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Drug and Chemical Toxicology, 2010; 33(1): 97–102

RESEARCH ARTICLE

Chromosomal damage induced by vanadium oxides in human peripheral lymphocytes
Juan J. Rodríguez-Mercado, Lucila Álvarez-Barrera, and Mario A. Altamirano-Lozano
Unidad de Investigación en Genética y Toxicología Ambiental (UNIGEN), Laboratorio L5-PA, Unidad Multidisciplinaria de Investigación Experimental (UMIE-Z), Facultad de Estudios Superiores–Zaragoza, Campus II, UNAM, A.P. 9-020, C.P. 15000, México, D.F., México

Abstract Fly ash, the inorganic residue resulting from the combustion of some fuels, may almost exclusively contain vanadium oxides, compounds which exert potential toxic effects on a wide variety of in vitro and in vivo biological systems. Because information related to the oxidation state responsible for inducing genotoxic effects is controversial, the aim of the present study was to evaluate the effects of three vanadium salts in vitro. Human peripheral lymphocyte cultures were exposed to 1, 2, 4, or 8 µg/mL of vanadium(III) ­ trioxide, vanadium(IV) tetraoxide, or vanadium(V) pentoxide (V2O3, V2O4, or V2O5, respectively). These cultures were then screened for structural chromosomal aberrations, and mitotic index (MI) measurements were made. Cytogenetic evaluations showed that only V2O4 increased the percentage of aberrant cells (without gaps) and chromosome damage (including and excluding gaps), while all compounds led to a decrease in the MI. These results demonstrate that vanadium(III), vanadium(IV), and vanadium(V) are all capable of inducing cytotoxicity, but only oxidation state IV induces clastogenic effects. Keywords:  Clastogenic effect; mitotic index; structural chromosomal aberrations; vanadium oxides

Introduction
Vanadium is present in natural and occupational environments and has been reported as both generally toxic and genotoxic (Altamirano-Lozano ­ et  al., 1998). Epidemiological studies have suggested that high atmospheric concentrations of vanadium are associated with increased lung ­ cancer frequency among residents of metropolitan areas (IPCS, 1988). Exposure of the general ­ population to airborne ­ vanadium is primarily the result of the combustion of petroleum, coal, and heavy oils. Vanadium from the burning of fossil fuels is ­ emitted as oxides, including VO, V2O3, V2O4, and V2O5, in oxidation states II, III, IV, and V, respectively (Crans et  al., 1998); however, during combustion, most of the vanadium is released into the atmosphere in vanadium pentoxide (V2O5) form as part of fly-ash

particulates (as PM10), with the vanadium content of fly-ash samples ranging from 1.4 to 12.5% (Mamane and Pirrone, 1998). utilized The majority of V2O5 and vanadates were ­ as alloying agents in the steel industry or in the production of ferrovanadium and other metal alloys. ­ A smaller portion of vanadium was used as an industrial catalyst and in the production of pesticides, ­ dyes, inks, and pigments. More recent applications of vanadium salts include the manufacture of semiconductors, vanadium glasses, vanadium tetraoxide (V2O4), which is used in electro-optical switches and aerospace technology (Guzman et  al., 1996; IPCS, 2001), and other compounds that are employed in diverse industrial processes, including vanadium trioxide (V2O3) (IPCS, 1988). ­ In an occupational environment, inhalation of dusts and fumes is the major route of exposure, and a

Address for Correspondence:  Mario A. Altamirano-Lozano, Unidad de Investigación en Genética y Toxicología Ambiental (UNIGEN), Laboratorio L5-PA, Unidad Multidisciplinaria de Investigación Experimental (UMIE-Z), Facultad de Estudios Superiores–Zaragoza, Campus II, UNAM, A.P. 9-020, 15000 México, D.F., México; Fax: +52 55 5773-6330. E-mail: maal@servidor.unam.mx (Received 20 March 2009; revised 07 May 2009; accepted 10 July 2009) ISSN 0148-0545 print/ISSN 1525-6014 online © 2010 Informa UK Ltd DOI: 10.3109/01480540903176602 http://www.informahealthcare.com/dct

1314-62-1) were dissolved in distilled water and added to ­ cultures at concentrations of 1. 2. Missouri. and V) on the induction of chromosomal damage in human peripheral blood cells in vitro. From these samples. and 4. with the aim of reducing the spontaneous ­ Two hundred metaphases from each concentration were examined for CA. Louis.57%.6%).5 mL of RPMI-1640 culture medium (Sigma. we ­ evaluated the effects of three vanadium oxides (oxidation states III. In serum. 2003. the type of aberrations scored included chromatid and chromosome types as well as gaps. After incubation. but data on the mutagenic potential of vanadium compounds are ­ controversial. Chromosomal aberration evaluation Materials and methods Cytogenetic analysis. IV. 3:1. All vanadium oxides were obtained from Aldrich Chemical Company (Milwaukee.. ­ frequency of CA.02%.000 cells were used to estimate the MI. Fixative was removed by centrifugation and changed twice. it is necessary to extend the incubation period to observe metaphase damage. CAS no. V2O4 (V = 61. Total number and type of aberrations. or 8 µg/ mL. O = 38. V2O4. the culture medium was removed. V2O3.. 4 µg/mL of colchicine (Sigma) was added to each ­ culture 1 hour before harvesting cells. Cultures were harvested and fixed according to Roldán and Altamirano (1990). When working with chemicals such as vanadium that delay the cell cycle. 1988).04% Giemsa ­ solution (Sigma). IV. 12036-21-4). 1998.98%.200 rpm for 10 minutes. it has been demonstrated that V2O4 and V2O5 interfere with chromosome distribution during cell division and that the three salts alter cell proliferation. however. the cell suspension was centrifuged and 5 mL of fixative ­ (methanol-glacial acetic acid. absorbed metal is ­ transported mainly to transferrin.4 µg/mL) as a positive control. V2O3 (V = 67. 1990. distributed throughout the body. 2006). data on sister chromatid exchanges (SCEs) or the structural chromosomal aberration (CA) frequencies of these salts are sparse (Altamirano-Lozano et al. 2004. flame-dried. .000 cells from each parallel culture. cultures. while metal ions in bodily fluid can exist in the III. The structural CA was classified according to previous reports (Rodríguez-Mercado et  al. and V2O5 (V  = 56.. while in mammalian cells. IPCS. Rodríguez-Mercado et al. 2004).075-M solution was added.5 mL of blood was cultured in 4. ≥ 99. and 5 mL of prewarmed (37°C) hypotonic KCl 0. and treatments Heparinized blood samples were obtained by venopuncture from a healthy nonsmoking male without a history of recent exposure to drugs and radiation.O = 43. and V2O5 are inorganic chemicals that have been show to induce toxic effects in vitro and in vivo. 44 hours after the cultures were started. Several organs and tissues accumulate vanadium in the form of vanadium(IV).. respectively. (1991) for chromosomal aberrations in mammalian cultures. Briefly. 4. Because information related to the vanadium chemical forms responsible for inducing mutagenic and clastogenic effects is controversial.43%. Toxicology data characterize vanadium(V) compounds (anionic form VO3−) as more toxic than oxidation states IV and III (cationic form VO2+ and ­ V3+) (IPCS. St. and 2. cells were centrifuged at 1. In all cases. 0. Another source of vanadium intake is food. and eliminated through the kidneys (Anke. The concentrations for V2O4 and V2O5 were selected based on preliminary reports (Roldán and Altamirano. and V oxidation states (Rodríguez-Mercado and Altamirano-Lozano. To prepare the slides for cytogenetic analysis. ­ Only metaphases containing 46 ± 2 centromeres were analyzed. O = 32. For the positive controls. All cultures were performed in duplicate and incubated ­ at 37°C for 72 hours. as well as the percentage of aberrant cells per treatment. Savage. were evaluated. Conflicting results regarding mutagenic activity have been shown in bacterial assay systems using Escherichia coli and Salmonella typhimurium. USA) (purity. Rodríguez-Mercado and Altamirano-Lozano. v/v) was added. All slides were coded and scored blindly. CAS no. Cells were resuspended and incubated in a water bath for 20 minutes. fraction of soluble vanadium compounds is quickly absorbed by the lungs following inhalation. Mitomycin C (Sigma) was used (0. 5 drops of the fixed cell suspension were placed on clean glass slides. USA) with 5 µg/mL of ­ phytohemagglutinin (Sigma) and treated with vanadium salts for ­ ­ cytogenetic analysis following the recommended protocols of Swierenga et  al. 1314-34-7). a ­ significant amount of vanadium absorption occurs in the upper gastrointestinal tract. 100 metaphases.02%. where most ingested vanadium is transformed to vanadium(IV) in the stomach. CAS no. and subsequently stained for 20 minutes with a 0. Wis. 2001). 2003) and preliminary cytotoxicity tests ­ measuring mitotic index (MI) for V2O3.98   Juan J et al. 2006).98%. an analysis of 100 metaphases was considered sufficient because of high toxicity.

5 µg/mL does not induce cytotoxicity. show .30 (41)b 8 100 3 3 0 0 3 3 6 12 3. A.26 (2) 14 5. while concentrations of 16 or 32 µg/mL were highly toxic. which was used as a positive control. compared vs. The frequency of all types of aberrations (including or excluding gaps) and the percentage of aberrant cells (without gaps) was higher in cultures treated control. the results show a significant concentration-related decrease in the frequency of mitoses in cultures treated with V2O3. a statistically significant increase in CA frequency and aberrant cells was observed after lymphocytes were treated with mitomycin C. but there may also be a ­ contribution from cells that have permanently lost their proliferative capacity. and chi-square tests were used for differences in CA.39 (44)b a a 8 100 3 7 3 0 6 6 13 25 5. first culture and A´.15 (49)b Vanadium(IV) tetraoxide (V2O4) 1 100 2 0 0 1 1 1 3 5 1.19 (28)a 4 100 1 2 0 0 3 3 3 9 1. Results Table 1 presents the mean data for structural CA and MI in cultures of human blood lymphocytes treated with different concentrations of vanadium oxides or with mitomycin C. chromatide and isochromatid gaps.9008. As expected. V2O4 y = 3.35 ± 0. chromosome type: breaks.5 1.5 1.48 ± 0.0 2.671 – 0. bP < 0. The cell-toxicity results obtained from experiments with V2O3 evaluated with the MI test showed that a concentration of 0. r = 0.  Chromosomal aberrations (CAs) and mitotic index (MI) in human peripheral blood lymphocyte cultures treated with different vanadium oxide salts and mitomycin C for 28 hours.00 ± 0.0c 0.5 1. control. and exchange figures. No differences were observed between duplicate cultures regarding the parameters evaluated in this study.59 ± 0.662 – 0.0 1.05) ­ ­ of chromatid breaks and acentric ­ fragments as well as dicentrics at concentrations of 2. using all of the tested vanadium oxides.Chromosomal damage induced by vanadium oxides   99 Table 1.4 50 41 42 0 0 5 7 83c a P < 0.15 (37)b 4 100 2 1 0 0 4 4 3 11 1.64 ± 0. V2O5 y = 2. acentric fragments. 4.0 1. reducing the MI to below 50% (data not shown).85 ± 0.35 control Vanadium(III) trioxide (V2O3) 1 100 4 3 1 0 3 6 8 17 4. duplicate culture.34 (38)b Mitomycin C 95 48.41 ± 0. V2O4 shows a significant (P < 0.5 2. G.15 (30)b 2 100 0 3 1 0 3 5 4 12 2. Discussion Reduction in MI is usually a consequence of a reduced rate of cell proliferation. standard deviation. dicentric. Ct.75 ± 0.80 ± 0. V2O4. the frequency of structural ­ aberrations and the percentage of aberrant ­ metaphases in cultures treated with V2O3 or V2O5 showed no significant increase.8009.0 1. and exchange figures.90 ± 0. Distribution and total number of structural CA Ct Cs G Total (A+A´) Cells % aberrant Test scored by Without cells without MI% ± SD substance culture A A´ A A´ A A´ G With G G (inhibition %) (µg/mL) Negative 100 2 1 0 0 1 2 3 6 1. experiments with Chinese hamster ovary (CHO) and V79 cells.276x. In with V2O4. cP < 0. r = 0.005.0 1. compared to the negative ­ induction particular. Statistical analysis Statistical significance for differences in MI were determined by the z-test.0 1.24 (32)b 2 100 3 4 1 4 2 0 12a a a 4 100 4 3 4 2 2 3 12 17 5.5 1.65 ± 0. SD. Regression lines MI: V2O3 y = 2.15 (70)c 0.05.5 2. meanwhile.31 (38)b 8 100 3 2 2 0 2 2 7 11 2.27 (24) 2 100 2 4 0 0 4 3 6 13 3. r = 0.357x.055 – 0. Further.01. and 8 µg/mL (differences between percent of aberrations and the number of cells with aberrations is due to some cells having more than one aberration).8121.66 ± 0. As we have reported previously.239x. acentric fragments.57 ± 0.27 (47)b Vanadium(V) pentoxide (V2O5) 1 100 3 3 0 0 4 3 6 13 3.66 ± 0. Cs. chromatid type: breaks.5a 1. and V2O5 (Table 1).

There are few studies on the genotoxic effects of vanadium(III). including metals. Natarajan and Obe. V2O5. 1998).. Huang et  al. ­ producing single. 1971). The frequency of CA in human peripheral blood cells. gaps. However. Rodríguez-Mercado and Altamirano-Lozano. 2004). 1971. all of which can lead to mitotic delay or cell death by apoptosis. and mercury(II). (2008) recently found that inhaled V2O5 caused DNA instability in workers. Conversely. 1998). measured with the classic cytogenetic assay in metaphase cells. 2007). Vanadium(III) (as VCl3) is thus a . resulting in multiple end-points. As mentioned in the Results section. has been classified by the IARC (2006) as a possible human carcinogen with genotoxic properties. (1990). ­ VO2+. 2000. The results obtained in the present study are consistent with results published by our own group and the studies of Zong et al.. Zong et al. 2004). It has been demonstrated experimentally that vanadium(III) can generate •OH radicals through the oxidation/reduction process (Du and Espenson. activate transcription factors. in which vanadium(IV) (VOSO4) increased frequencies of structural AC and MN cells. chromosome aberrations are the final response in a chain of events initiated by molecular lesions in DNA (Khilman. and selenium (Biswas et  al. Migliore et  al. significantly reduced MI in human lymphocyte cultures (­ ­ Owusu-Yaw et al. 2003.. 1998) and causing subsequent structural chromosomal alterations. which is able to compete with other metallic cations (Crans et al. Since similar results have been found with other metals and metalloids. Roldán and Altamirano. Lu et  al. such as nickel(II). 2006. RodríguezMercado and Altamirano-Lozano.. we observed an increase in gap frequency with all three vanadium compounds. De Boeck et  al. 1990. Rodríguez-Mercado et  al. hyper-. including mostly hypo-.. 2007). K+-... 1990. Reports in the literature about the clastogenic action of the three vanadium salts used are few (Owusu-Yan et  al. sugars. and bases of DNA and induce single­ and double-strand breaks. 1994. V2O4. This type of effect has also been observed in mammalian cell cultures treated with metals that generate oxidative stress. or Ca2+ATPases. 1990. lead. 2003. and inhibit proliferation signals and cellular growth mediated by MAPK ­ proteins (Chen and Shi. in our study. Zhang et  al... some researchers proposed previously that gaps could be indicators of chromosomal damage (Savage. as evaluated with CA or SCE. AltamiranoLozano et  al. 2000. Prousek. Pasha et  al. Geyikoglu and Turkez. represent an enormous amplification of the initial damage produced by many chemical agents. and Ehrlich et al. while V2O3 has not been studied. who found an increase in structural CA frequencies induced by V2O3 in CHO cells. as well as the ion. In solution. which can injure the phosphate skeleton. Ye et al. 1984. including vanadium(IV) ions. 1989. and other vanadium compounds in the V or IV oxidation state induced aneuploidogenic effects in cell cultures.or double-stranded breaks in pBluescript Kt plasmid DNA and salmon sperm DNA (Lloyd et  al. 1990. generate •OH radicals by ­ Fenton-type reactions (Helen and Sicilio. biochemical tests and cell-free systems have ­ demonstrated that several transition metals. Possible mechanisms that explain the increase in structural aberrations with vanadium tetraoxide treatments include the capability of vanadium(IV) ion VO2+ to bind DNA through interactions with guanine and adenine N-7 atoms and backbone PO2 groups (Ouameur et  al.. which is considered a strong reducing agent. 1999. Many reports have shown that µM concentrations of V2O5 and vanadium compounds IV or V interfere with the activity of several Na+-. particularly the chromatid type. 2002). a previous study by Lener et al. 2002. leading to primary DNA damage (Kawanishi et  al. 2006). since it is known that the toxicological effects of individual metals in mammals depend on their chemical structure and ­ oxidation state. Rojas et al.. 1996. (1994) Owusu-Yaw in using V2O5.. The compound. 2006). Zhong et al..... (1995). the chromosomal damage observed in our lymphocyte cultures induced by V2O4 are consistent with the previous in vivo study of Ciranni et  al. H+-. 1994). 2006) or its ability to react with ­ hydrogen peroxide and generate hydroxyl radicals (•OH) (Helen and Sicilio.100   Juan J et al. However. such as antimony. 1971. In par­ ticular. 2003. inorganic vanadium(III) compounds form the vanadic ion (V3+). 1999. (1998) did not observe genotoxic effects in the blood cells of children living in the vicinity of vanadium factories. titanium(IV). the ­ genotoxic potential of vanadium salts in vitro was assessed by also accounting for speciation.. Because a correlation was found between clastogenic effects (including gaps in ­ structural AC) and the induction of primary DNA damage ­ measured by comet assay (Paz-y-Miño et  al. 1993.. 1994. but differ from those of ­ et al. 2005. Savage. 2006). Zhong et al.. In general. has been used routinely as a tool to evaluate genotoxic carcinogens in vivo and in vitro.. while treatment with vanadium(V) compounds NH4VO3 or Na3VO4 had no effect. It is known that V2O5. 2008). which indicates that gaps contain important information and should be assessed regardless of whether they are included in the CA. Prousek. cobalt. IARC. and polyploidy (Roldán and Altamirano.

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