissions with short term exposures is also not well known. To address the paucity of findings on the toxicity of combusted biodiesel emissions, studies were undertaken at the U.S. Environmental Protection Agency laboratories in Research Triangle Park, North Carolina. The studies used a variety of approaches with nonhuman animal models to examine biological responses of the lung and cardiovascular systems induced by acute and repeated exposures to pure biodiesel and biodiesel blended with petroleum diesel. Effects of the emissions on induction of mutations in bacterial test strains and mammalian DNA adducts were also characterized and normalized to engine work load. The emissions were characterized as to the physicochemical composition in order to determine the magnitude of the differences among the emissions utilized in the studies. This article summarizes the major finding of these studies which are contained within this special issue of Inhalation Toxicology. The findings provided in these articles provide information about the toxicity of biodiesel emissions relative to petroleum diesel emissions and which can be utilized in a life cycle analyses of the effects of increased biodiesel usage.
- Published
- 2015
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32. Diesel exhaust modulates ozone-induced lung function decrements in healthy human volunteers.
- Author
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Madden MC, Stevens T, Case M, Schmitt M, Diaz-Sanchez D, Bassett M, Montilla TS, Berntsen J, and Devlin RB
- Subjects
- Adult, Bicycling, Biomarkers blood, Cross-Over Studies, Drug Synergism, Female, Follow-Up Studies, Forced Expiratory Volume drug effects, Genetic Association Studies, Glutathione Transferase blood, Glutathione Transferase genetics, Humans, Lung physiopathology, Lung Diseases blood, Lung Diseases genetics, Lung Diseases physiopathology, Male, Single-Blind Method, Young Adult, Air Pollutants toxicity, Inhalation Exposure adverse effects, Lung drug effects, Lung Diseases chemically induced, Oxidants, Photochemical toxicity, Ozone toxicity, Vehicle Emissions toxicity
- Abstract
The potential effects of combinations of dilute whole diesel exhaust (DE) and ozone (O₃), each a common component of ambient airborne pollutant mixtures, on lung function were examined. Healthy young human volunteers were exposed for 2 hr to pollutants while exercising (~50 L/min) intermittently on two consecutive days. Day 1 exposures were either to filtered air, DE (300 μg/m³), O₃ (0.300 ppm), or the combination of both pollutants. On Day 2 all exposures were to O₃ (0.300 ppm), and Day 3 served as a followup observation day. Lung function was assessed by spirometry just prior to, immediately after, and up to 4 hr post-exposure on each exposure day. Functional pulmonary responses to the pollutants were also characterized based on stratification by glutathione S-transferase mu 1 (GSTM1) genotype. On Day 1, exposure to air or DE did not change FEV1 or FVC in the subject population (n = 15). The co-exposure to O₃ and DE decreased FEV1 (17.6%) to a greater extent than O₃ alone (9.9%). To test for synergistic exposure effects, i.e., in a greater than additive fashion, FEV1 changes post individual O₃ and DE exposures were summed together and compared to the combined DE and O₃ exposure; the p value was 0.057. On Day 2, subjects who received DE exposure on Day 1 had a larger FEV1 decrement (14.7%) immediately after the O₃ exposure than the individuals' matched response following a Day 1 air exposure (10.9%). GSTM1 genotype did not affect the magnitude of lung function changes in a significant fashion. These data suggest that altered respiratory responses to the combination of O₃ and DE exposure can be observed showing a greater than additive manner. In addition, O₃-induced lung function decrements are greater with a prior exposure to DE compared to a prior exposure to filtered air. Based on the joint occurrence of these pollutants in the ambient environment, the potential exists for interactions in more than an additive fashion affecting lung physiological processes.
- Published
- 2014
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33. Are urinary PAHs biomarkers of controlled exposure to diesel exhaust?
- Author
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Lu SS, Sobus JR, Sallsten G, Albin M, Pleil JD, Gudmundsson A, Madden MC, Strandberg B, Wierzbicka A, and Rappaport SM
- Subjects
- Creatinine urine, Female, Humans, Male, Biomarkers urine, Polycyclic Aromatic Hydrocarbons urine, Vehicle Emissions toxicity
- Abstract
Urinary polycyclic aromatic hydrocarbons (PAHs) were evaluated as possible biomarkers of exposure to diesel exhaust (DE) in two controlled-chamber studies. We report levels of 14 PAHs from 28 subjects in urine that were collected before, immediately after and the morning after exposure. Using linear mixed-effects models, we tested for effects of DE exposure and several covariates (time, age, gender and urinary creatinine) on urinary PAH levels. DE exposures did not significantly alter urinary PAH levels. We conclude that urinary PAHs are not promising biomarkers of short-term exposures to DE in the range of 106-276 µg/m(3).
- Published
- 2014
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34. Estimating common parameters of lognormally distributed environmental and biomonitoring data: harmonizing disparate statistics from publications.
- Author
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Pleil JD, Sobus JR, Stiegel MA, Hu D, Oliver KD, Olenick C, Strynar M, Clark M, Madden MC, and Funk WE
- Subjects
- Humans, Publishing standards, Research Design, Biomedical Research standards, Data Interpretation, Statistical, Environmental Health, Environmental Monitoring, Models, Statistical
- Abstract
The progression of science is driven by the accumulation of knowledge and builds upon published work of others. Another important feature is to place current results into the context of previous observations. The published literature, however, often does not provide sufficient direct information for the reader to interpret the results beyond the scope of that particular article. Authors tend to provide only summary statistics in various forms, such as means and standard deviations, median and range, quartiles, 95% confidence intervals, and so on, rather than providing measurement data. Second, essentially all environmental and biomonitoring measurements have an underlying lognormal distribution, so certain published statistical characterizations may be inappropriate for comparisons. The aim of this study was to review and develop direct conversions of different descriptions of data into a standard format comprised of the geometric mean (GM) and the geometric standard deviation (GSD) and then demonstrate how, under the assumption of lognormal distribution, these parameters are used to answer questions of confidence intervals, exceedance levels, and statistical differences among distributions. A wide variety of real-world measurement data sets was reviewed, and it was demonstrated that these data sets are indeed of lognormal character, thus making them amenable to these methods. Potential errors incurred from making retrospective estimates from disparate summary statistics are described. In addition to providing tools to interpret "other people's data," this review should also be seen as a cautionary tale for publishing one's own data to make it as useful as possible for other researchers.
- Published
- 2014
- Full Text
- View/download PDF
35. Controlled human exposures to diesel exhaust.
- Author
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Ghio AJ, Sobus JR, Pleil JD, and Madden MC
- Subjects
- Adult, Humans, Oxidative Stress physiology, Threshold Limit Values, Air Pollutants toxicity, Cardiovascular System physiopathology, Inhalation Exposure adverse effects, Lung physiopathology, Particulate Matter toxicity, Vehicle Emissions toxicity
- Abstract
Diesel exhaust is a complex mixture of gaseous and particulate compounds resulting from an incomplete combustion of diesel fuel. Controlled human exposures to diesel exhaust and diesel exhaust particles (DEP) have contributed to understanding health effects. Such acute exposure studies of healthy subjects to diesel exhaust and DEP demonstrate a pro-inflammatory effect in the lung and systemically but only at higher concentrations (with a threshold dose approximating 300 µg/m3). Unexpectedly, there appears to be a lack of an inflammatory response to diesel exhaust and DEP in asthmatic individuals. Controlled human exposure studies of cardiovascular effects show that, comparable to other particle-associated exposures, diesel exhaust has a capacity to precipitate coronary artery disease. In addition, there is a relationship between diesel exhaust and DEP exposure and vascular endpoints; these effects in diesel exhaust may be diminished with removal of DEP. Many extra-pulmonary health effects of diesel exhaust exposure, including systemic inflammation, pro-thrombotic changes, and cardiovascular disease, are considered consequent to pro-inflammatory events and inflammation in the lung. Future research will focus on the relative importance of diesel exhaust components, potential interactions between components and other pollutants, effects in sensitive individuals, and effects of longer or repeated exposures.
- Published
- 2012
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36. Circulating factors induce coronary endothelial cell activation following exposure to inhaled diesel exhaust and nitrogen dioxide in humans: evidence from a novel translational in vitro model.
- Author
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Channell MM, Paffett ML, Devlin RB, Madden MC, and Campen MJ
- Subjects
- Cells, Cultured, Coronary Vessels metabolism, Endothelium, Vascular metabolism, Gene Expression, Humans, Inhalation Exposure, Intercellular Adhesion Molecule-1 genetics, Intercellular Adhesion Molecule-1 metabolism, Pneumonia blood, RNA, Messenger metabolism, Vascular Cell Adhesion Molecule-1 genetics, Vascular Cell Adhesion Molecule-1 metabolism, Air Pollutants toxicity, Coronary Vessels drug effects, Endothelium, Vascular drug effects, Inflammation Mediators pharmacology, Nitrogen Dioxide toxicity, Pneumonia chemically induced, Vehicle Emissions toxicity
- Abstract
The vascular toxicity of inhaled agents may be caused by soluble factors that are released into the systemic circulation. To confirm this in a straightforward manner, we obtained plasma from healthy human volunteers before and after exposure to diesel exhaust (DE) and nitrogen dioxide (NO(2)). Plasma samples were obtained from human volunteers exposed to 100 μg/m(3) DE or filtered air for 2 h. A second cohort was exposed to 500 ppb NO(2) or filtered air in an identical protocol. Primary human coronary artery endothelial cells (hCAECs) were grown to confluence and treated for 24 h with a 10 or 30% (in media) mixture of plasma obtained before, immediately post or 24 h postexposure to pollutant exposures. Messenger RNA (mRNA) was isolated from hCAECs following the incubation and probed for intracellular cell adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1) expression. ICAM-1 mRNA expression was increased by plasma obtained at both timepoints following the NO(2) exposures. VCAM-1 was significantly elevated in cells treated with plasma obtained 24 h following diesel exposure and at both timepoints following NO(2) exposure. Interleukin-8 protein was elevated in the hCAEC supernatant when cells were incubated with plasma from NO(2) exposures. These data indicate that proinflammatory circulating factors are elevated acutely following exposure to both DE and a primary component thereof, NO(2). These functional translational assays offer novel approaches to assessing the cardiovascular risk associated with air pollution exposure.
- Published
- 2012
- Full Text
- View/download PDF
37. Composition of air pollution particles and oxidative stress in cells, tissues, and living systems.
- Author
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Ghio AJ, Carraway MS, and Madden MC
- Subjects
- Air Pollutants chemistry, Air Pollutants toxicity, Animals, Humans, Oxidants metabolism, Particulate Matter chemistry, Reactive Oxygen Species metabolism, Air Pollution adverse effects, Oxidative Stress, Particulate Matter toxicity
- Abstract
Epidemiological studies demonstrated an association between increased levels of ambient air pollution particles and human morbidity and mortality. Production of oxidants, either directly by the air pollution particles or by the host response to the particles, appears to be fundamental in the biological effects seen after exposure to particulate matter (PM). However, the precise components and mechanisms responsible for oxidative stress following PM exposure are yet to be defined. Direct oxidant generation by air pollution particles is attributed to organic and metal components. Organic compounds generate an oxidative stress through redox cycling of quinone-based radicals, by complexing of metal resulting in electron transport, and by depletion of antioxidants by reactions between quinones and thiol-containing compounds. Metals directly support electron transport to generate oxidants and also diminish levels of antioxidants. In addition to direct generation of oxidants by organic and metal components, cellular responses contribute to oxidative stress after PM exposure. Reactive oxygen species (ROS) production occurs in the mitochondria, cell membranes, phagosomes, and the endoplasmic reticulum. Oxidative stress following PM exposure initiates a series of cellular reactions that includes activation of kinase cascades and transcription factors and release of inflammatory mediators, which ultimately lead to cell injury or apoptosis. Consequently, oxidative stress in cells and tissues is a central mechanism by which PM exposure leads to injury, disease, and mortality.
- Published
- 2012
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38. Observing the human exposome as reflected in breath biomarkers: heat map data interpretation for environmental and intelligence research.
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Pleil JD, Stiegel MA, Sobus JR, Liu Q, and Madden MC
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- Environmental Pollutants analysis, Exhalation, Humans, Public Health, Biomarkers metabolism, Breath Tests methods, Environmental Exposure analysis, Environmental Monitoring methods, Exosomes metabolism, Lung physiology, Systems Biology methods
- Abstract
Over the past decade, the research of human system biology and the interactions with the external environment has permeated all phases of environmental, medical and public health research. Similar to the fields of genomics and proteomics research, the advent of new instrumentation for measuring breath biomarkers and their associated meta-data also provide very useful, albeit complex, data structures. The biomarker research community is beginning to invoke tools from system biology to assess the impact of environmental exposures, as well as from internal health states, on the expression of suites of chemicals in exhaled breath. This new approach introduces the concept of the exposome as a complement to the genome in exploring the environment-gene interaction. In addition to answering questions regarding health status for the medical community, breath biomarker patterns are useful for assessing public health risks from environmental exposures. Furthermore, breath biomarker patterns can inform security risks from suspects via covert interrogation of blood borne chemical levels that reflect previous activities. This paper discusses how different classes of exhaled breath biomarker measurements can be used to rapidly assess patterns in complex data. We present exhaled breath data sets to demonstrate the value of the graphical 'heat map' approach for hypothesis development and subsequent guidance for stochastic and mixed effect data interpretation. We also show how to graphically interpret exhaled breath measurements of exogenous jet fuel components, as well as exhaled breath condensate measurements of endogenous chemicals.
- Published
- 2011
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- View/download PDF
39. Plasma matrix metalloproteinase-9 response to eccentric exercise of the elbow flexors.
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Madden MC, Byrnes WC, Lebin JA, Batliner ME, and Allen DL
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- Adolescent, Adult, Biomarkers blood, Biomarkers metabolism, Elbow Joint metabolism, Humans, Isometric Contraction physiology, Male, Matrix Metalloproteinase 9 metabolism, Matrix Metalloproteinase 9 physiology, Muscle Contraction physiology, Muscle Fatigue physiology, Muscular Diseases blood, Muscular Diseases diagnosis, Muscular Diseases enzymology, Muscular Diseases metabolism, Range of Motion, Articular physiology, Torque, Young Adult, Elbow physiology, Elbow Joint physiology, Exercise physiology, Matrix Metalloproteinase 9 blood
- Abstract
Recent efforts to establish a role for plasma matrix metalloproteinase-9 (MMP-9) as a marker of exercise-induced muscle damage have been inconsistent. Methodological and experimental design issues have contributed to confusion in this area. The purpose of this study was to use a damaging eccentric arm task to evaluate the relationship between activity-induced muscle damage and plasma MMP-9 levels in humans while controlling for physical activity history and quantifying day-to-day variability of the dependent variables. Fourteen physically inactive males performed 6 sets of 10 eccentric contractions of the elbow flexors at 120% of their voluntary concentric maximum. Soreness ratings, maximum voluntary isometric strength, range of motion (ROM), limb circumference, and plasma creatine kinase (CK) and MMP-9 levels were measured at 2 time points before, immediately after, and 1, 2, 4, and 7 days post-exercise. Changes in traditional markers of muscle damage mirrored patterns previously reported in the literature, but plasma MMP-9 concentration and activity measured by ELISA and gelatin zymography were unchanged at all time points examined. Plasma levels of the MMP-9 inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1), were also unchanged post-exercise. Finally, although mean MMP-9 levels were not significantly different between the two pre-exercise timepoints, the high total error of measurement and low day-to-day correlation suggest substantial within and between subject variability. Plasma MMP-9 levels are not a robust or reliable marker for eccentric exercise-induced damage of the elbow flexor musculature, though this may not preclude a role for MMPs in skeletal muscle remodeling in response to injury.
- Published
- 2011
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40. The oxidized low-density lipoprotein receptor mediates vascular effects of inhaled vehicle emissions.
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Lund AK, Lucero J, Harman M, Madden MC, McDonald JD, Seagrave JC, and Campen MJ
- Subjects
- Adolescent, Adult, Animals, Antibodies, Neutralizing pharmacology, Apolipoproteins E genetics, Atherosclerosis metabolism, Endothelin-1 metabolism, Endothelium, Vascular metabolism, Humans, Lipid Peroxidation, Lipoproteins, LDL metabolism, Male, Matrix Metalloproteinase 9 metabolism, Mice, Mice, Knockout, Oxidative Stress, Reactive Oxygen Species metabolism, Scavenger Receptors, Class E blood, Scavenger Receptors, Class E immunology, Signal Transduction, Thiobarbituric Acid Reactive Substances metabolism, Up-Regulation, Young Adult, Air Pollutants adverse effects, Aorta metabolism, Scavenger Receptors, Class E metabolism, Vehicle Emissions
- Abstract
Rationale: To determine vascular signaling pathways involved in inhaled air pollution (vehicular engine emission) exposure-induced exacerbation of atherosclerosis that are associated with onset of clinical cardiovascular events., Objectives: To elucidate the role of oxidized low-density lipoprotein (oxLDL) and its primary receptor on endothelial cells, the lectin-like oxLDL receptor (LOX-1), in regulation of endothelin-1 expression and matrix metalloproteinase activity associated with inhalational exposure to vehicular engine emissions., Methods: Atherosclerotic apolipoprotein E knockout mice were exposed by inhalation to filtered air or mixed whole engine emissions (250 μg particulate matter [PM]/m(3) diesel + 50 μg PM/m(3) gasoline exhausts) 6 h/d for 7 days. Concurrently, mice were treated with either mouse IgG or neutralizing antibodies to LOX-1 every other day. Vascular and plasma markers of oxidative stress and expression proatherogenic factors were assessed. In a parallel study, healthy human subjects were exposed to either 100 μg PM/m(3) diesel whole exhaust or high-efficiency particulate air and charcoal-filtered "clean" air (control subjects) for 2 hours, on separate occasions., Measurements and Main Results: Mixed emissions exposure increased oxLDL and vascular reactive oxygen species, as well as LOX-1, matrix metalloproteinase-9, and endothelin-1 mRNA expression and also monocyte/macrophage infiltration, each of which was attenuated with LOX-1 antibody treatment. In a parallel study, diesel exhaust exposure in volunteer human subjects induced significant increases in plasma-soluble LOX-1., Conclusions: These findings demonstrate that acute exposure to vehicular source pollutants results in up-regulation of vascular factors associated with progression of atherosclerosis, endothelin-1, and matrix metalloproteinase-9, mediated through oxLDL-LOX-1 receptor signaling, which may serve as a novel target for future therapy.
- Published
- 2011
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41. Heat map visualization of complex environmental and biomarker measurements.
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Pleil JD, Stiegel MA, Madden MC, and Sobus JR
- Subjects
- Biomarkers metabolism, Environmental Monitoring methods, Environmental Pollutants analysis, Environmental Pollutants metabolism, Environmental Pollutants toxicity, Humans, Polycyclic Aromatic Hydrocarbons analysis, Polycyclic Aromatic Hydrocarbons metabolism, Polycyclic Aromatic Hydrocarbons toxicity, Proteome metabolism, Systems Biology, Audiovisual Aids, Environmental Monitoring instrumentation
- Abstract
Over the past decade, the assessment of human systems interactions with the environment has permeated all phases of environmental and public health research. We are invoking lessons learned from the broad discipline of Systems Biology research that focuses primarily on molecular and cellular networks and adapting these concepts to Systems Exposure Science which focuses on interpreting the linkage from environmental measurements and biomonitoring to the expression of biological parameters. A primary tool of systems biology is the visualization of complex genomic and proteomic data using "heat maps" which are rectangular color coded arrays indicating the intensity (or amount) of the dependent variable. Heat maps are flexible in that both the x-axis and y-axis can be arranged to explore a particular hypothesis and allow a fast overview of data with a third quantitative dimension captured as different colors. We are now adapting these tools for interpreting cumulative and aggregate environmental exposure measurements as well as the results from human biomonitoring of biological media including blood, breath and urine. This article uses existing EPA measurements of environmental and biomarker concentrations of polycyclic aromatic hydrocarbons (PAHs) to demonstrate the value of the heat map approach for hypothesis development and to link back to stochastic and mixed effects models that were originally used to assess study results., (Published by Elsevier Ltd.)
- Published
- 2011
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- View/download PDF
42. Acute daily psychological stress causes increased atrophic gene expression and myostatin-dependent muscle atrophy.
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Allen DL, McCall GE, Loh AS, Madden MC, and Mehan RS
- Subjects
- Animals, Corticosterone blood, Mice, Muscle, Skeletal physiology, Muscular Atrophy genetics, Myostatin genetics, Organ Size, RNA, Messenger genetics, RNA, Messenger metabolism, Spleen anatomy & histology, Thymus Gland anatomy & histology, Weight Loss, Gene Expression Regulation physiology, Muscular Atrophy metabolism, Myostatin metabolism, Stress, Psychological metabolism
- Abstract
Psychological stress is known to attenuate body size and lean body mass. We tested the effects of 1, 3, or 7 days of two different models of psychological stress, 1 h of daily restraint stress (RS) or daily cage-switching stress (CS), on skeletal muscle size and atrophy-associated gene expression in mice. Thymus weights decreased in both RS and CS mice compared with unstressed controls, suggesting that both models activated the hypothalamic-pituitary-adrenal axis. Body mass was significantly decreased at all time points for both models of stress but was greater for RS than CS. Mass of the tibialis anterior (TA) and soleus (SOL) muscles was significantly decreased after 3 and 7 days of RS, but CS only significantly decreased SOL mass after 7 days. TA mRNA levels of the atrophy-associated genes myostatin (MSTN), atrogin-1, and the phosphatidylinositol 3-kinase inhibitory subunit p85alpha were all significantly increased relative to unstressed mice after 1 and 3 days of RS, and expression of MSTN and p85alpha mRNA remained elevated after 7 days of RS. Expression of muscle ring finger 1 was increased after 1 day of RS but returned to baseline at 3 and 7 days of RS. MSTN, atrogin-1, and p85alpha mRNA levels also significantly increased after 1 and 3 days of CS but atrogen-1 mRNA levels had resolved back to normal levels by 3 days and p85alpha with 7 days of CS. p21CIP mRNA levels were significantly decreased by 3 days of CS or RS. Finally, body mass was minimally affected, and muscle mass was completely unaffected by 3 days of RS in mice null for the MSTN gene, and MSTN inactivation attenuated the increase in atrogin-1 mRNA levels with 4 days of RS compared with wild-type mice. Together these data suggest that acute daily psychological stress induces atrophic gene expression and loss of muscle mass that appears to be MSTN dependent.
- Published
- 2010
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43. Cumulative exposure assessment for trace-level polycyclic aromatic hydrocarbons (PAHs) using human blood and plasma analysis.
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Pleil JD, Stiegel MA, Sobus JR, Tabucchi S, Ghio AJ, and Madden MC
- Subjects
- Chemical Fractionation, Environmental Exposure, Freezing, Hexanes, Humans, Regression Analysis, Gas Chromatography-Mass Spectrometry methods, Polycyclic Aromatic Hydrocarbons blood
- Abstract
Humans experience chronic cumulative trace-level exposure to mixtures of volatile, semi-volatile, and non-volatile polycyclic aromatic hydrocarbons (PAHs) present in the environment as by-products of combustion processes. Certain PAHs are known or suspected human carcinogens and so we have developed methodology for measuring their circulating (blood borne) concentrations as a tool to assess internal dose and health risk. We use liquid/liquid extraction and gas chromatography-mass spectrometry and present analytical parameters including dynamic range (0-250 ng/ml), linearity (>0.99 for all compounds), and instrument sensitivity (range 2-22 pg/ml) for a series of 22 PAHs representing 2-6-rings. The method is shown to be sufficiently sensitive for estimating PAHs baseline levels (typical median range from 1 to 1000 pg/ml) in groups of normal control subjects using 1-ml aliquots of human plasma but we note that some individuals have very low background concentrations for 5- and 6-ring compounds that fall below robust quantitation levels., (Published by Elsevier B.V.)
- Published
- 2010
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44. The effects of ambient particulate matter on human alveolar macrophage oxidative and inflammatory responses.
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Sawyer K, Mundandhara S, Ghio AJ, and Madden MC
- Subjects
- Adolescent, Adult, Cytokines metabolism, Humans, Interleukin-6 metabolism, Interleukin-8 metabolism, Lipopolysaccharides pharmacology, Macrophages, Alveolar immunology, Macrophages, Alveolar microbiology, Oxygen metabolism, Superoxides metabolism, Tetradecanoylphorbol Acetate pharmacology, Tumor Necrosis Factor-alpha metabolism, Vehicle Emissions toxicity, Young Adult, Air Pollution adverse effects, Inflammation chemically induced, Macrophages, Alveolar drug effects, Particulate Matter adverse effects
- Abstract
Epidemiologic and occupational studies demonstrated that ambient particulate matter (PM) and diesel exhaust particles (DEP) exert deleterious effects on human cardiopulmonary health, including exacerbation of pre-existing lung disease and development of respiratory infections. The effects of ambient PM on lung cell responsiveness are poorly defined. Human alveolar macrophages (AM) were exposed to SRM 1649 (Washington, DC, urban dust; UD), SRM 2975 (forklift diesel exhaust particles; DEP), and fine or coarse ambient PM collected in Chapel Hill, NC, during the late fall (November) and early summer (June) of 2001-2002. AM were subsequently incubated with lipopolysaccharide (LPS), phorbol myristate acetate (PMA), or calcium ionophore A23817 for 6 or 24 h after PM exposure. UD and DEP markedly suppressed O2- release 24 h post-PM exposure. UD exposure significantly inhibited tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-8 release after exposure to 10 nanog/ml LPS. DEP significantly suppressed only TNF-alpha and IL-6 release. Suppressed cytokine release may also be produced by reduced cellular cytokine production. Data suggested that decreased cytokine release is not produced by the presence of benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon. Comparison of TNF-alpha release after LPS, PMA, or A23817 revealed that suppressive effects of UD are LPS dependent, whereas inhibitory effects of DEP may work across multiple mechanistic pathways. November and June Chapel Hill PM exposure stimulated TNF-alpha and IL-8 release before LPS exposure. Fine and coarse November PM exposure markedly suppressed TNF-alpha release 6 h after LPS stimulation, but appeared to exert a stimulatory effect on IL-8 release 24 h after LPS exposure. June fine and coarse PM suppressed IL-8 release after LPS exposure. Data suggest that seasonal influences on PM composition affect AM inflammatory response before and after bacterial exposure. Overall, delayed or inhibited AM immune responses to LPS after PM exposure suggest human exposure to ambient PM may enhance pulmonary susceptibility to respiratory infections.
- Published
- 2010
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45. Application of novel method to measure endogenous VOCs in exhaled breath condensate before and after exposure to diesel exhaust.
- Author
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Hubbard HF, Sobus JR, Pleil JD, Madden MC, and Tabucchi S
- Subjects
- Adsorption, Gas Chromatography-Mass Spectrometry, Humans, Models, Theoretical, Exhalation, Vehicle Emissions toxicity, Volatile Organic Compounds analysis
- Abstract
Polar volatile organic compounds (PVOCs) such as aldehydes and alcohols are byproducts of normal human metabolism and thus are found in blood and exhaled breath. Perturbation of the normal patterns of such metabolites may reflect exposures to environmental stressors, disease state, and human activity. Presented herein is a specific methodology for assaying PVOC biomarkers in exhaled breath condensate (EBC) samples with application to a series of samples from a controlled chamber exposure to dilute diesel exhaust (DE) or to purified air. The collection/analysis method is based on condensation of normal (at rest) exhaled breaths for 10 min (resulting in 1-2 ml of liquid) with subsequent analyte adsorption onto Tenax cartridges followed by thermal desorption and analysis by gas chromatography/mass spectrometry (GC/MS). Analytical data have linearity of response (R(2)>0.98) across a range of 0-160 ng/ml with a detection limit ranging from 0.2 to 7 ng/ml depending on the compound. Statistical analyses of the results of the controlled exposure study indicate that metabolism, as reflected in simple breath-borne oxygenated species, is not affected by exposure to ambient airborne levels of DE. Linear mixed-effects models showed that PVOC biomarker levels are affected by gender and vary significantly among nominally healthy subjects. Differences among PVOCs analyzed in clinic air, purified chamber air, and chamber air containing dilute DE confirm that most of the compounds are likely of endogenous origin as the exogenous exposure levels did not perturb the EBC measurements.
- Published
- 2009
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46. Vehicular emissions induce vascular MMP-9 expression and activity associated with endothelin-1-mediated pathways.
- Author
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Lund AK, Lucero J, Lucas S, Madden MC, McDonald JD, Seagrave JC, Knuckles TL, and Campen MJ
- Subjects
- Administration, Oral, Adolescent, Adult, Animals, Antioxidants administration & dosage, Aorta enzymology, Apolipoproteins E deficiency, Apolipoproteins E genetics, Atherosclerosis enzymology, Atherosclerosis genetics, Cyclic N-Oxides administration & dosage, Endothelin-1 blood, Endothelin-1 genetics, Female, Humans, Infusion Pumps, Implantable, Inhalation Exposure, Male, Matrix Metalloproteinase 2 metabolism, Matrix Metalloproteinase 9 blood, Matrix Metalloproteinase 9 genetics, Mice, Mice, Knockout, Nitrates metabolism, Nitrites metabolism, Peptides, Cyclic administration & dosage, RNA, Messenger metabolism, Reactive Oxygen Species metabolism, Receptor, Endothelin A drug effects, Receptor, Endothelin A metabolism, Spin Labels, Time Factors, Tissue Inhibitor of Metalloproteinase-2 metabolism, Up-Regulation, Young Adult, Aorta drug effects, Atherosclerosis chemically induced, Endothelin-1 metabolism, Matrix Metalloproteinase 9 metabolism, Vehicle Emissions toxicity
- Abstract
Objective: Mechanisms of air pollution-induced exacerbation of cardiovascular disease are currently unknown, thus we examined the roles of vascular endothelin-1 (ET-1) and reactive oxygen species (ROS) in regulating mediators of vascular remodeling, namely matrix metalloproteinases (MMPs), after exposure to vehicle engine emissions., Methods and Results: ApoE(-/-) mice were exposed by inhalation to filtered air or gasoline engine exhaust (GEE, 1:12 dilution) 6 hours per day for 1 or 7 days. Concurrently, mice were treated with either ET(A) receptor antagonist BQ-123 (100 ng/kg/d) via osmotic minipumps, Tempol (approximately 41 mg/kg/d, orally), or vehicle. GEE-exposure increased vascular MMP-2 and -9, endothelin-1 (ET-1), tissue inhibitor of metalloproteinases (TIMP)-2 mRNA and ROS levels. Aortic MMP protein and plasma MMP-9 were similarly upregulated. GEE-mediated increases in vascular ROS were attenuated by Tempol-treatment, as were MMP-2 and TIMP-2; whereas BQ-123 ameliorated GEE-induced vascular expression of MMP-9, MMP-2, ROS, and ET-1. In a parallel study, diesel exhaust exposure in volunteer human subjects induced significant increases in plasma ET-1 and MMP-9 expression and activity., Conclusions: These findings demonstrate that acute exposure to vehicular source air pollutants results in upregulation of circulating and vascular factors associated with progression of atherosclerosis, mediated in part through activation of ET-1-ET(A) receptor pathways.
- Published
- 2009
- Full Text
- View/download PDF
47. Identification of surrogate measures of diesel exhaust exposure in a controlled chamber study.
- Author
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Sobus JR, Pleil JD, Madden MC, Funk WE, Hubbard HF, and Rappaport SM
- Subjects
- Adult, Air, Biomarkers analysis, Humans, Naphthalenes analysis, Phenanthrenes analysis, Polycyclic Aromatic Hydrocarbons analysis, Volatile Organic Compounds analysis, Volatilization, Environment, Controlled, Environmental Exposure, Vehicle Emissions analysis
- Abstract
Exposure to diesel exhaust (DE) has been associated with acute cardiopulmonary and vascular responses, chronic noncancer health effects, and respiratory cancers in humans. To better understand DE exposures and eventually their related health effects, we established a controlled chamber experiment wherein human volunteer subjects were exposed to approximately 100 microg/m3 DE. In general, human exposure assessment for DE is based on ambient air measurements of surrogates such as elemental carbon (EC) or total organic carbon (OC) collected on filters. As specific health effect mechanisms and dose-response are obscured bythe complex composition of DE, the linkage from exposure to internal dose can presumably be improved by use of specific biomarkers and metabolites in blood, breath, or urine. Because EC and OC are not suitable as biomarkers, in this study, we focus on identifying compounds that are demonstrated indicators of DE and can also be found in biological fluids. We measured an assortment of volatile, semivolatile, and particle-bound aromatic compounds in the chamber air and report their airborne concentrations in DE and purified air, as well as the estimated values of the corresponding exposure ratios (mean DE air concentration:mean purified air concentration). These estimated exposure ratios were used to identify naphthalene (Nap) and phenanthrene (Phe) as potentially useful surrogates for DE exposure that could also serve as biomarkers. Estimated mean levels of Nap and Phe associated with the nominal 100 microg/m3 DE were 2600 and 765 ng/m3 with estimated exposure ratios of 252 and 92.4, respectively. Nap levels were significantly correlated with OC and total particle-bound polycyclic aromatic hydrocarbons (PAHs); Phe levels were significantly correlated with total volatile + semivolatile PAHs. These results suggest that Nap and Phe may be particularly useful surrogates for DE concentrations. While Nap and Phe are not validated here as internal biomarkers of DE exposure, we are currently assessing human biological specimens collected during this study and will discuss those results in ensuing papers.
- Published
- 2008
- Full Text
- View/download PDF
48. Responses measured in the exhaled breath of human volunteers acutely exposed to ozone and diesel exhaust.
- Author
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Sawyer K, Samet JM, Ghio AJ, Pleil JD, and Madden MC
- Abstract
Exhaled breath collection is used to identify and monitor inflammatory or oxidative components in breath. Exhaled breath sample collection is noninvasive and would greatly benefit human pollutant exposure research. We demonstrate the efficacy of exhaled breath collection and analysis in two human exposure studies to ozone (O(3)) and diesel exhaust, respectively. O(3) study: we collected exhaled breath (gas phase) from healthy human volunteers (age 18-35 years, 12 subjects) immediately before and after exposure to filtered air or 0.4 ppm O(3) for 2 h with and without intermittent exercise. Six subjects received antioxidant supplementation for 2 weeks before their O(3) exposure, while the remaining six subjects received placebo treatments. We demonstrate increased amounts of non-polar carbonyls exhaled immediately post O(3) exposure. The O(3)-induced increase in exhaled carbonyl concentrations was attenuated in the group receiving antioxidants. Our data demonstrate that exhaled exposure biomarkers can be measured in the breath gas phase in humans exposed to O(3). Diesel study: we collected exhaled breath condensate (EBC; liquid phase) from healthy human volunteers (age 18-40 years; 10 subjects) immediately before, immediately after and 20 h post filtered air or diesel exhaust (106 ± 9 µg m(-3)) exposure. Clean air and diesel exposures were separated by 3 weeks to 6 months. We obtained reproducible intra-subject EBC volumes and total protein concentrations across our six collection time points. Diesel exposure did not affect either EBC volume or total protein concentrations. Our data demonstrated EBC volume and total protein reproducibility over several months. Volume and total protein concentration may serve as normalizing factors for other EBC constituents.
- Published
- 2008
- Full Text
- View/download PDF
49. Volatile polar metabolites in exhaled breath condensate (EBC): collection and analysis.
- Author
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Pleil JD, Hubbard HF, Sobus JR, Sawyer K, and Madden MC
- Abstract
Environmental exposures, individual activities and disease states can perturb normal metabolic processes and be expressed as a change in the patterns of polar volatile organic compounds (PVOCs) present in biological fluids. We explore the measurement of volatile endogenous biomarkers to infer previous exposures to complex mixtures of environmental stressors. It is difficult to extract such compounds for ultra-trace level analysis due to their high solubility in water, especially when assaying complex liquid biological media such as exhaled breath condensate (EBC). Existing methods tend to be limited in sample volume processed and restricted in sample throughput. We have developed an alternative passive extraction method wherein a 2 ml sample is injected into a 75 ml glass bulb creating a small pool of liquid; a standard Tenax® sampling tube is inserted above the fluid and allowed to equilibrate with the headspace for ∼24 h. The biomarker compounds are preferentially transferred by diffusion from the aqueous sample onto the Tenax® adsorbent; blanks and calibration samples are similarly processed. Numerous samples can be simultaneously prepared and stored awaiting routine analysis for a suite of alcohols and aldehydes using thermal desorption gas chromatography-mass spectrometry (GC-MS). We have optimized the procedures and estimated the sensitivity, precision and extraction efficiency resulting from the preparation and analytical procedures using synthetic samples. We subsequently demonstrated the method using anonymous biological specimens of EBC from healthy adults. The ultimate goal is to develop normal ranges and patterns for PVOCs to infer population-based environmental health states with simple spot measurements based on outlier determinations.
- Published
- 2008
- Full Text
- View/download PDF
50. Complex issues with examining diesel exhaust toxicity: is the task getting easier or harder?
- Author
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Madden MC
- Subjects
- Animal Testing Alternatives, Cells, Cultured, Humans, Lung pathology, Lung physiopathology, Lung Diseases pathology, Lung Diseases physiopathology, Models, Animal, Particulate Matter adverse effects, Tissue Culture Techniques, Environmental Exposure adverse effects, Inhalation Exposure, Lung drug effects, Lung Diseases chemically induced, Vehicle Emissions toxicity
- Abstract
Petroleum diesel exhaust (DE) exposure has been linked to several health effects including lung cancer. The role of DE in the cardiopulmonary effects associated with particulate matter (PM) exposures is unclear; this uncertainty drives current research efforts to better understand how the DE exerts toxicity. Several issues present complexities to the design of DE health effects research. One issue is to better establish the health effects and biological responses from DE exposure. Lung responses have been examined with variable findings with controlled exposures, but to date relatively little is known about cardiovascular responses. Additionally, induction of other health effects from DE exposure has been examined mainly through either controlled nonhuman animal model exposures or epidemiological approaches. Due to changing regulations and technology to achieve compliance with regulatory standards, DE from more modern emissions contains less PM and certain gases, making comparisons to older emissions complicated. In addition, the gas phase contains proportionally more mass than the PM phase, presenting technological problems in terms of the collection of the DE for future studies and across-laboratory comparison. Therefore, in order to study the toxicity of DE, whole exhaust (PM and gases) exposures should ideally be performed, at least as part of establishing the role that the PM or gases may play in the biological responses being examined.
- Published
- 2008
- Full Text
- View/download PDF
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