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ABSTRACT: Tobacco smoke causes lung cancer in smokers and in never-smokers exposed to second-hand tobacco smoke (SHS). Nonetheless, molecular mechanisms of lung cancer in SHS-exposed never-smokers are still elusive. We studied lung cancers from current smokers (n = 109), former smokers (n = 56) and never-smokers (n = 47) for promoter hypermethylation of five tumour suppressor genes--p16, RARB, RASSF1, MGMT and DAPK1--using methylation-specific polymerase chain reaction. Lung tumours from ever-smokers suggested an increased risk of p16 hypermethylation as compared to never-smokers (P = 0.073), with former smokers having the highest frequency of p16 hypermethylation (P = 0.044 versus current smokers and P = 0.009 versus never-smokers). In the never-smoking group, p16 hypermethylation was seen in lung tumours from SHS-exposed individuals (4/33; 12%) but in none of the non-exposed individuals (0/9). The overall occurrence of hypermethylation (measured both as methylation index and as number of genes affected) was similar in those ever exposed to tobacco smoke (smokers, SHS-exposed never-smokers) and differed from non-exposed never-smokers. In multivariate analysis, p16 hypermethylation was more prevalent in lung tumours from male than female patients (P = 0.018) and in squamous cell carcinomas than in adenocarcinomas (P = 0.025). Occurrence of TP53 mutation in the tumour was associated with hypermethylation of at least one gene (P = 0.027). In all, our data suggest that promoter hypermethylation pattern in SHS-exposed never-smokers resembles that observed in smokers. Association between TP53 mutation, a hallmark of smokers' lung cancer, and methylation of one or more of the lung cancer-related genes studied, provides further evidence for common tobacco smoke-related origin for both types of molecular alterations.
Mutagenesis 01/2012; 27(4):423-9. · 3.18 Impact Factor
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ABSTRACT: ZAC/PLAGL1 is a novel imprinted tumor suppressor gene encoding an important inducer of cell cycle arrest and apoptosis, and found to be lost during tumorigenesis. We analyzed the significance of ZAC in the development of a rare, usually benign tumor of the adrenal gland: pheochromocytoma (PCC). Twenty-four PCCs were analyzed for the loss of the active nonimprinted allele of ZAC, and nine of the twenty-four PCCs were also assayed for expression of the protein. In thirteen of the cases, a paired nonmalignant tissue was available for analysis. Methylation-specific polymerase chain reaction revealed frequent (15 of 23, 65%) loss of unmethylated DNA in the imprinting control region of ZAC. Immunohistochemistry identified reduced ZAC expression in 56% (5 of 9) of the subset cases. Four of the five PCC cases where reduced expression of ZAC was observed were also positive for the loss of the active ZAC allele. Additionally, the loss of ZAC expression was also found to be frequent in a series of capillary hemangioblastomas and gliomas (6 of 6, 100%, and 17 of 27, 63%, respectively) examined for comparison. In conclusion, our study suggests the involvement of the imprinted ZAC gene in the pathogenesis of PCC.
Cancer Genetics 07/2011; 204(7):398-404.
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ABSTRACT: Genetic alterations underlying the development of the cancer of the nose and paranasal sinuses (sinonasal cancer, SNC), a rare cancer that can be included in the group of head and neck cancers, are still largely unknown. We recently reported that TP53 mutations are a common feature of SNC, with an overall frequency of 77%, and they show association to adenocarcinoma and wood-dust exposure [15]. In this study, we report in detail the sequence change for 159 TP53 mutations identified by direct sequencing. More than half of the mutations (60%, 95/159) were missense mutations; there were also 28 (18%) frameshift or nonsense mutations, and 36 (23%) intronic or silent mutations. In coding region, the most common base change detected was C-->T transition (43/125; 34% of base changes in the coding region). G-->T transversions occurred at a frequency of 10% (12/125), which is less than reported in mutation databases for head and neck squamous cell carcinoma (24%). Characteristically, in our SNC series, the mutations were scattered over a large number of codons, codon 248 being the most frequent target of base substitution. Codon 135 was the second most frequently mutated codon; this nucleotide position has not been reported before as frequently mutated in head and neck cancer or human cancer in general. About half of all tumours with TP53 mutations carried more than one mutation. Interestingly, 86% (19/22) of the silent mutations detected had occurred in tumours with multiple mutations.
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 12/2009; 686(1-2):9-14. · 2.85 Impact Factor
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Reetta Holmila,
Jette Bornholdt,
Pirjo Heikkilä,
Tuula Suitiala,
Joëlle Févotte,
Diane Cyr,
Johnni Hansen,
Satu-Marja Snellman,
Michael Dictor,
Torben Steiniche,
Vivi Schlünssen,
Thomas Schneider,
Eero Pukkala,
Kai Savolainen,
Henrik Wolff,
Håkan Wallin,
Danièle Luce, Kirsti Husgafvel-Pursiainen
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ABSTRACT: The causal role of work-related exposure to wood dust in the development of sinonasal cancer has long been established by numerous epidemiologic studies. To study molecular changes in these tumors, we analyzed TP53 gene mutations in 358 sinonasal cancer cases with or without occupational exposure to wood dust, using capillary electrophoresis single-strand conformation polymorphism analysis and direct sequencing. A significant association between wood-dust exposure and adenocarcinoma histology was observed [adjusted odds ratio (OR) 12.6, 95% confidence interval (CI), 5.0-31.6]. TP53 mutations occurred in all histologies, with an overall frequency of 77%. TP53 mutation positive status was most common in adenocarcinoma (OR 2.0, 95% CI, 1.1-3.7; compared with squamous cell carcinoma), and mutation positivity showed an overall, nonsignificant association with wood-dust exposure (OR 1.6, 95% CI, 0.8-3.1). Risk of TP53 mutation was significantly increased in association with duration (> or =24 years, OR 5.1, 95% CI, 1.5-17.1), average level (>2 mg/m(3); OR 3.6, 95% CI, 1.2-10.8) and cumulative level (> or =30 mg/m(3) x years; OR 3.5, 95% CI, 1.2-10.7) of wood-dust exposure; adjustment for formaldehyde affected the ORs only slightly. Smoking did not influence the occurrence of TP53 mutation; however, it was associated with multiple mutations (p = 0.03). As far as we are aware, this is the first study to demonstrate a high prevalence of TP53 mutation-positive cases in a large collection of sinonasal cancers with data on occupational exposure. Our results indicate that mutational mechanisms, in particular TP53 mutations, are associated with work-related exposure to wood dust in sinonasal cancer.
International Journal of Cancer 11/2009; 127(3):578-88. · 5.44 Impact Factor
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ABSTRACT: Non-muscle invasive bladder cancer (BC) is a highly recurrent disease, with the first recurrences arising shortly after transurethral resection of the bladder (TURB). Topical administration of interleukin-2 (IL-2) has been shown as an effective adjuvant therapy for BC; however, predictive biomarkers that may identify suitable subgroups of patients are lacking. In this pilot study we sought to determine the prognostic value of epigenetic and genetic inactivation of tumour suppressor genes (TSGs) among BC patients treated with IL-2.
After complete TURB, patients with multifocal superficial BC were treated with five daily intravesical instillations of IL-2. Promoter hypermethylation in six TSGs and the TP53 gene mutations were prospectively assessed by methylation-specific PCR and automated capillary single-strand conformation polymorphism in 21 primary bladder cancer specimens and ten bladder wall biopsies collected during follow-up.
After IL-2 treatment, 9 out of 21 (43%) patients did not develop recurrent tumour within the 1 year of follow-up period. The mean duration of recurrence-free survival in the rest of the study group was 112 days. In the current pilot study, BC with p16 gene hypermethylation had a lower risk of recurrence after treatment with IL-2, as compared to IL-2 treated BC without p16 hypermethylation (p = 0.02). Significant associations were observed between tumour grade and the mean methylation index (p = 0.003), as well as the hypermethylation of the RARbeta gene (p = 0.048).
Our preliminary data suggest that DNA methylation biomarkers may assist in selection of BC patients for efficient IL-2 therapy.
Journal of Cancer Research and Clinical Oncology 11/2009; 136(6):847-54. · 2.56 Impact Factor
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ABSTRACT: Wood dusts are associated with several respiratory symptoms, e.g. impaired lung function and asthma, in exposed workers. However, despite the evidence from epidemiological studies, the underlying mechanisms are not well understood. In the present study, we investigated different wood dusts for their capacity to induce cytotoxicity and production of radical oxygen species (ROS) as well as activation of the apoptotic caspase-3 enzyme in human bronchial epithelial cells (BEAS-2B). Dusts from three different tree species widely used in wood industry were studied; birch and oak represented hardwood species, and pine a common softwood species. All the experiments were carried out in three different concentrations (10, 50, and 500 microg/ml) and the analysis was performed after 0.5, 2, 6, and 24h exposure. All wood dusts studied were cytotoxic to human bronchial epithelial cells in a dose-dependent manner after 2 and 6h treatment. Exposure to pine, birch, or oak dust had a significant stimulating effect on the production of ROS. Also an induction in caspase-3 protease activity, one of the central components of the apoptotic cascade, was seen in BEAS-2B cells after 2 and 6h exposure to each of the wood dusts studied. In summary, we demonstrate that dusts from pine, birch and oak are cytotoxic, able to increase the production of ROS and the apoptotic response in human broncho-epithelial cells in vitro. Thus, our current data suggest oxidative stress by ROS as an important mechanism likely to function in wood dust related pulmonary toxicity although details of the cellular targets and cell-particle interactions remain to be solved. It is though tempting to speculate that redox-regulated transcription factors such as NFkappaB or AP-1 may play a role in this wood dust-evoked process leading to apparently induced apoptosis of target cells.
Toxicology 07/2009; 262(3):265-70. · 3.68 Impact Factor
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Lívia Anna,
Reetta Holmila,
Katalin Kovács,
Erika Gyorffy,
Zoltán Gyori,
Judit Segesdi,
János Minárovits,
Ibolya Soltész,
Szilárd Kostic,
Attila Csekeo, Kirsti Husgafvel-Pursiainen,
Bernadette Schoket
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ABSTRACT: Lung cancer rate in Hungary is one of the highest in the world among men and also very high among women, for reasons not clearly understood yet. The aim of the study was to explore characteristics of DNA damage and TP53 gene mutations in lung cancer from Hungary. Tissue samples from 104 lung resections for lung cancer patients, both men and women, operated on for non-small cell lung cancer, specifically, primary squamous cell carcinoma or adenocarcinoma were studied. Of the cases, 37% smoked up to the surgery, 24% stopped smoking within 1 year before the surgery, 26% stopped smoking more than a year before the surgery and 13% never smoked. TP53 mutations were detected by denaturant gradient gel electrophoresis, automated capillary electrophoresis single-strand conformation polymorphism and sequencing. Bulky DNA adduct levels were determined by (32)P-post-labelling in non-tumorous lung tissue. In total, 45% (47/104) of the cases carried TP53 mutation. The prevalence of TP53 mutations was statistically significantly associated with duration of smoking, tumour histology and gender. Smokers had approximately twice as high bulky adduct level as the combined group of former- and never-smokers (10.9 +/- 6.5 versus 5.5 +/- 3.4 adducts/10(8) nucleotides). The common base change G --> T transversion (8/43; 19%) was detected exclusively in smokers. For the first time, we demonstrate that most carriers of G --> T transversions had also a high level of bulky DNA adducts in their non-tumourous lung tissue. Our study provides evidence for a high burden of molecular alterations occurring concurrently in the lung of lung cancer patients.
Mutagenesis 07/2009; 24(6):475-80. · 3.18 Impact Factor
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ABSTRACT: The present survey comprises analysis of sister chromatid exchange (SCE) frequencies in the peripheral blood lymphocytes of 100 subjects: 83 healthy men and women, both cigarette smokers and nonsmokers and 17 children. Both for men (30 smoking, 22 nonsmoking) and for women (13 smoking, 18 nonsmoking) the frequency of SCEs is significantly higher among smokers (group mean 9.6±S.E. 0.2) than among nonsmokers (group mean 8.1±S.E. 0.2). No difference is detected in the frequencies of metaphase chromosome aberrations analysed in the cultured lymphocytes of the same subjects. Young children (17 subjects, mean age 1.5 years) show a significantly lower frequency of SCEs (mean 5.1±0.6) than adults.While the induction of SCEs is known to provide a sensitive indicator of mutagen/carcinogen exposure in experimental assays, it may also give important information of in vivo exposure to genotoxic agents. However, on the basis of the present data, which confirm previous results, the effects of individual smoking habits should carefully be taken into account in evaluations of the effects of exogenous agents on SCE frequencies.
Hereditas 02/2009; 92(2):247 - 250. · 0.79 Impact Factor
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ABSTRACT: Superficial bladder cancer is a highly recurrent disease, with progression to muscle invasiveness occurring in 15-30% of cases. Promoter hypermethylation in a panel of tumour suppressor genes involved in cell cycle control, apoptosis and DNA repair was analyzed in superficial bladder tumours in order to evaluate the suitability of epigenetic biomarkers for an earlier prediction of the aggressive course of the disease.
Promoter hypermethylation in p16, RARbeta, RASSF1A, DAPK, and MGMT genes was analyzed in 58 cases with superficial bladder cancer and 2 cases with benign urological disease using methylation-specific PCR.
Promoter hypermethylation was frequently detected in RARbeta, RASSF1A and DAPK genes, and 62% of bladder tumours exhibited hypermethylation in at least one gene. The overall frequency of hypermethylation and the number of genes involved increased with tumour stage, grade and muscle invasiveness. Aberrant methylation of RASSF1A and RARbetawas predominant (p < 0.05) in muscle-invasive tumours and high-grade tumours, respectively. Cases with concurrent hypermethylation in DAPK, p16 and RARbeta genes were moresusceptible to relapse.
The results suggest analysis of promoter hypermethylation as a valuable biomarker for prognosis of the aggressive course of disease in bladder cancer.
Oncology 10/2008; 75(3-4):145-51. · 2.27 Impact Factor
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Reetta Holmila,
Diane Cyr,
Danièle Luce,
Pirjo Heikkilä,
Michael Dictor,
Torben Steiniche,
Tuula Stjernvall,
Jette Bornholdt,
Håkan Wallin,
Henrik Wolff, Kirsti Husgafvel-Pursiainen
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ABSTRACT: The causal role of wood-dust exposure in sinonasal cancer (SNC) has been established in epidemiological studies, but the mechanisms of SNC carcinogenesis are still largely unknown. Increased amounts of COX-2 are found in both premalignant and malignant tissues, and experimental evidence link COX-2 to development of cancer. Many signals that activate COX-2 also induce tumor suppressor p53, a transcription factor central in cellular stress response. We investigated COX-2 and p53 expressions by immunohistochemistry in 50 SNCs (23 adenocarcinomas, and 27 squamous cell carcinomas (SCC); 48 analyzed for COX-2; 41 for p53). Occupational histories and smoking habits were available for majority of the cases. Most of the adenocarcinoma cases with exposure history data had been exposed to wood dust at work in the past (88%, 14/16). For smokers, 63% (12/19) presented with SSC, whereas 64% (7/11) of nonsmokers displayed adenocarcinoma. COX-2 was expressed at higher levels in adenocarcinoma as compared to SSC (p < 0.001). COX-2 expression showed significant association with occupational exposure to wood dust (p = 0.024), and with nonsmoking status (p = 0.001). No statistically significant associations between the exposures and p53 accumulation were found; however, the p53 accumulation pattern (p = 0.062 for wood dust exposure) resembled that of COX-2 expression. In summary, our findings show increased COX-2 expression in SNC adenocarcinoma with wood dust exposure, suggesting a role for inflammatory components in the carcinogenesis process. In contrast, SCCs predominated among smokers and expressed COX-2 rarely; this may suggest at least partially different molecular mechanisms.
International Journal of Cancer 05/2008; 122(9):2154-9. · 5.44 Impact Factor
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ABSTRACT: This register-based population study determined incidence rates of clinically verified asthma among woodworkers, other blue-collar workers, and administrative personnel employed in wood-processing industries in Finland. Exposure to wood dust was under special scrutiny.
All Finns employed in wood-processing industries were followed for asthma incidence via record linkage in the years 1986-1998. Incident cases included people with asthma reimbursed for medication by the national health insurance or registered as having occupational asthma. Age-adjusted incidence rates and relative risks (RR) by gender were estimated for wood workers, other blue-collar workers, and administrative employees (referents) in wood industries.
The relative risk of asthma was increased for all woodworkers among both genders [men: RR 1.5, 95% confidence interval (95% CI) 1.2-1.8; women: RR 1.5, 95% Cl 1.2-1.7]; a similarly elevated risk was also found for other blue-collar workers (men: RR 1.5, 95% Cl 1.2-1.8; women: RR 1.4, 95% Cl 1.2-1.6) in the same wood industries. Statistically increased relative risks were found for low and medium exposure to wood dust, but not for high exposure. Altogether 217 of the 4074 clinically verified asthma cases were reported as occupational asthma in the Finnish Register on Occupational Diseases.
The incidence rates for asthma were significantly increased both among the woodworkers and the other blue-collar workers in wood industries but without a clear dose-response. Cases recognized as occupational asthma accounted for only a small part of the total asthma excess, indicating that much of the work-related asthma excess remains unrecognized in these industries.
Scandinavian journal of work, environment & health 03/2008; 34(1):66-72. · 3.12 Impact Factor
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Jette Bornholdt,
Johnni Hansen,
Torben Steiniche,
Michael Dictor,
Annemarie Antonsen,
Henrik Wolff,
Vivi Schlünssen,
Reetta Holmila,
Danièle Luce,
Ulla Vogel, Kirsti Husgafvel-Pursiainen,
Håkan Wallin
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ABSTRACT: Cancer in the sinonasal tract is rare, but persons who have been occupationally exposed to wood dust have a substantially increased risk. It has been estimated that approximately 3.6 million workers are exposed to inhalable wood dust in EU. In previous small studies of this cancer, ras mutations were suggested to be related to wood dust exposure, but these studies were too limited to detect statistically significant associations.
We examined 174 cases of sinonasal cancer diagnosed in Denmark in the period from 1991 to 2001. To ensure uniformity, all histological diagnoses were carefully reviewed pathologically before inclusion. Paraffin embedded tumour samples from 58 adenocarcinomas, 109 squamous cell carcinomas and 7 other carcinomas were analysed for K-ras codon 12, 13 and 61 point mutations by restriction fragment length polymorphisms and direct sequencing. Information on occupational exposure to wood dust and to potential confounders was obtained from telephone interviews and from registry data.
Among the patients in this study, exposure to wood dust was associated with a 21-fold increased risk of having an adenocarcinoma than a squamous cell carcinoma compared to unexposed [OR = 21.0, CI = 8.0-55.0]. K-ras was mutated in 13% of the adenocarcinomas (seven patients) and in 1% of squamous cell carcinomas (one patient). Of these eight mutations, five mutations were located in the codon 12. The exact sequence change of remaining three could not be identified unambiguously. Among the five identified mutations, the G-->A transition was the most common, and it was present in tumour tissue from two wood dust exposed adenocarcinoma patients and one patient with unknown exposure. Previously published studies of sinonasal cancer also identify the GGT --> GAT transition as the most common and often related to wood dust exposure.
Patients exposed to wood dust seemed more likely to develop adenocarcinoma compared to squamous cell carcinomas. K-ras mutations were detected in 13% of adenocarcinomas. In this study and previously published studies of sinonasal cancer the found K-ras mutations, were almost exclusively G --> A transitions. In conclusion, our study, based on a large representative collection of human SNC tumours, indicates that K-ras mutations are relatively infrequent, and most commonly occur in adenocarcinomas. Wood dust exposure alone was not found to be explanatory for the G-->A mutations, but combination of exposure to tobacco, wood dust, and possibly other occupational agents may be a more likely explanation. Overall, the study suggests a limited role for K-ras mutations in development of sinonasal cancer.
BMC Cancer 01/2008; 8:53. · 3.01 Impact Factor
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ABSTRACT: Capillary hemangioblastomas (CHBs) are vascular, usually benign, tumors of the CNS, occurring either as a component of familial von Hippel-Lindau (VHL) disease or as a sporadic entity. Both familial and sporadic forms of VHL-associated tumors involve inactivation of the VHL gene; for CHB, 20% to 50% of sporadic cases are affected. However, other molecular alterations involved in the pathogenesis of sporadic CHBs, which represent up to 70% of CHBs, remain largely unknown. We previously identified a minimal deleted area at 6q23-24 in CHB, and the present study focused on the ZAC1 gene (6q24-25). ZAC1 is a maternally imprinted tumor suppressor gene with antiproliferative properties. We investigated loss of heterozygosity (LOH), promoter methylation, and expression status of ZAC1 in mainly sporadic cases of CHB. Our LOH analysis with 6 microsatellite markers spanning the ZAC1 gene region revealed a high frequency (6 of 10, 60%) of LOH. The promoter methylation analysis detected predominance of the methylated ZAC1 sequence in the majority (9 of 10, 90%) of the tumors. Immunohistochemistry exhibited a strongly reduced expression of ZAC1 in stromal cells of all CHBs studied. Collectively, our current results indicate that the absence of the unmethylated ZAC1 sequence was highly concurrent with ZAC1 region LOH or 6q loss and with lack of ZAC1 expression, suggesting preferential loss of the nonimprinted, expressed ZAC1 allele in CHB. This novel finding highlights the importance of ZAC1 in development of CHB, particularly in non-VHL-associated cases.
Journal of Neuropathology and Experimental Neurology 10/2007; 66(9):860-7. · 4.26 Impact Factor
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ABSTRACT: Repeated airway exposure to wood dust has been reported to cause adverse respiratory effects such as asthma and chronic bronchitis. In our recent study, we found that exposure of mice to oak dust induced more vigorous lung inflammation compared to birch dust exposure. In the present study, we assessed the immunomodulatory effects of repeated intranasal exposure to oak dust both in nonallergic and in ovalbumin-sensitized, allergic mice. Allergen-induced influx of eosinophils and lymphocytes was seen in the lungs of allergic mice. Oak dust exposure elicited infiltration of neutrophils, lymphocytes, and macrophages in nonallergic mice. Interestingly, oak dust-induced lung neutrophilia as well as oak dust-induced production of the proinflammatory cytokine TNF-alpha and chemokine CCL3 were significantly suppressed in allergic mice. On the other hand, allergen-induced expression of IL-13 mRNA and protein was significantly reduced in oak dust-exposed allergic mice. Finally, allergen-induced airway hyperreactivity to inhaled metacholine was significantly suppressed in oak dust-exposed allergic mice. The present results suggest that repeated airway exposure to oak dust can regulate pulmonary inflammation and airway responses depending on the immunological status of the animal.
Toxicological Sciences 10/2007; 99(1):260-6. · 4.65 Impact Factor
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Timo Kauppinen,
Raymond Vincent,
Tuula Liukkonen,
Michel Grzebyk,
Antti Kauppinen,
Irma Welling,
Pedro Arezes,
Nigel Black,
Frank Bochmann,
Filipe Campelo, [......],
Nils Plato,
Vivi Schlünssen,
Johannes Schulze,
Roland Sonntag,
Violaine Verougstraete,
Maria Angeles De Vicente,
Joachim Wolf,
Marta Zimmermann, Kirsti Husgafvel-Pursiainen,
Kai Savolainen
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ABSTRACT: The aim of this study was to estimate occupational exposure to inhalable wood dust by country, industry, the level of exposure and type of wood dust in 25 member states of the European Union (EU-25) for the purposes of hazard control, exposure surveillance and assessment of health risks. National labour force statistics, a country questionnaire (in 15 member states, EU-15), a company survey (in Finland, France, Germany and Spain), exposure measurements (from Denmark, Finland, France, Germany, The Netherlands and the United Kingdom) and expert judgements were used to generate preliminary estimates of exposure to different types of wood dust. The estimates were generated according to industrial class (six wood industries, four other sectors) and level of exposure (five classes). These estimates were reviewed and finalized by national experts from 15 member states. Crude estimates were generated also for 10 new member states (EU-10). The basic data and final estimates were included in the WOODEX database. In 2000-2003, about 3.6 million workers (2.0% of the employed EU-25 population) were occupationally exposed to inhalable wood dust. Of those, construction employed 1.2 million exposed workers (33%), mostly construction carpenters. The numbers of exposed workers were 700,000 (20%) in the furniture industry, 300,000 (9%) in the manufacture of builders' carpentry, 200,000 (5%) in sawmilling, 150,000 (4%) in forestry and <100,000 in other wood industries. In addition, there were 700,000 exposed workers (20%) in miscellaneous industries employing carpenters, joiners and other woodworkers. The numbers of exposed workers varied by country ranging from <3,000 in Luxembourg and Malta to 700,000 in Germany. The highest exposure levels were estimated to occur in the construction sector and furniture industry. Due to limited exposure data there was considerable uncertainty in the estimates concerning construction woodworkers. About 560,000 workers (16% of the exposed) may be exposed to a level exceeding 5 mg m(-3). Mixed exposure to more than one species of wood and dust from wooden boards was very common, but reliable data on exposure to different species of wood could not be retrieved. This kind of assessment procedure integrating measurement data, company data, country-specific data and expert judgement could also serve as one model for the assessment of other occupational exposures.
Annals of Occupational Hygiene 09/2006; 50(6):549-61. · 1.95 Impact Factor
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Juha Määttä,
Maili Lehto,
Marina Leino,
Sari Tillander,
Rita Haapakoski,
Marja-Leena Majuri,
Henrik Wolff,
Sari Rautio,
Irma Welling, Kirsti Husgafvel-Pursiainen,
Kai Savolainen,
Harri Alenius
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ABSTRACT: Repeated airway exposure to wood dust has long been known to cause adverse respiratory effects such as asthma and chronic bronchitis and impairment of lung function. However, the mechanisms underlying the inflammatory responses of the airways after wood dust exposure are poorly known. We used a mouse model to elucidate the mechanisms of particle-induced inflammatory responses to fine wood dust particles. BALB/c mice were exposed to intranasally administered fine (more than 99% of the particles had a particle size of < or = 5 microm, with virtually identical size distribution) birch or oak dusts twice a week for 3 weeks. PBS, LPS, and titanium dioxide were used as controls. Intranasal instillation of birch or oak dusts elicited influx of inflammatory cells to the lungs in mice. Enhancement of lymphocytes and neutrophils was seen after oak dust exposure, whereas eosinophil infiltration was higher after birch dust exposure. Infiltration of inflammatory cells was associated with an increase in the mRNA levels of several cytokines, chemokines, and chemokine receptors in lung tissue. Oak dust appeared to be a more potent inducer of these inflammatory mediators than birch dust. The results from our in vivo mouse model show that repeated airway exposure to wood dust can elicit lung inflammation, which is accompanied by induction of several proinflammatory cytokines and chemokines. Oak and birch dusts exhibited quantitative and qualitative differences in the elicitation of pulmonary inflammation, suggesting that the inflammatory responses induced by the wood species may rise via different cellular mechanisms.
Toxicological Sciences 09/2006; 93(1):96-104. · 4.65 Impact Factor
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ABSTRACT: We investigated the roles of EPHX1 Tyr113His and His139Arg polymorphisms in lung cancer susceptibility in a Finnish study population comprising of 230 lung cancer cases and a large control group (n=2105). The controls were distributed into five age strata, which enabled us to examine the potential age-related changes in the putative EPHX1 at-risk genotypes in the cancer free population. Although the exon 3 slow activity associated allele (His113) containing genotypes posed a decreased lung cancer risk compared with the homozygous wild-type Tyr113/Tyr113 genotype (OR, 0.68; 95% CI, 0.49-0.94), no association was seen for the EPHX1 phenotypes interpreted from the combined exons 3 and 4 genotype data. Neither was any difference seen in the prevalence of the EPHX1 Tyr113His genotypes or interpreted EPHX1 phenotypes in the different age groups.
Cancer Letters 07/2006; 237(1):102-8. · 4.24 Impact Factor
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ABSTRACT: Multiple genetic alterations have been associated with pheochromocytoma (PCC). Most PCCs are sporadic, but they also occur in inherited tumor syndromes, including von Hippel-Lindau disease. Although the etiology of most inherited PCCs is well documented, little is known about the etiology of sporadic tumors. Mutations of those genes that harbor germ-line mutations in familial cases cover only 10% to 15% of somatic mutations in sporadic PCCs. A previous cytogenetic analysis indicated frequent loss of 6q in sporadic PCCs. We therefore investigated in detail 18 PCCs using 22 microsatellite markers spanning 6q to search for the presence of allele deletions and identify specific regions likely to contain tumor suppressor genes involved in PCC. Moreover, we sought to compare PCC with capillary hemangioblastoma, another von Hippel-Lindau disease-associated tumor that we previously found to harbor frequent loss of heterozygosity (LOH) at 6q. Our study revealed a high frequency (13/18; 72%) of overall 6q LOH in PCCs. Loss of heterozygosity at 6q was observed in 6 benign (6/9; 67%) and 7 borderline (7/9; 78%) tumors. We identified 2 regions where LOH or allelic imbalance was common (ie, 6q14 [9/18; 50%] and 6q23-24 [6/18; 33%]). We further focused the search using markers specific for the ZAC1 gene region located at 6q24-25. Altogether, for all 6q23-25 markers, including the ZAC1-specific ones, LOH or allelic imbalance was observed in 50% (9/18) of the PCCs. Similar to our findings for capillary hemangioblastomas, our data for the first time suggest that one or several tumor suppressor genes located at 6q, particularly at 6q23-24, may play a role in the tumorigenesis of PCCs.
Human Pathlogy 07/2006; 37(6):749-54. · 2.88 Impact Factor
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ABSTRACT: Automated capillary electrophoresis single strand conformation polymorphism (CE-SSCP), denaturant gradient gel electrophoresis (DGGE), and direct sequencing were compared to investigate the benefits and sensitivity of each of the methods for detection of unknown TP53 mutations in human lung cancer.
Twenty previously analyzed DNA samples from lung tumors were examined under dummy laboratory codes for occurrence of mutations of the TP53 gene.
Mutations were found in 17 samples; 15 (88%) of them were detected by DGGE, 16 (94%) by CE-SSCP and 12 (71%) by direct sequencing. One of the two mutations that remained undetected in DGGE was in fact outside the sequence area covered by DGGE screening, thus rendering DGGE and CE-SSCP equally efficient in mutation detection. Direct sequencing performed less well in finding mutations than the two other assays, as also shown previously.
The study showed that CE-SSCP is a fast and highly reproducible method, which is considerably less laborious compared to DGGE, for screening of unknown TP53 mutations.
Cancer Detection and Prevention 02/2006; 30(1):1-6. · 2.52 Impact Factor
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ABSTRACT: Numerous epidemiological studies have shown that occupational exposure to wood dust can induce several respiratory diseases such as allergic rhinitis, chronic bronchitis, asthma, and sino-nasal adenocarcinoma. However, comparison of the harmful potential of different wood dust species on the basis of epidemiological studies is complicated because in the occupational environment workers are usually exposed to several wood dust species simultaneously. In the present study, we have characterized and compared the effects of two hardwood dusts, beech and teak, and two softwood dusts, pine and spruce, on cytokine and chemokine expression utilizing an in vitro model, murine macrophage cell line RAW 264.7. The expression patterns of selected cytokines and chemokines were assessed by real-time quantitative PCR and by ELISA. All the tested hardwood and softwood dusts induced TNF-alpha expression and inhibited IL-1beta expression. Similarly, all the wood dusts induced the expression of CCL2, CCL3, CCL4, and CXCL2/3 chemokines and inhibited CCL24 expression. Our results indicate that both hardwood and softwood dusts influence the cytokine and chemokine expression of RAW 264.7 cells. Although some differences could be detected in the magnitude of responses to different wood dust species, the two tested wood dust groups, hardwoods and softwoods, have quite similar effects on cytokine and chemokine expression in RAW 264.7 cell line.
Toxicology 02/2006; 218(1):13-21. · 3.68 Impact Factor
