Markers of nitrosamine carcinogenesis?

BrooklynDodger(s) comment: These novel assay experiments should be related to exposure levels in which toxicity or carcinogenicity is expressed in an intact animal.


Toxicology and Applied Pharmacology
Volume 241, Issue 2, 1 December 2009, Pages 230-245

Toxicogenomic analysis of N-nitrosomorpholine induced changes in rat liver: Comparison of genomic and proteomic responses and anchoring to histopathological parameters

References and further reading may be available for this article. To view references and further reading you must purchase this article.

A. Oberemm^{a, ,} , H.-J. Ahr^b, P. Bannasch^c, H. Ellinger-Ziegelbauer^b, M. Glückmann^e, J. Hellmann^d, C. Ittrich^{c, 1}, A. Kopp-Schneider^c, P.-J. Kramer^d, E. Krause^f, M. Kröger^d, E. Kiss^c, H.-B. Richter-Reichhelm^a, G. Scholz^{b, 2}, K. Seemann^d, M. Weimer^c and U. Gundert-Remy^a

^aFederal Institute for Risk Assessment (BfR), 14195 Berlin, Germany

^bBayer Schering Pharma AG, Special Toxicology, 42096 Wuppertal, Germany

^cGerman Cancer Research Center (DKFZ), 69120 Heidelberg, Germany

^dMerck KGaA, Institute for Toxicology, 64293 Darmstadt, Germany

^eApplied Biosystems Deutschland GmbH, 64293 Darmstadt, Germany

^fLeibniz Institute for Molecular Pharmacology (FMP), 13125 Berlin, Germany

Received 29 July 2009;

accepted 18 August 2009.

Available online 28 August 2009.

Abstract

A common animal model of chemical hepatocarcinogenesis was used to examine the utility of transcriptomic and proteomic data to identify early biomarkers related to chemically induced carcinogenesis. N-nitrosomorpholine, a frequently used genotoxic model carcinogen, was applied via drinking water at 120 mg/L to male Wistar rats for 7 weeks followed by an exposure-free period of 43 weeks. Seven specimens of each treatment group (untreated control and 120 mg/L N-nitrosomorpholine in drinking water) were sacrificed at nine time points during and after N-nitrosomorpholine treatment. Individual samples from the liver were prepared for histological and toxicogenomic analyses. For histological detection of preneoplastic and neoplastic tissue areas, sections were stained using antibodies against the placental form of glutathione-S-transferase (GST-P). Gene and protein expression profiles of liver tissue homogenates were analyzed using RG-U34A Affymetrix rat gene chips and two-dimensional gel electrophoresis-based proteomics, respectively. In order to compare results obtained by histopathology, transcriptomics and proteomics, GST-P-stained liver sections were evaluated morphometrically, which revealed a parallel time course of the area fraction of preneoplastic lesions and gene plus protein expression patterns. On the transcriptional level, an increase of hepatic GST-P expression was detectable as early as 3 weeks after study onset. Comparing deregulated genes and proteins, eight species were identified which showed a corresponding expression profile on both expression levels. Functional analysis suggests that these genes and corresponding proteins may be useful as biomarkers of early hepatocarcinogenesis.

Another endpoint for nano titanium dioxide

BrooklynDodger(s) comment: Continuing to run nano particles through novel test systems. Historically, titanium dioxide is the negative control for lung damage. What's needed is a systematic testing of a spectrum of particles in the same system - full size titanium dioxide, silica (a known human carcinogen), diesel, carbon materials. So that relative potency can be measured.

Toxicology and Applied Pharmacology
Volume 241, Issue 2, 1 December 2009, Pages 182-194

Disturbed mitotic progression and genome segregation are involved in cell transformation mediated by nano-TiO2 long-term exposure

Shing Huang^a, Pin Ju Chueh^a, Yun-Wei Lin^b, Tung-Sheng Shih^c and Show-Mei Chuang^{a, ,}

^aInstitute of Biomedical Sciences, National Chung Hsing University, 250 Kuo-Kuang Road, Taichung 402, Taiwan

^bMolecular Oncology Laboratory, Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan

^cInstitute of Occupational Safety and Healthy Council of Labor Affairs, Executive Yuan, Taipei 221, Taiwan

Received 9 March 2009;

revised 10 August 2009;

accepted 11 August 2009.

Available online 18 August 2009.

Abstract

Titanium dioxide (TiO2) nano-particles (< 100 nm in diameter) have been of interest in a wide range of applications, such as in cosmetics and pharmaceuticals because of their low toxicity. However, recent studies have shown that TiO2 nano-particles (nano-TiO2) induce cytotoxicity and genotoxicity in various lines of cultured cells as well as tumorigenesis in animal models. The biological roles of nano-TiO2 are shown to be controversial and no comprehensive study paradigm has been developed to investigate their molecular mechanisms. In this study, we showed that short-term exposure to nano-TiO2 enhanced cell proliferation, survival, ERK signaling activation and ROS production in cultured fibroblast cells. Moreover, long-term exposure to nano-TiO2 not only increased cell survival and growth on soft agar but also the numbers of multinucleated cells and micronucleus (MN) as suggested in confocal microscopy analysis. Cell cycle phase analysis showed G2/M delay and slower cell division in long-term exposed cells. Most importantly, long-term TiO2 exposure remarkably affected mitotic progression at anaphase and telophase leading to aberrant multipolar spindles and chromatin alignment/segregation. Moreover, PLK1 was demonstrated as the target for nano-TiO2 in the regulation of mitotic progression and exit. Notably, a higher fraction of sub-G1 phase population appeared in TiO2-exposed cells after releasing from G2/M synchronization. Our results demonstrate that long-term exposure to nano-TiO2 disturbs cell cycle progression and duplicated genome segregation, leading to chromosomal instability and cell transformation

IRIS Summary for 1,2,3-trichloropropane

BrooklynDodger(s) comment: The Dodger(s) figure this is a drinking water contaminant. As with most IRIS chemicals, the chronic RfC is essentially zero. This came to attention because other bloggers noted OMB meddling. OMB was selling site specificity, animal to man, which is an old Houdini chestnut.


http://www.epa.gov/iris/subst/0200.htm

Critical Effect	Point of Departure*	UF	Chronic RfC
peribronchial lymphoid hyperplasia in male rats 13-week inhalation Study Johannsen et al., 1988	BMC10: 1.6 ppm BMCL10: 0.84 ppm BMCLADJ: 0.90 mg/m3 BMCLHEC: 0.90 mg/m3	3000	0.0003 mg/m3

Gene Environmental Interactions for Bladder Cancer

BrooklynDodger(s) comment: First, urothelial carcinoma is the most common type of bladder cancer - the Dodger(s) had to google it. Learn something every day. The trouble with most genetic studies of cancer is they end with blaming the victim - or the victims' ancestors - and yield no new ideas for intervention. Controlling for less resistant genetic types would enable better human studies of associations with exposures. Glutathione continues to get more play, compared to cytochrome. CYP can be thought of as activating and dotoxicating, while GST is mostly detox unless there's an ad hoc Houdini hypothesis, as for methylene chloride.


Toxicology and Applied Pharmacology
Volume 241, Issue 1, 15 November 2009, Pages 111-118

A significantly joint effect between arsenic and occupational exposures and risk genotypes/diplotypes of CYP2E1, GSTO1 and GSTO2 on risk of urothelial carcinoma

This article is not included in your organization's subscription. However, you may be able to access this article under your organization's agreement with Elsevier.

Yuan-Hung Wang^{a, b}, Shauh-Der Yeh^b, Kun-Hung Shen^c, Cheng-Huang Shen^d, Guang-Dar Juang^e, Ling-I Hsu^f, Hung-Yi Chiou^{a, ,} and Chien-Jen Chen^{f, g}

^aSchool of Public Health, Taipei Medical University, Taipei 110, Taiwan

^bDepartment of Urology, Taipei Medical University Hospital, Taipei 110, Taiwan

^cDepartment of Urology, Chi-Mei Medical Center, Tainan 710, Taiwan

^dDepartment of Urology, Chiayi Christian Hospital, Chia-Yi 600, Taiwan

^eDivision of Urology, Department of Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan

^fThe Genomics Research Center, Academia Sinica, Taipei 115, Taiwan

^gGraduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei 100, Taiwan

Received 17 April 2009;

revised 3 August 2009;

accepted 7 August 2009.

Available online 15 August 2009.

Abstract

Cigarette smoking, arsenic and occupational exposures are well-known risk factors for the development of urothelial carcinoma (UC). Therefore, the aim of this study is to investigate whether the effect of cigarette smoking, alcohol consumption, arsenic and occupational exposures on risk of UC could be modified by genetic polymorphisms of cytochrome P450 2E1 and glutathione S-transferase omega. A hospital-based case–control study consisted of 520 histologically confirmed UC cases, and 520 age- and gender-matched cancer-free controls were carried out from September 1998 to December 2007. Genotyping of CYP2E1, GSTO1 and GSTO2 was determined by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP). Subjects with both of cigarette smoking and alcohol consumption have a significantly increased UC risk (odds ratio [OR] = 2.9; 95% confidence interval [CI] = 1.9–4.4). Significantly increased UC risks of 1.5 and 1.9 were found for study subjects with high arsenic exposure and those who have been exposed to two or more occupational exposures, respectively. A significantly increased UC risk of 3.9 was observed in study subjects with H2–H2 diplotype of GSTO1 and GSTO2. The significantly highest UC risk of 9.0 was found for those with all environmental risk factors of cigarette smoking, alcohol consumption, arsenic and occupational exposures and two or more risk genotypes/diplotypes of CYP2E1, GSTO1 and GSTO2. Our findings suggest that a significantly joint effect of cigarette smoking, alcohol consumption, arsenic and occupational exposures and risk genotypes/diplotypes of CYP2E1, GSTO1 and GSTO2 on risk of UC was found.

Arsenic Cardiac Effects

BrooklynDodger(s) comment: Another exploration of the neglected organ system. Hazard ID in a specialized strain of mice. Need to think about potency (exposure response) assessment.



Toxicology and Applied Pharmacology
Volume 241, Issue 1, 15 November 2009, Pages 90-100

Arsenic exacerbates atherosclerotic lesion formation and inflammation in ApoE-/- mice

References and further reading may be available for this article. To view references and further reading you must purchase this article.

Sanjay Srivastava^{a, d, ,} , Elena N. Vladykovskaya^a, Petra Haberzettl^a, Srinivas D. Sithu^b, Stanley E. D'Souza^b and J. Christopher States^{c, d}

^aDiabetes and Obesity Center and Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40202, USA

^bDepartment of Physiology and Biophysics, University of Louisville, Louisville, KY 40202, USA

^cDepartment of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA

^dCenter for Environmental Genomics and Integrative Biology, University of Louisville, Louisville, KY 40202, USA

Received 23 February 2009;

revised 3 August 2009;

accepted 4 August 2009.

Available online 12 August 2009.

Abstract

Exposure to arsenic-contaminated water has been shown to be associated with cardiovascular disease, especially atherosclerosis. We examined the effect of arsenic exposure on atherosclerotic lesion formation, lesion composition and nature in ApoE-/- mice. Early post-natal exposure (3-week-old mice exposed to increased the atherosclerotic lesion formation by 3- to 5-fold in the aortic valve and the aortic arch, wit49 ppm arsenic as NaAsO₂ in drinking water for 7 weeks) without affecting plasma cholesterol. Exposure to arsenic for 13 weeks (3-week-old mice exposed to 1, 4.9 and 49 ppm arsenic as NaAsO₂ in drinking water) increased the lesion formation and macrophage accumulation in a dose-dependent manner. Temporal studies showed that continuous arsenic exposure significantly exacerbated the lesion formation throughout the aortic tree at 16 and 36 weeks of age. Withdrawal of arsenic for 12 weeks after an initial exposure for 21 weeks (to 3-week-old mice) significantly decreased lesion formation as compared with mice continuously exposed to arsenic. Similarly, adult exposure to 49 ppm arsenic for 24 weeks, starting at 12 weeks of age increased lesion formation by 2- to 3.6-fold in the aortic valve, the aortic arch and the abdominal aorta. Lesions of arsenic-exposed mice displayed a 1.8-fold increase in macrophage accumulation whereas smooth muscle cell and T-lymphocyte contents were not changed. Expression of pro-inflammatory chemokine MCP-1 and cytokine IL-6 and markers of oxidative stress, protein-HNE and protein-MDA adducts were markedly increased in lesions of arsenic-exposed mice. Plasma concentrations of MCP-1, IL-6 and MDA were also significantly elevated in arsenic-exposed mice. These data suggest that arsenic exposure increases oxidative stress, inflammation and atherosclerotic lesion formation.

Metals in PM associated with Cardiac Toxicity

BrooklynDodger(s) comment: Risk assessments for particulate exposure in the workplace, and also community, typically ignore cardiac effects. Cohort studies in workplace populations are typically null for associations with chemical exposure, probably resulting from the healthy worker effect. This endpoint needs more work. Good to see EPA in the science game.

Toxicology and Applied Pharmacology
Volume 241, Issue 1, 15 November 2009, Pages 71-80

Differential pulmonary and cardiac effects of pulmonary exposure to a panel of particulate matter-associated metals

References and further reading may be available for this article. To view references and further reading you must purchase this article.

J. Grace Wallenborn^{a, ,} , Mette J. Schladweiler^b, , Judy H. Richards^b, and Urmila P. Kodavanti^b,

^aDepartment of Environmental Sciences and Engineering, UNC School of Public Health, Chapel Hill, NC 27599, USA

^bPulmonary Toxicology Branch, Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, ORD, Environmental Protection Agency, Durham, NC 27711, USA

Received 28 May 2009;

revised 29 July 2009;

accepted 3 August 2009.

Available online 11 August 2009.

Abstract

Biological mechanisms underlying the association between particulate matter (PM) exposure and increased cardiovascular health effects are under investigation. Water-soluble metals reaching systemic circulation following pulmonary exposure are likely exerting a direct effect. However, it is unclear whether specific PM-associated metals may be driving this. We hypothesized that exposure to equimolar amounts of five individual PM-associated metals would cause differential pulmonary and cardiac effects. We exposed male WKY rats (14 weeks old) via a single intratracheal instillation (IT) to saline or 1 μmol/kg body weight of zinc, nickel, vanadium, copper, or iron in sulfate form. Responses were analyzed 4, 24, 48, or 96 h after exposure. Pulmonary effects were assessed by bronchoalveolar lavage fluid levels of total cells, macrophages, neutrophils, protein, albumin, and activities of lactate dehydrogenase, γ-glutamyl transferase, and n-acetyl glucosaminidase. Copper induced earlier pulmonary injury/inflammation, while zinc and nickel produced later effects. Vanadium or iron exposure induced minimal pulmonary injury/inflammation. Zinc, nickel, or copper increased serum cholesterol, red blood cells, and white blood cells at different time points. IT of nickel and copper increased expression of metallothionein-1 (MT-1) in the lung. Zinc, nickel, vanadium, and iron increased hepatic MT-1 expression. No significant changes in zinc transporter-1 (ZnT-1) expression were noted in the lung or liver; however, zinc increased cardiac ZnT-1 at 24 h, indicating a possible zinc-specific cardiac effect. Nickel exposure induced an increase in cardiac ferritin 96 h after IT. This data set demonstrating metal-specific cardiotoxicity is important in linking metal-enriched anthropogenic PM sources with adverse health effects.

More Wands for Houdini

BrooklynDodger(s) comment: A publication from EPA - it appears that EPA is arming itself for the next Houdini Risk Assessment war over trichloroethylene and solvents.


Characterizing uncertainty and population variability in the toxicokinetics of trichloroethylene and metabolites in mice, rats, and humans using an updated database, physiologically based pharmacokinetic (PBPK) model, and Bayesian approach
Pages 36-60
Weihsueh A. Chiu, Miles S. Okino, Marina V. Evans
http://www.sciencedirect.com/science?_ob=GatewayURL&_method=citationSearch&_urlVersion=4&_origin=SDVIALERTASCII&_version=1&_uoikey=B6WXH-4WXHBRS-2&md5=cf7e18939eb53611bdbca3e68c564dc1

We have developed a comprehensive, Bayesian, PBPK model-based analysis of the population toxicokinetics of trichloroethylene (TCE) and its metabolites in mice, rats, and humans, considering a wider range of physiological, chemical, in vitro, and in vivo data than any previously published analysis of TCE. The toxicokinetics of the “population average,” its population variability, and their uncertainties are characterized in an approach that strives to be maximally transparent and objective. Estimates of experimental variability and uncertainty were also included in this analysis. The experimental database was expanded to include virtually all available in vivo toxicokinetic data, which permitted, in rats and humans, the specification of separate datasets for model calibration and evaluation. The total combination of these approaches and PBPK analysis provides substantial support for the model predictions. In addition, we feel confident that the approach employed also yields an accurate characterization of the uncertainty in metabolic pathways for which available data were sparse or relatively indirect, such as GSH conjugation and respiratory tract metabolism. Key conclusions from the model predictions include the following: (1) as expected, TCE is substantially metabolized, primarily by oxidation at doses below saturation; (2) GSH conjugation and subsequent bioactivation in humans appear to be 10- to 100-fold greater than previously estimated; and (3) mice had the greatest rate of respiratory tract oxidative metabolism as compared to rats and humans. In a situation such as TCE in which there is large database of studies coupled with complex toxicokinetics, the Bayesian approach provides a systematic method of simultaneously estimating model parameters and characterizing their uncertainty and variability. However, care needs to be taken in its implementation to ensure biological consistency, transparency, and objectivity.

A Screening Test for Autoimmunity Potential

BrooklynDodger(s) comment: The Dodger(s) have to look up the full text, to find the activity of silicone implants.

Assessment of autoimmunity-inducing potential using the Brown Norway rat challenge model
Toxicology Letters, Volumes 112-113, 15 March 2000, Pages 443-451
Kimber L. WhiteJr, Daniel W. David, Leon F. Butterworth, Paal C. Klykken

The development of autoimmune disease in humans is thought to occur as a result of the interactions of a genetic predisposition of the host and environmental factors. There is evidence that treatment with When exposed to certain chemicals, Brown Norway (BN) rats develop autoimmune disease similar to human systemic lupus erythematosus (SLE) characterized bycertain drugs and exposure to environmental toxicants increase the risk associated with the development and severity of autoimmune disease. elevation of antibody levels to self and non-self antigens which can result in the formation of immune complexes and lead to a fatal glomerulonephritis. A unique characteristic of the BN rat model is that the increase in IgE is self-limiting with levels eventually returning to normal. The objective of these studies was to determine if the BN rat and the self-limiting nature of the IgE response could be used in identifying compounds capable of initiating autoimmune responses. Two compounds known to produce autoimmunity, mercuric chloride and -penicillamine, were studied as were, trichloroethylene and silicone gel, two agents suspected of inducing autoimmune disease. The results indicated that the BN rat model may prove useful for detecting compounds with the potential to produce autoimmunity, particularly if a HgCl₂ challenge is incorporated into the evaluation.

Even in Canada You Can't Get Reliable Road Accident Data

BrooklynDodger(s) comments: Maybe there's generalizable solution to the problem of under reporting in passive data collection for injuries and accidents. A sampling approach seems better than a census. Public health can't rely on self-reporting by interested authorities.

Cross-analysis of hazmat road accidents using multiple databases
Pages 1192-1198
Martin Trépanier, Marie-Hélène Leroux, Nathalie de Marcellis-Warin

Road selection for hazardous materials transportation relies heavily on risk analysis. With risk being generally expressed as a product of the probability of occurrence and the expected consequence, one will understand that risk analysis is data intensive. However, various authors have noticed the lack of statistical reliability of hazmat accident databases due to the systematic underreporting of such events. Also, official accident databases alone are not always providing all the information required (economical impact, road conditions, etc.). In this paper, we attempt to integrate many data sources to analyze hazmat accidents in the province of Quebec, Canada. Databases on dangerous goods accidents, road accidents and work accidents were cross-analyzed. Results show that accidents can hardly be matched and that these databases suffer from underreporting. Police records seem to have better coverage than official records maintained by hazmat authorities. Serious accidents are missing from government's official databases (some involving deaths or major spills) even though their declaration is mandatory.

Humoral Markers of TCE auto immunity - Epiphenonmena?

BrooklynDodger(s) Comment: This is not the Dodger(s)' field, although not clear what that field is. Nevertheless, the investigators here identify markers of humoral auto immunity, not cell mediated. But the health consequences quoted as being associated with TCE are not sneezing and wheezing (humoral) but allergic dermatitis, cell mediated.

Oxidative and nitrosative stress in trichloroethene-mediated autoimmune response
Toxicology, Volume 229, Issue 3, 18 January 2007, Pages 186-193
Gangduo Wang, Ping Cai, G.A.S. Ansari, M. Firoze Khan

Trichloroethene (TCE) is an industrial degreasing solvent and widespread environmental contaminant. Exposure to TCE is associated with autoimmunity. The mode of action of TCE is via its oxidative metabolism, and most likely, immunotoxicity is mediated via haptenization of macromolecules and subsequent induction of immune responses. To better understand the role of protein haptenization through TCE metabolism, we immunized MRL+/+ mice with albumin adducts of various TCE reactive intermediates. Serum immunoglobulins and cytokine levels were measured to determine immune responses against haptenized albumin. We found antigen-specific IgG responses of the IgG subtypes IgG₁, IgG_2a, and IgG_2b, with IgG₁ predominating. Serum levels of G-CSF were increased in immunized mice, suggesting macrophage activation. Liver histology revealed lymphocyte infiltration in the lobules and the portal area following immunization with formyl-albumin. Our findings suggest that proteins haptenized by metabolites of TCE may act as neo-antigens that can induce humoral immune responses and T cell-mediated hepatitis.

TCE induced auto immunity - protein modifications

BrooklynDodger(s) comment: This continues posts on TCE induced auto immunity, which is apparently well established in China, and is driving a series of mechanistic studies. Dodger(s) too lazy to convert the dose to mg/kg.


Increased nitration and carbonylation of proteins in MRL +/+ mice exposed to trichloroethene: Potential role of protein oxidation in autoimmunity

Toxicology and Applied Pharmacology, Volume 237, Issue 2, 1 June 2009, Pages 188-195
Gangduo Wang, Jianling Wang, Huaxian Ma, M. Firoze Khan

Even though reactive oxygen and nitrogen species (RONS) are implicated as mediators of autoimmune diseases (ADs), little is known about contribution of protein oxidation (carbonylation and nitration) in the pathogenesis of such diseases. The focus of this study was, therefore, to establish a link between protein oxidation and induction and/or exacerbation of autoimmunity. To achieve this, female MRL +/+ mice were treated with trichloroethene (TCE), an environmental contaminant known to induce autoimmune response, for 6 or 12 weeks (10 mmol/kg, i.p., every 4^th day). TCE treatment resulted in significantly increased formation of nitrotyrosine (NT) and induction of iNOS in the serum at both 6 and 12 weeks of treatment, but the response was greater at 12 weeks. Likewise, TCE treatment led to greater NT formation, and iNOS protein and mRNA expression in the livers and kidneys. Moreover, TCE treatment also caused significant increases (3 fold) in serum protein carbonyls (a marker of protein oxidation) at both 6 and 12 weeks. Significantly increased protein carbonyls were also observed in the livers and kidneys (2.1 and 1.3 fold, respectively) at 6 weeks, and to a greater extent at 12 weeks (3.5 and 2.1 fold, respectively) following TCE treatment. The increases in TCE-induced protein oxidation (carbonylation and nitration) were associated with significant increases in Th1 specific cytokine (IL-2, IFN-γ) release into splenocyte cultures. These results suggest an association between protein oxidation and induction/exacerbation of autoimmune response. The results present a potential mechanism by which oxidatively modified proteins could contribute to TCE-induced autoimmune response and necessitates further investigations for clearly establishing the role of protein oxidation in the pathogenesis of ADs.

TCE induced auto immunity

BrooklynDodger(s) Comments: Reading this abstract, the Dodger(s) discovered an apparently well accepted association between TCE exposure and exfoliative dermatitis, as Type II cell mediated auto immune condition. Waving hands, the Dodger(s) imagine TCE induced cell necrosis, possibly liver, triggering lymphocyte attack on debris, growing a clone of lymphocytes targeting cell surface proteins of a variety of tissues.



Toxicology and Applied Pharmacology
Volume 240, Issue 3, 1 November 2009, Pages 393-400

Identification of antigenic proteins associated with trichloroethylene-induced autoimmune disease by serological proteome analysis

References and further reading may be available for this article. To view references and further reading you must purchase this article.

Jianjun Liu^{1, a}, Xiumei Xing^{1, a}, Haiyan Huang^a, Yingzhi Jiang^a, Haowei He^a, Xinyun Xu^a, Jianhui Yuan^a, Li Zhou^a, Linqing Yang^a and Zhixiong Zhuang^{, a,}

^aKey Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, No. 21, Rd 1st Tianbei, 518020 Shenzhen, PR China

Received 1 April 2009;

revised 8 July 2009;

accepted 25 July 2009.

Available online 6 August 2009.

Abstract

Although many studies indicated that trichloroethylene (TCE) could induce autoimmune diseases and some protein adducts were detected, the proteins were not identified and mechanisms remain unknown. To screen and identify autoantigens which might be involved in TCE-induced autoimmune diseases, three groups of sera were collected from healthy donors (I), patients suffering from TCE-induced exfoliative dermatitis (ED) (II), and the healed ones (III). Serological proteome analysis (SERPA) was performed with total proteins of TCE-treated L-02 liver cells as antigen sources and immunoglobins of the above sera as probes. Highly immunogenic spots (2-fold or above increase compared with group I) in group II and III were submitted to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and tandem mass spectrometry sequencing. Western blot analysis was followed using commercial antibodies and individual serum. Six proteins were identified. Among them, Enoyl Coenzyme A hydratase peroxisoma 1 and lactate dehydrogenase B only showed stronger immunogenicity for group II sera, while Purine nucleoside phosphorylase, ribosomal protein P0 and proteasome activator subunit1 isoform1 also showed stronger immunogenicity for group III sera. Noteworthy, NM23 reacted only with group II sera. Western blot analysis of NM23 expression indicated that all of the individual serum of group II showed immune activity, which confirmed the validity of SERPA result. These findings revealed that there exist autoantibodies in group II and III sera. Besides, autoantibodies of the two stages of disease course were different. These autoantigens might serve as biomarkers to elucidate mechanisms underlying TCE toxicity and are helpful for diagnosis, therapy and prognosis of TCE-induced autoimmune diseases.

Screening interval depends on how fast workers get sick

BrooklynDodger(s) comment: If one person, from a similarly exposed population gets sick, it should be assumed the environment poses a risk to everyone and the hazard should be abated. Protection should be implemented, not transfer.

Chest 2009;136 1086-1094

http://chestjournal.chestpubs.org/cgi/content/abstract/136/4/1086?etoc

How Frequently Should Workplace Spirometry Screening Be Performed?

Optimization Via Analytic Models

1. Philip Harber, MD, MPH, FCCP,
2. Jessica Levine and
3. Siddharth Bansal, MD

+ Author Affiliations

1. From Occupational-Environmental Preventive Medicine, Department of Family Medicine, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, CA.

1. Philip Harber, MD, MPH, FCCP, UCLA Occupational Medicine, 10880 Wilshire Blvd, No. 1800, Los Angeles, CA 90024; e-mail: pharber@mednet.ucla.edu

Abstract

Background: Our objective was to determine how to select the optimal frequency of workplace spirometry screening using diacetyl-exposed workers as an example.

Methods: A Markov model was constructed to assess the likelihood of progressing from healthy status to early or advanced disease, starting from four different exposure levels, and performing longitudinal or cross-sectional interpretation of spirometry results over time. Projected outcomes at 10 years were evaluated to inform the optimal frequency of workplace spirometry testing.

Results: The optimal screening interval depends on the population risk and is highly sensitive to the real-life impact (utility) associated with false-positive results (eg, related to the availability of alternative work). Screening interval is particularly important for high-risk individuals with rapid transition from early to advanced disease, where the 10-year prevalence of advanced disease would be reduced from 5.3 to 2.5% using a 6-month interval rather than a 12-month interval. Longitudinal test interpretation, based on observing trends within each person over time, is marginally preferable to traditional cross-sectional spirometry interpretation.

Conclusions: There is no single best screening interval. For high-risk populations, annual testing may be too infrequent.

Does Obesity Cause Stress which Causes Asthma

BrooklynDodger(s): Maybe the causality is that psychosocial stress causes both obesity and asthma?

Chest 2009;136 1055-1062

http://chestjournal.chestpubs.org/cgi/content/abstract/136/4/1055?etoc

Obesity-Asthma Association

Is It Explained by Systemic Oxidant Stress?

1. Akshay Sood, MD, MPH, FCCP,
2. Clifford Qualls, PhD,
3. Alexander Arynchyn, MD, PhD,
4. William S. Beckett, MD, MPH, FCCP,
5. Myron D. Gross, PhD,
6. Michael W. Steffes, MD, PhD,
7. Lewis J. Smith, MD,
8. Paul Holvoet, PhD,
9. Bharat Thyagarajan, MD, PhD and
10. David R. Jacobs, Jr, PhD

+ Author Affiliations

1. From the Department of Medicine (Dr. Sood) and Clinical Translational Sciences Center (Dr. Qualls), University of New Mexico Health Sciences Center, Albuquerque, NM; Department of Preventive Medicine (Dr. Arynchyn), University of Alabama at Birmingham, Birmingham, AL; Department of Medicine (Dr. Beckett), Mount Auburn Hospital, Cambridge, MA; Department of Laboratory Medicine and Pathology (Drs. Gross, Steffes, and Thyagarajan) and Division of Epidemiology (Dr. Jacobs), University of Minnesota, Minneapolis, MN; Department of Medicine (Dr. Smith), Feinberg School of Medicine, Northwestern University, Chicago, IL; Department of Experimental Surgery and Anesthesiology (Dr. Holvoet), Katholieke Universiteit Leuven, Leuven, Belgium; and Institute for Nutrition Research (Dr. Jacobs), University of Oslo, Oslo, Norway.

1. Akshay Sood, MD, MPH, FCCP, Associate Professor of Medicine, University of New Mexico Health Sciences Center School of Medicine, Department of Medicine, 1 University of New Mexico, MSC 10 5550, Albuquerque, NM 87131; e-mail: asood@salud.unm.edu

Abstract

Background: The mechanism for the obesity-asthma association is unknown. This study evaluated the hypothesis that systemic oxidant stress explains this association.

Methods: This cross-sectional study used year-20 follow-up evaluation data of 2,865 eligible participants in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. Current asthma was self-reported. Oxidant stress primarily was assessed by plasma F2-isoprostane concentrations. Obesity measures included categories of BMI and dual-energy x-ray absorptiometry-assessed fat mass index (FMI) and lean mass index (LMI). Logistic and linear regressions were used for analyses.

Results: Asthma was associated with higher plasma F2-isoprostane concentrations (p = 0.049); however, this association was not significant when adjusted for either gender or BMI. The BMI-asthma association was seen only among women (p = 0.03; gender-specific interaction, p = 0.01), and this association was not explained by plasma F2-isoprostane levels. Similarly, both FMI and LMI were positively associated with asthma in women (p = 0.20 and 0.01, respectively). These associations also were not explained by plasma F2-isoprostane levels. Similar results were obtained when plasma levels of oxidized low-density lipoprotein were used instead of F2-isoprostane levels to study the BMI-asthma association at the year-15 evaluation.

Conclusions: Systemic oxidant stress, primarily assessed by plasma F2-isoprostane concentrations, was not independently associated with asthma and, therefore, may not explain the obesity-asthma association in women. The asthma-oxidant stress association is confounded by gender and obesity. This study is limited by the inability to measure airway oxidant stress. It is possible that another (as yet undetermined) measure of systemic oxidant stress may be more relevant in asthma.

How Far Do Germs Travel?

BrooklynDodger(s) comment: Seems like 3 feet is the standard travel distance, for sneezes and for patient ventilation.

Chest 2009;136 998-1005

http://chestjournal.chestpubs.org/cgi/content/abstract/136/4/998?etoc

Exhaled Air Dispersion Distances During Noninvasive Ventilation via Different Respironics Face Masks

1. David S. Hui, MD, FCCP,
2. Benny K. Chow, MPH,
3. Susanna S. Ng, MBChB,
4. Leo C. Y. Chu, MBChB,
5. Stephen D. Hall, PhD,
6. Tony Gin, MD,
7. Joseph J. Y. Sung, MD and
8. Matthew T. V. Chan, MD

+ Author Affiliations

1. From the Department of Medicine and Therapeutics (Drs. Hui, Ng, and Sung, and Mr. Chow), the Center for Housing Innovations (Mr. Chow), Institute of Space and Earth Information Science, and the Department of Anesthesia and Intensive Care (Drs. Chu, Gin, and Chan), The Chinese University of Hong Kong, Hong Kong, People's Republic of China; and the School of Mechanical Engineering (Dr. Hall), The University of New South Wales, Sydney, NSW, Australia.

1. David S. Hui, MD, FCCP, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, 30-32 Ngan Shing St, Shatin, NT, Hong Kong, People's Republic of China; e-mail: dschui@cuhk.edu.hk

Abstract

Background: As part of our influenza pandemic preparedness, we studied the exhaled air dispersion distances and directions through two different face masks (Respironics; Murrysville, PA) attached to a human-patient simulator (HPS) during noninvasive positive-pressure ventilation (NPPV) in an isolation room with pressure of −5 Pa.

Methods: The HPS was positioned at 45° on the bed and programmed to mimic mild lung injury (oxygen consumption, 300 mL/min; lung compliance, 35 mL/cm H₂O). Airflow was marked with intrapulmonary smoke for visualization. Inspiratory positive airway pressure (IPAP) started at 10 cm H₂O and gradually increased to 18 cm H₂O, whereas expiratory pressure was maintained at 4 cm H₂O. A leakage jet plume was revealed by a laser light sheet, and images were captured by high definition video. Normalized exhaled air concentration in the plume was estimated from the light scattered by the smoke particles.

Findings: As IPAP increased from 10 to 18 cm H₂O, the exhaled air of a low normalized concentration through the ComfortFull 2 mask (Respironics) increased from 0.65 to 0.85 m at a direction perpendicular to the head of the HPS along the median sagittal plane. When the IPAP of 10 cm H₂O was applied via the Image 3 mask (Respironics) connected to the whisper swivel, the exhaled air dispersed to 0.95 m toward the end of the bed along the median sagittal plane, whereas higher IPAP resulted in wider spread of a higher concentration of smoke.

Conclusions: Substantial exposure to exhaled air occurs within a 1-m region, from patients receiving NPPV via the ComfortFull 2 mask and the Image 3 mask, with more diffuse leakage from the latter, especially at higher IPAP.