Genotoxic and oxidative effects induced on A549 cells by extract of PM10 collected in an electric steel plant, D Cavallo, CL Ursini, R Maiello, P Apostoli

Tags: DNA damage, oxidative DNA damage, electric steel plant, occupational exposure, DNA, Mutat Res, PM10, exposure, stainless steel, comet assay, Beyersmann D. Molecular, Free radicals, genotoxic effects, Smagghe G. Mortality, nested case control study, Lison D. Influence, complex mixtures, Valko M, bladder cancer, Norpoth K. Investigations, Tola S. Epidemiology, steel manufacturing plant, Hechtenberg S. Cadmium, Ministry of Health, Christensen JM, Frentzel-Beyme R. Cancer, Lison D. Cobalt, toxic metal ions, iron and steel foundry, iron and steel foundries, cancer, steel manufacturer, DNA methylation, metal, Wang L. Arsenic, steel workers, occupational exposures, electric arc furnace, metal ions, epithelial cells, D. Cavallo, pulmonary cells, experiments, Bagchi D. Oxidative, toxicity, Shi H, Hengstler JG, Izakovic M, cells, pathogenic effects, metal exposure, welding fumes, Department of Occupational Medicine ISPESL, electric steel, lung cancer, R. Maiello, oxidative stress, Free Radic Biol, Curr Med Chem, carcinogenic risk, carcinogenesis, heavy metals
Content: ACTA BIOMED 2008; 79; Suppl 1: 87-96
ORIGINAL ARTICLE
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Genotoxic and oxidative effects induced on A549 cells by extract of PM10 collected in an electric steel plant Delia Cavallo1, Cinzia L. Ursini1, Raffaele Maiello1, Pietro Apostoli2, Simona Catalani2, Aureliano Ciervo1, Sergio Iavicoli1 1 Department of occupational medicine ISPESL, National Institute of Occupational Safety and Prevention Monteporzio Catone, Rome, Italy; 2 Laboratory of industrial Hygiene, Department of Experimental and Applied Medicine, University of Brescia, Brescia, Italy Abstract. The present study was aimed at assessing the carcinogenic risk of occupational exposure to PM10 in electric steel plants. PM10 was collected on cellulose filter respectively outside (site 1) and inside (site 2) the furnace area, was measured, extracted and its metal content was analysed by ICP-MS. Cells were exposed for 30 min, 2 and 4 hours to extract of filter from each site diluted at 0.004, 0.008 and 0.02%. The direct/Oxidative DNA damage caused by PM10 was evaluated on A549 cells by Fpg-modified comet assay, analysing Tail moment (TM) and comet percentage. air samples contained 1.08 mg/m3 of PM10 in site 1 and 5.54 mg/m3 in site 2 and different amounts of metals with higher levels of Zn, Al, Ni, Pb, Cd, Cr, Ba in site 2 and of Fe, Mn, Sb in site 1. In cells exposed for 2h to PM10 from both sites, an oxidative DNA damage was found concentrations of 0.008% and 0.02%. For site 2, a direct DNA damage at 0.02% was also found. After 4h a direct/oxidative DNA damage was detected at 0.02% for site 2 and an oxidative DNA damage for site 1. The results indicate a moderate DNA damage induction by used diluitions of PM10 extracts with higher extent for more polluted site 2. These findings show the suitability of this experimental model to evaluate early DNA damage induced by complex mixtures containing metals on target organ, suggesting its use to study biological effects of occupational exposure to such substances. (www.actabiomedica.it) Key words: DNA damage, comet assay, electric steel plant, PM10, metal compounds, A549 cells
Introduction Carcinogenic risk for specific metal compounds (Cr(VI), Ni3S2, As, Cd), polycyclic aromatic hydrocarbons (PAHs), persistent organic pollutants (POPs) or type of production (iron and steel founding) have been individuated in metallurgical industry. Foundry ambient air contains very high concentrations of noxious substances such as particulate matter (PM) and gaseous pollutants, which can target the respiratory epithelium (1) or bladder organ (2). Elevated risks of lung cancer have been observed in several studies concerning foundry workers of iron and steel foundries (3-7). Observations of increased incidence of cancers of upper aero-digestive tract (pharynx, esophagus, lar-
ynx, lung) were reported for foundry workers in Germany (8) and on workers exposed to iron compounds and fumes in foundries and smelting of central-eastern Europe (9). Moreover increased mortality and morbidity risks from numerous causes including cancer were found by a retrospective Chinese iron-steel cohort study (10). Different respiratory diseases such as chronic bronchitis, pneumonia and upper respiratory tract infections and inflammation were reported for foundry workers (11). On the base of 23 epidemiological studies, welding fumes were classified as possible carcinogenic to humans (Group 2B) by the International Agency for Research on Cancer (IARC) (12). Occupational exposure to welding fumes (a complex mixture of gases,
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PAHs and small particles of metal oxides or salts, such as oxides of chromium (Cr) and nickel (Ni)) generated by stainless steel welding, has been associated with an increased risk of lung cancer (13). The mechanism involved in the carcinogenic process could be correlated with the genotoxicity of metals and PAHs. Several studies have reported the induction of DNA damage and chromosome/genome mutations by Heavy Metals or welding fumes using comet assay and micronucleus test (14-17). Other biomonitoring studies indicate that welders have higher levels of genotoxic damage than control groups. In particular welding fumes were found to induce an elevation of DNA-protein cross linking (18, 19), higher frequency of chromosomal aberration (CA) and SCE (20, 21). An increased frequency of micronuclei was also found in epithelial buccal cells of 102 welders (22). Occupational exposure of electric steel plant workers is very complex and still poorly characterized. This category of workers performs different job tasks that chronically expose them both by inhalation and dermal contamination to different metals and PAHs present in high amount in dust and fumes. Many metals can cause alterations in target tissues of exposed humans that, if they occur in tumour suppressor genes, may cause cancer in target organ. Several possible mechanisms of metal carcinogenicity have been proposed: induction of DNA strand breaks, direct or indirect induction of oxidative DNA damage, interference with DNA repair systems, changes in the expression of certain oncogenes or tumor suppressor genes by interference with signal transduction processes (23) or changes in DNA methylation pattern (24, 25) with consequent alterations of cell cycle progression and control (26). Metals could interact directly with DNA and DNA replication causing DNA damage (DNA base modifications, depurination, inter- and intra-molecular crosslinking of DNA and proteins, DNA strand breaks, chromosome rearrangements) (27). Moreover, particle-induced inflammation in the lungs has been shown to cause the release of reactive oxygen species (ROS) by macrophages. Transition metals on the particle surface could also generate ROS through the Fenton reaction and lead to oxidative DNA damage induction. Moreover other free radical species arising from metal-catalysed redox reactions could be in-
volved in oxidative DNA damage. Metal-mediated pathogenic effects (increase of inflammation response, inhibition of cellular anti-oxidant defences, lipid peroxidation, inhibition of DNA repair) might contribute to mutations, changes in gene expression and modification of cell cycle. These mechanisms could contribute to carcinogenic process in workers exposed to heavy metals in steel foundry. It has been reported that two of the most powerful human metal carcinogens chromium and nickel were related to their strong oxidative capacities (17, 28-30). Similar capacities have also been suggested for aluminium, cadmium, cobalt, manganese and lead (31-35). However DNA damage caused by welding fumes has been shown to differ from single metal exposure due to either additive or synergistic effects of multiple genotoxic compounds, as reported in in vivo studies on rats (36,37). The capacity of welding fumes, that contain transition metals such as Fe, Cr and Ni, to generate free radicals by pulmonary cells together with DNA damage and apoptosis induction was observed in animal and in vivo studies (38). In this study we investigated the effects of occupational exposure in an important area of Italian metallurgy (steel production by electric arc furnace). In particular we evaluated on human lung epithelial cells (A549) the genotoxic and oxidative effects of extract of inhalable particulate matter (PM10) collected in two different sites: site 1 outside furnace area and site 2 inside furnace area of an Italian electric steel plant. The identification of biomarkers of early biological effect, could contribute to clarify the mechanisms of action of inhalable complex mixtures of metals at low doses on target organ. Moreover the study could furnish useful indications also in terms of risk prevention and management. Methods Environmental Monitoring Airborne particulate matter (PM10) was collected at two sites of an Italian electric steel plant: site 1 (distant from furnace area) and site 2 (inside furnace area). PM10 was collected with a flow rate of 15
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lt/min over six-hour period by PM20 HMA Air Sampler on cellulose filter 37-mm, 0.8 µm (Sartorius Ag, 37070 Goettingen, Germany). Filters were conditioned in a climatic hood (temperature: 20°C ± 2; humidity 50% ± 5; Activa, Acquaria) and weighted first and before the sampling with a precision balance to determine PM10 amount. Filters were digested with nitric acid 70% in a water bath for 1 hour at 70°C. The obtained extracts were diluted with distilled water and injected into inductively coupled plasma-mass spectrometer (ICPMS, Perkin Elmer ELAN DRC II, Perkin Elmer, Sciex Canada) to analyze metallic elements. Accuracy was assessed and verified using certified reference material Nist 1640 (trace elements in water). The detection limit was included between 0,0001 and 0,0006 µg/l and CV% 6,5-9,0. Cell culture and exposure conditions A commercially available human lung epithelial cell line (A549) was used. The cells obtained from the American Type Culture Collection (ATCC) (Rockville, MD) were cultured in RPMI 1640 (EuroClone, United Kingdom) supplemented with 10% fetal calf serum, at 37°C in 5% CO2. The A549 cells were seeded into 15,6 mm diameter culture dishes (7x104 cells/dish) and cultured for 24h before the exposure. Semiconfluent cell cultures were exposed for 30 min, 2 and 4 hours, to extract of half filter from each sampling site, dissolved in DMSO and diluted at 0.004, 0.008 and 0.02%. Unexposed cells were used as negative control. Fpg comet assay We used comet assay modified with Fpg enzyme that recognizes and cuts the oxidized DNA bases indirectly allowing the detection of oxidative DNA damage. The experiments were performed at least in duplicate. The procedure of Collins et al. (1993) (39) was followed. Slides were examined at 200X magnification under a fluorescent microscope. Images of 50 randomly selected comets stained with ethidium bromide either from Fpg enzyme treated or untreated slides, were acquired and analyzed from each sample,
with specific image analyzer software (Delta Sistemi, Rome, Italy). Measurements of Comet parameters: % DNA in the tail, tail length and tail moment (the product of relative tail intensity and length, that provides a parameter of DNA damage), were obtained from the analysis. For each experimental point we calculated the mean tail moment of 50 comets from enzyme untreated cells (TM), which indicates the direct DNA damage, and the mean tail moment for Fpg enzyme treated cells (TMenz) (directly proportional to the number of oxidized DNA bases) indicating the oxidative DNA damage. The oxidative DNA damage was evaluated comparing TMenz value of exposed cells in respect to unexposed at each experimental point. The direct DNA damage was evaluated comparing TM of exposed in respect to unexposed cells. Moreover about 1000 cells from each slide were examined for presence of comets (cells with a detectable tail) by an experienced observer and the percentages of comets were calculated. The comet percentages values of exposed cells were compared with that found in unexposed cells at each experimental point. Treatment-related differences were evaluated using Student's t-test. A difference was considered significant at p0.05. Results Environmental monitoring The monitored air samples contained 1.08 mg/m3 of PM10 at site 1 and 5.54 mg/m3 of PM10 at site 2. In particular, the metals present in higher concentrations at site 1 were: Mn (17 µg/m3), Al (38 µg/m3), Fe (37 µg/m3), Ba (3.7 µg/m3), Zn (2.5 µg/m3), Pb (1.7 µg/m3), Cu (1.2 µg/m3) and Ni (0.6 µg/m3); while those present in higher concentrations at site 2 were: Zn (383 µg/m3), Al (85 µg/m3), Pb (72 µg/m3), Mn (17 µg/m3), Ba (10 µg/m3), Ni (5 µg/m3), Cu (3,4 µg/m3), Sr (1,5 µg/m3), Cr (0,7 µg/m3). Fpg comet assay The used dilutions of extract from site 1 were equivalent to 4.64 mg/ml, 9.28 mg/ml and 23.2
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Figure 1. Comet percentages in A549 cells exposed for 30 min, 2 and 4 hours to extracts from PM10 metals collected at site 1, evaluated by Fpg-Comet test. The left panels are related to comet percentage + SD in cells untreated with Fpg enzyme, the right panels are related to comet percentage + SD in Fpg enzyme treated cells. The experiments were performed in triplicate. DNA damage was evaluated comparing comet percentage value of exposed cells in respect to unexposed at each experimental point by Student's t test. Not statistically significant differences between exposed and unexposed cells were found
mg/ml of PM10 while those from site 2 were 23.85 mg/ml, 47.7 mg/ml and 119.25 mg/ml of PM10. Comet results showed a dose-time dependent increase, although not significant, of comet percentage
in cells exposed to extract from site 1 (Fig. 1), while the extract from site 2 induced a slight increase already at lowest dose after 2 and 4h exposure (Fig. 2). Analysis of tail moment values did not show DNA damage
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Figure 2. Comet percentages in A549 cells exposed for 30 min, 2 and 4 hours to extracts from PM10 metals collected at site 2, evaluated by Fpg-Comet test. The left panels are related to comet percentage + SD in cells untreated with Fpg enzyme, the right panels are related to comet percentage + SD in Fpg enzyme treated cells. The experiments were performed in triplicate. DNA damage was evaluated comparing comet percentage value of exposed cells in respect to unexposed at each experimental point by Student t test. Not statistically significant differences between exposed and unexposed cells were found
induction after 30 min of exposure to extracts from both sites (Fig 3 and 4). While in cells exposed for 2h to extract from site 1 an oxidative DNA damage was found both at 0.008% (near to statistical significance,
p=0.06) and at 0.02% (Fig. 3). In cells exposed to extract from site 2 (Fig. 4) a significant induction of oxidative DNA damage was found at 0.008% and direct/oxidative at 0.02% dilution after 2h exposure. Af-
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* * Figure 3. Direct and oxidative DNA damage induced in A549 cells by 30 min, 2 and 4 hours exposure to extracts from PM10 metals collected at site 1, evaluated by Fpg-Comet test. The left panels are related to Tail moment (TM) + SD of cells untreated with Fpg enzyme, the right panels are related to Tail moment of Fpg enzyme treated cells (TMenz) + SD. The experiments were performed in triplicate. At each experimental point Student's t test was used to compare TM value (indicative of direct DNA damage) and TMenz value (indicative of oxidative DNA damage) of exposed cells in respect to unexposed cells. * p<0.05 ter 4h a significant oxidative DNA damage at 0.02% damage extend for more polluted site 2 for which also was detected for extract from both sites with higher a direct DNA damage was found (Fig. 3 and 4).
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*
*
*
* *
Figure 4. Direct and oxidative DNA damage induced in A549 cells by 30 min, 2 and 4 hours exposure to extracts from PM10 metals collected at site 2, evaluated by Fpg-Comet test. The left panels are related to Tail moment (TM) + SD of cells untreated with Fpg enzyme, the right panels are related to Tail moment of Fpg enzyme treated cells (TMenz) + SD. The experiments were performed in triplicate. At each experimental point Student's t test was used to compare TM value (indicative of direct DNA damage) and TMenz value (indicative of oxidative DNA damage) of exposed cells in respect to unexposed cells.* p<0.05
Conclusions In the present work we analyze metal composition of PM10 collected in differently polluted sites of an electric steel plant, characterized by a complex mix-
tures of high concentrations of metals and PAHs at lower concentrations. The aim of the study was to evaluate, by the sensitive Fpg comet assay, the possible early genotoxic and oxidative effects induced by occupational exposure to steel dusts using an in vitro ex-
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perimental model that reproduces the exposure to low doses of such particulate matter on target organ. As expected, we found inside the furnace area (site 2) higher amount of total PM10 in respect to area distant from it (site 1) (five-fold higher in site 2 vs site1) and higher concentrations for 12 of 17 metals analysed on extracts from PM10, that however were all below TLV established by ACGIH in the 2002 (40). The in vitro short-term exposures to different dilutions of extracts from the two sites indicate a moderate DNA damage induction with higher extent for more polluted site 2. In particular, after 2 and 4h exposure to extract from site 1, only an oxidative DNA damage was found at the highest concentration, while for site 2, in addition to oxidative DNA damage, found also at intermediate concentration, a direct DNA damage was observed. The oxidative damage induced by extract from site 1 could be related to high level of iron found by environmental monitoring and known to induce ROS through Fenton reaction. This oxidative DNA damage induction could be also explained by the high amount in this site of manganese whose oxidative capacity has been reported (41, 34). The higher extend of oxidative damage and the presence of direct DNA damage, observed for extract from site 2, could be related to other metals such as Al, Ni, Pb, Cu present in much higher amount at this site. These metals are well known for their oxidative and genotoxic properties (31, 42-47). Although the environmental concentrations of individual metal were in examined sites below TLV and the concentrations of PM10 extracts used to shortly expose lung cells were very low, a moderate induction of oxidative and, for more polluted site also direct, DNA damage was found by the high sensitive Fpg comet assay able to assess early and still repairable DNA damage. The results of our study that evaluates the final genotoxic effect of complex metals mixture could be related to the suggested synergic or additive effects of co-exposure to different metals (48, 49) and also to the presence of PAHs that although present at low doses could have been induced a synergic effect. The presence of oxidative and direct DNA damage found on pulmonary epithelial cells demonstrates the suitability of this experimental model to point out early genotoxic effects of inhalable PM10 exposure and confirms the high sensitivity of comet assay to as-
sess early DNA damage contributing to elucidate the final effect of complex mixtures of metals at low concentrations, on target organ. It is of important relevance since exposures to complex mixtures particularly of metals in the workplace or environment are more likely to occur than exposures to a single metal alone and the final effects of different metal combinations are not still known. Moreover an evidence that exposures to complex metal mixtures can enhance the risk of cancer in certain human populations it is reported (49). In conclusion our study identifying an experimental model that represents a good biomarker of early genotoxic effects contributes to clarify the biological effects of occupational exposure of steel workers and call for further investigations in the field. Acknowledgements The research was supported by the Ministry of Health within the project "Strategie ed indicatori innovativi per la valutazione delle interazioni gene-ambiente nei tumori polmonari professionali" (PMS/026/2003). References 1. Finkelstein MM, Foulard M, Wilk N. Increased risk of lung cancer in the melting department of a second Ontario steel manufacturer. Am J Ind Med 1991; 19/2: 183-94. 2. Mallin KA. Nested case-control study of bladder cancer incidence in a steel manufacturing plant. Am J Ind Med 1998; 34/4: 393-8. 3. Tola S. Epidemiology of lung cancer in foundries. J Toxicol Environ Health 1980; 6/5-6: 1195-200. 4. Tossavainen A. Estimated risk of lung cancer attributable to occupational exposures in iron and steel foundries. IARC Sci Publ 1990; 104: 363-7. 5. Moulin JJ, Wild P, Mantout B, Fournier-Betz M, Mur JM, Smagghe G. Mortality from lung cancer and cardiovascular diseases among stainless-steel producing workers. Cancer Causes Control 1993; 4/2: 75-81. 6. Filkestein MM. Lung cancer among steelwokers in Ontario. Am J Ind Med 1994; 26/4: 549-57. 7. Rodrнguez V, Tardуn A, Kogevinas M, et al. Lung cancer risk in iron and steel foundry workers: a nested case control study in Asturias, Spain. Am J Ind Med 2000; 38/6: 644-50. 8. Adzersen KH, Becker N, Steindorf K, Frentzel-Beyme R. Cancer mortality in a cohort of male German iron foundry workers. Am J Ind Med 2003; 43/3:295-305. 9. Shangina O, Brennan P, Szeszenia-Dabrowska N, et al. Occupational exposure and laryngeal and hypopharyngeal can-
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43. Valko M, Morris H, Cronin MT. Metals, toxicity and oxidative stress. Curr Med Chem 2005; 12/10: 1161-208. 44. Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact 2006; 160 (1): 1-40. 45. Stohs SJ, Bagchi D. Oxidative mechanisms in the toxicity of metal ions. Free Radic Biol Med 1995; 18/2: 321-36. 46. Shi H, Hudson LG, Liu KJ. Oxidative stress and apoptosis in metal ion-induced carcinogenesis. Free Radic Biol Med 2004; 37/5: 582-93. 47. Lankoff A, Banasik A, Duma A, et al. A comet assay study reveals that aluminium induces DNA damage and inhibits the repair of radiation-induced lesions in human peripheral blood lymphocytes. Toxicol Lett 2006; 161/1: 27-36. 48. Hengstler JG, Bolm-Audorff U, Faldum A, et al. Occupational exposure to heavy metals: DNA damage induction
and DNA repair inhibition prove co-exposures to cadmium, cobalt and lead as more dangerous than hitherto expected. Carcinogenesis 2003; 24/1: 63-73. 49. Madden EF. The role of combined metal interactions in metal carcinogenesis: a review. Rev Environ Health 2003; 18/2: 91-109. Accepted: May 15th 2008 Correspondence: Delia Cavallo ISPESL - Dipartimento di Medicina del Lavoro via Fontana Candida 1 00040 Monteporzio Catone (Rome), Italy Tel. +39 06 94181409 Fax +39 06 94181410 E-mail: [email protected]; www.actabiomedica.it

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