Genotoxic effects of aluminum, iron and manganese in human cells and experiment
Review Human and Experimental Toxicology 30(10) 1435–1444Genotoxic effects of aluminum, ª The Author(s) 2011 Reprints and permission: sagepub.co.uk/journalsPermissions.naviron and manganese in human DOI: 10.1177/0960327110396531 het.sagepub.comcells and experimental systems:A review of the literaturePDL Lima1, MC Vasconcellos2, RC Montenegro3,MO Bahia3, ET Costa4, LMG Antunes5 and RR Burbano3AbstractThere is considerable evidence indicating an increase in neurodegenerative disorders in industrialized countries.The clinical symptoms and the possible mutagenic effects produced by acute poisoning and by chronic exposureto metals are of major interest. This study is a review of the data found concerning the genotoxic potential ofthree metals: aluminum (Al), iron (Fe) and manganese (Mn), with emphasis on their action on human cells.Keywordsaluminum, iron, manganese, genotoxicityIntroduction in daily life that provides easy exposure to human beings. The exposure to this toxic metal occursMetals are among the oldest toxic agents known by through air, food, water and it is also present in medi-humans.1 In an industrialized world, there are thou- cal, cosmetic and environmental products. Aluminumsands of types of metals in use, and humans are chloride (AlCl3) is an important coagulant used inexposed to them at work, or as a result of contamina- water treatment and purification. This wide distribu-tion of food, water and environment. One feature of tion of the element clearly facilitates the potential forthe normal human diet is the simultaneous presence human exposure and for causing harm.7-12of both essential and toxic metals.2 There is also abun-dant evidence indicating an increase of neurodegen-erative disorders in industrialized countries.3-5 Thus, 1the clinical symptoms and the possible mutagenic Molecular Biology Laboratory, Center of Biological and Health ´ ´ Sciences, Estadual University of Para, Belem/PA, Brazileffects produced by acute poisoning and chronic 2 School of Pharmaceutical Sciences, Federal University ofexposure to metals are of considerable interest.3,6 Amazonas, Manaus/AM, Brazil In this review, we compare the potential genotoxic 3 Human Cytogenetics Laboratory, Institute Biological Sciences,effects of exposure to Al, Fe and Mn from different ´ ´ Federal University of Para, Belem/PA, Brazil 4sources, both in in vitro and in vivo assays. Although ˜ Experimental Neuropathology Laboratory, Joao de Barrosthere are numerous studies in the literature on the ´ ´ Barreto University Hospital, Federal University of Para, Belem/ PA, Braziltoxicological effects of exposure to these metals, 5 Department of Clinical, Toxicological and Bromatologicalinvestigations on direct genotoxicity/mutagenicity are ˆ ˆ ˜ Analyses, Faculdade de Ciencias Farmaceuticas de Ribeirao Preto,scarce. Much remains to be established regarding the ˜ ˜ Universidade de Sao Paulo, Ribeirao Preto/SP, Brazilgenotoxic effects of metals. Corresponding author: ´ ´ Burbano RR, Rommel Rodrıguez Burbano – Laboratorio deLiterature review ´ ´ ´ Citogenetica Humana e Genetica Toxicologica, Instituto deGeneral information ˆ ´ ´ Ciencias Biologicas, Universidade Federal do Para, Campus ´ ´ Universitario do Guama, Av. Augusto Correa, 01 CEP 66075-Aluminum. Aluminum (Al) is the most widely distrib- ´ ´ 110, Belem/Para, Braziluted metal in the environment and is extensively used Email: firstname.lastname@example.org
1436 Human and Experimental Toxicology 30(10) No biological function of the element has been Manganese. Manganese (Mn) is an essential element foridentified, whereas some aspects of its toxicity have humans, animals and plants and is required for growth,been described.7,13-16 Daily consumed dose of Al by development, and maintenance of health. In plants, Mnfood and beverages is 2.5 to 13 mg, where drinking participates in the respiratory process, where its defi-water can contribute to 0.2 to 0.4 mg of Al daily. ciency can affect agriculture worldwide.31 In animals,Drugs can contribute with increased levels of Al. Mn acts in physiological processes such as the regula-Antiacid drugs (2 tablets) can contribute up to 500 tion of reproduction, formation of connective tissuesmg of Al.17 and bone marrow, lipid and carbohydrate metabolism It has been suggested that there might be a and in the maintenance of the brain. Mn is present inrelationship between high levels of Al and increased most tissues of all living organisms and is present natu-risk of a number of pathogenic disorders, such as rally in rocks, soil, water and food.32-34 Daily recom-microcytic anemia, osteomalacia and, possibly, mended doses of Mn for children is 0.3 mg/kg/daily,neurodegenerative disorders including dialysis ence- being 3 times more for adults (10 mg/kg/daily).35phalopathy, Alzheimer’s disease and Parkinson’s This metal is also an important cofactor fordisease.6,7,12,14,18-21 numerous enzymes involved in the biosynthesis of DNA and neurotransmitters and in transduction sig-Iron. Populations are exposed to iron mainly through nals.33,36 Despite the fact that the absorption of Mn isfoods and beverages.22 Iron (Fe) is an essential trace of only 3%–5%, food is the primary source of theelement used by almost all living organisms, being metal ingested by human beings and animals. 31,36often incorporated into the heme complex, which Other sources of Mn exposure are related to workingmediate redox reactions, and of oxygen transport pro- conditions, where Mn particles can be inhaled orteins, such as hemoglobin in red cells and myoglobin absorbed.31,35in muscle cells. It can also be found in the bone mar- Mn deficiency during the initial phases of develop-row, liver and spleen and is required for the immune ment can induce skeletal muscle abnormalities andsystem response and for the production of energy.23,24 irreversible ataxia, in addition to fertility problems.32Also, daily recommended doses of Fe varies among Poisoning by high levels of Mn can lead to some altera-age. For children up to 3 months, 1.7 mg/kg/daily are tions in the organism, where the lungs and the centralrecommended, whereas for adults this is 10 times nervous system (CNS) are the main target organs.31more (18 mg/kg/daily).25 Moreover, exposure to Mn doses 5 to 6 times Although the intake of iron is regulated, when it is higher than the required daily amount together withingested in large amounts it can cause excessive blood trace element Mn was reported in parenteral nutritioniron levels, which in turn can cause damage to the and can cause neurotoxicity. The regulatory mechan-cells of the gastrointestinal tract, preventing them isms of Mn homeostasis are bypassed via the parent-from regulating its absorption.26 The corrosive nature eral route, consequently elimination via theof iron seems to further increase its absorption, lead- hepatobiliary system is impaired resulting in tissueing to poisoning. In human beings, several alterations Mn accumulation.37have been related to high iron intake, especially in the Exposures to high levels of manganese by ingestionpulmonary tract, leading to cancer caused by inhala- or inhalation can damage the central nervous system.38tion of iron oxide (FeO), skin rashes by inhalation High doses (1800–2250 mg/kg/day as manganese (II)of iron salts, heart, kidney, liver and gastrointestinal sulfate) in mice induce hyperplasia, erosion andtract alterations and also diabetes mainly because of inflammation in the stomach.39 Chronic exposure tothe ingestion of high concentrations of iron sulfate high levels of Mn can also induce a syndrome known(FeSO4; 0.5–2.5 g), found currently in drugs.27 as manganism, characterized by extrapyramidal dys- Iron is moreover toxic to neural tissue, leading to function (bradykinesia, rigidity and dystonia) and neu-neurodegenerative disorders.28,29 Advanced neuroi- ropsychiatric symptoms that resemble idiopathicmaging techniques and pathological studies have Parkinson’s disease.31,40,41demonstrated increased brain iron with aging, andincreased iron deposition has also been observed inpatients with a constellation of neurological diseases, Metal genotoxicityincluding Alzheimer’s disease, Parkinson’s disease Genotoxicity of aluminum. There are only few studies inand stroke.30 the literature about the genotoxic activities of Al.
Lima PDL et al. 1437Its mutagenic potential has been studied by micronu- lymphocytes. We analyzed the mitotic index (MI),cleus assay, sister chromatid exchange, Ames and chromosomal aberrations (CAs) and DNA damagechromosomal aberration analysis. index as detected by the comet assay. That study Moreno et al. showed the induction in vitro of chro- indicated that AlCl3 produces DNA damage and ismosomal aberrations, mostly numeric (anaphasic), in cytotoxic during all phases of the cell cycle, and thethe Balb c 3T3 cell line exposed to atmospheric dust treatment of the cells at phase G1 resulted in poly-(20–80 mg/mL) from the city of Mexicali, Mexico, a ploidy and endoreduplication, consistent with AlCl3mixture of particles of potassium aluminum silicates interacting with the mitotic spindle apparatus.52 Also(98%) and sodium dioxide (2%).42 Dovgaliuk et al. was reported that iron- and aluminum-sulfate together,studied the cytogenetic effects of toxic metal salts at nanomolar concentrations, trigger the production ofincluding aluminum (Al[NO3]3; 0.01 mM–1 mM) reactive oxygen species (ROS) in cultures of humanusing meristematic cells from Allium cepa and demon- brain cells, up-regulating pro-inflammatory and pro-strated clastogenic and aneugenic effects (disturbances apoptotic genes that redirect cellular fate toward cyto-in mitosis and cytokinesis) in these cells.43,44 plasmic dysfunction, nuclear DNA fragmentation and Yi et al. investigated the genotoxic potential of cell death.53AlCl3 using Vicia faba cytogenetic tests, demonstrat- Taking together, our results and other studiesing that aluminum (0.01À10 mM for 12 h) causes sig- reported in the literature indicate that AlCl3 is geno-nificant increases in the frequencies of micronuclei toxic and should be used with caution.and anaphase chromosome aberrations in Vicia fabaroot cells.45 In cells from Parkinson’s disease Genotoxicity of Fe. Several studies have been con-patients, Al (1 mM) treatment did not increase the ducted to demonstrate the potential induction ofmicronucleus frequency, indicating that Al had no DNA aberrations by Fe and also by drugs and com-amplified mutagenic effect on these patients.46 pounds containing this metal. However, the resultsThere was also observed absence of any teratogenic are inconclusive, and the mutagenic effect of Fe haseffects on the mouse fetus or genotoxic effects as yet to be elucidated.detected by the Ames assay for aluminum-containing Free iron catalyzes the conversion of superoxidecosmetic formulations.47 and hydrogen peroxide into hydroxyl radicals, On the other hand, other studies have demonstrated which promote oxidative stress by the Fenton reac-the mutagenic potential of Al in human cells. For tion.54 In this way, organic Fe may increase the gen-example, genotoxicity of the dust derived from an otoxic effects of other compounds when they areelectrolytic Al plant was evaluated using the Ames combined. For example, the mutagenic activity ofassay, unscheduled DNA synthesis test, sister chro- doxorubicin is significantly increased by this metal,matid exchange and micronuclei frequencies in as evaluated by the Ames test.55 In addition, it washuman lymphocytes. The results of these four experi- demonstrated in Jurkat cells that simultaneous treat-ments indicated a high genotoxicity of the dust ment with desferrioxamine (Fe chelator) and hydro-organic extract.48 There was also observed chromo- gen peroxide inhibited significantly the DNAsome breaks in V79-4 Chinese hamster cells irra- damage induced by hydrogen peroxide, indicatingdiated with low-energy aluminum ions.49 that intracellular Fe, which is a redox-active metal, The mutagenic activity of waste material originated plays a role in the induction of DNA breaks inducedfrom an Al products factory was determined by the Sal- by hydrogen peroxide.56monella/microsome assay. All the extracts from the High levels of chromosome and chromatid aberra-factory had mutagenic activity, especially in the tions were found in human lymphocytes and TK6 lym-YG1024 strain, suggesting the presence of aromatic phoblast cells exposed to high-energy iron ionsamines.50 Since aluminum is biochemically attracted (56Fe).57-59 Significant DNA damage was detected,to interact to the phosphates that form an active part microgel electrophoresis, in differentiated humanof the DNA, their interactions may explain the relation- colon tumor cells (HT29 clone 19A) incubated withship of its genotoxic and mutagenic potential.51 ferric-nitrilotriacetate (Fe-NTA; 250–1000 mM).60 Our research group recently published a study on Mutagenic activity was also found in elemental andthe genotoxic, clastogenic and cytotoxic effects of salt forms of Fe, evaluated by mutagenicity tests in Sal-AlCl3 (5, 10, 15 and 25 mM) in different phases of the monella typhimurium and L5178Y mouse lymphomacell cycle using in vitro temporary cultures of human cells.61 Iron compounds have also been reported to
1438 Human and Experimental Toxicology 30(10)be mutagenic in cultured mammalian cells, as detected aberrations and DNA damage index as detected by theby the Syrian hamster embryo cell transformation/viral comet assay. Our results showed that, despite theenhancement assay, sister chromatid exchange doses, Fe induces alterations and inhibition of DNA(SCE) in hamster cells and base tautomerization in synthesis (in a dose-dependent manner).74rat hepatocyte cultures.62-64 Furthermore, ROS interacts with a variety of mole- Its also reported that little or no DNA damage cules, including in saturated fatty acids, proteins and(detected by the comet assay) occurred after treatment DNA leading to subsequent cell death/apoptosis, espe-of human lymphocytes with the iron compounds ferric cially in the CNS tissue, where the antioxidant defenseschloride (FeCl3) and ferrous chloride (FeCl2).65,66 are rare.75-77 Taking all together, all those mechanismsHowever, at high concentrations of ferrous sulfate, may explain all those effects and the concomitancesignificant DNA damage was observed, probably as occurrence of mutagenicity and cytotoxicity.a consequence of chemical contamination of the metalsalt. Low concentrations of either Fe2þ or Fe3þ (1.25; Genotoxicity of Mn. The association of Mn with the risk2.5 and 5 mg/mL) were not mutagenic in Chinese of developing neurodegenerative processes can behamster ovary cells (CHO-9) treated in vitro, and the related to DNA damage. Relatively high doses of Mnmitotic indices were also unaffected when compared can disrupt DNA integrity and DNA replication.78-80to negative control cultures.67 Also, neurotoxic effect of Mn can be due to its interac- George et al. related that high-energy iron ions tion with detoxification enzymes that protects the cells,(LET ¼ 151 keV/microm) induces chromosomal and/or its interaction with the redox system. In thisaberrations (measured using the fluorescence whole- way, Mn2þ (essential to the brain) can be oxidized tochromosome painting technique) in normal and Mn3þ, a toxic compound that enhances the oxidationrepair-deficient human fibroblasts cell lines.68 of dopamine leading to the generation of several neuro- Mutagenic potential of metallic agents used in toxic products and thus genotoxicity.81,82dietary supplementation, including iron sulfate, was There are few studies in the literature on the geno-investigated by means of the comet assay. The authors toxic action of Mn. Its mutagenic potential has beenreported a genotoxic effect of this metal in mouse studied by in vitro tests in bacteria and by in vivo/inblood cells after 24 h of treatment, at all concentra- vitro tests in insect and mammalian cells, showingtions used.69 Genotoxic effects of Fe were also that some chemical forms of this metal have muta-reported by Garry et al. in rats treated with iron oxide genic potential. Gerber et al. demonstrated that high(Fe2O5; .75 mg) for 24 h; they observed that this metal doses (0.05 M) of various Mn compounds can affectonly showed mutagenic potential when the animals DNA replication and repair in bacteria.31 As for mam-were simultaneously treated with benzopyrene.70 malian cells, high doses of Mn (compared to the Mn Furthermore, Hasan et al. reported that ferritin, a doses recommended for daily consumption) can affectubiquitously distributed iron storage protein, interacts fertilization and are toxic to the embryo and fetus,with microtubules in vitro.71 In a study conducted by demonstrating the teratogenic potential of this metal.Maenosono et al. the bacterial reverse mutation Manganese chloride (MnCl2) was also subjected toassay using S. typhimurium was weakly positive for the wing spot test of Drosophila melanogaster andwater-soluble FePt nanoparticles capped with tetra- was shown to be clearly effective in inducing spotsmethylammonium hydroxide.72 Mice subchronically with one or two mutant hairs (small spots) at concen-exposed to 33.2 mg/kg Fe showed genotoxic effects trations over 12 mM.83in whole blood in the alkaline version of the comet Brega et al. demonstrated that farm workersassay, with a significant increase in the hepatic level exposed to pesticides containing Mn, even at a lowof Fe.73 levels, revealed an increased mutagenic potential of In our experiments, we used iron sulfate alone to those pesticides, as evidenced by an increased numberdetermine at which concentration this metal begins of CAs. It is possible that chronic exposure to lowto exert its genotoxic effects. An in vitro study aiming doses of Mn induces CAs over the years, since theyto investigate the genotoxic, clastogenic and cytotoxic are not acutely cytotoxic.84effects of FeSO4 (4.5, 9.0 and 18 mM) were performed It is also possible that, at low doses (aroundin different phases of the cell cycle, using short-term 0.19À1.39 mg/m3 for 1À45 years), Mn has genotoxiccultures of human lymphocytes. The bioactivity para- effects only with long-term exposure, and this may bemeters tested were the mitotic index, chromosomal the reason why Timchenko et al. did not find CAs in
Lima PDL et al. 1439the nasal mucosa of mammals exposed to Mn dioxide Conclusionaerosol (40–12,000 Hz, 80–100 dB).85 In contrast, When we compare the mutagenic/genotoxic effectsDutta et al. related manganese dioxide as an estab- of the three metals under study based on the data pre-lished genotoxicant and clastogen which could viously published by our research team, we can seecause induction of DNA strand break, chromosomal that Al is the one that induces the greatest amountaberration and micronucleus in human peripheral of chromosomal aberrations and DNA damage, aslymphocytes.86 observed by the comet test, suggesting that this metal Manganese sulfate (MnSO4) did not show muta- has a direct interaction with the DNA. This effectgenic potential in different strains of Salmonella was smaller, in decreasing order, for Fe and fortyphimurium, while, in contrast, MnCl2 showed muta- Mn, suggesting that these metals interact with thegenicity in the TA1537 strain of S. typhimurium as biochemical replication or repair system machinerywell as in the T7 strain of Saccharomyces cerevisiae to induce the chromosomal alterations observed(doses over 0.5 mM). In vivo studies have demon- (Table 1; Figure 1). This could be the reason why thestrated that oral doses of MnSO4 or potassium per- cells have to be in proliferation for Fe and Mn to bemanganate induce CAs in the bone marrow of able to exert their effects on the DNA molecule.animals, whereas no CAs have been observed after However, in a preliminary screening, we can con-the administration of oral doses of manganese chlor- clude that all three metals studied have genotoxicide, even at concentrations over 12 mM. These results potential.52,74,87show that the mutagenic potential of compounds of The objective of our studies was to evaluate theMn may be different in permanganate salts and in genotoxicity of the three metals in similar concentra-manganese salts.35 tions of those tested in studies about the toxicity of the De Meo et al. evaluated the genotoxicity of potas- metals in human neural cells. Thus, the concentrationssium permanganate (KMnO4), MnSO4 and MnCl2 of Al, Fe and Mn used in our studies are based on theusing the Ames test with the tester strains TA97, literature references, adapted to lymphocyte cell cul-TA98, TA100 and TA102, with and without metabolic tures. The final concentrations used were 5, 10, 15 andactivation. The presence of direct-acting mutagens was 25 mM for AlCl3; 4.5, 9 and 18 mM for FeSO4 and 15,detected in all the Mn samples with the tester strain 20 and 25 mM for MnCl2.52,74,87TA102 without metabolic activation. Only MnCl2 An important observation was that Mn was the onlyinduced DNA damage in human lymphocytes with a metal assumed to have exerted an induction effect ondose-response relationship, as determined by the comet the repair system, probably because it is lessassay. The mutagenic potential was 2.4 revertant/ toxic than Al and Fe. Al also interacts with thenmol.80 According to WHO data, other chemical forms mitotic apparatus preventing its polymerization, prob-of Mn have mutagenic potential, both in vitro and in ably by direct interaction with tubulin, whereas Fe,vivo. More studies are necessary in order to elucidate based on the results presented, indirectly prevents thethe probable mutagenicity of Mn and its chemical building-up of the mitotic apparatus, interfering withforms and their effects on human health.35 the tubulin synthesis. Mn did not present any evi- Our research group also conducted a study in vitro dence, with the techniques used, of blocking the for-on the genotoxic, clastogenic and cytotoxic effects mation of microtubuli. This observation is pertinentof MnCl2-4H2O (15, 20 and 25 mM; one of the most since the morphology and physiology of the nervouscommon forms of Mn) in different phases of the cell cells depend directly on the formation of microtubularcycle, using short-term cultures of human lympho- structures, which are responsible for the constructioncytes. These effects were determined by the mitotic of axons and dendrites. Thus, in our evaluation, Alindex (MI), chromosomal aberrations (CAs) and appears to be the most toxic metal for nervous cells.DNA damage index as detected by the comet assay. Fe seems to have an indirect effect, via tubulin synth-MnCl2-4H2O shows strong cytotoxicity in all phases esis, and Mn does not seem to have any influence on theof the cell cycle. The genotoxicity observed at phase microtubular structures. We can however see that allG2 and in the comet assay may be related to the lack metals analyzed have a cytotoxic action, where Al is theof time for the cellular repair system to act. The one with the strongest effect, followed by Fe and Mn.absence of CAs in the other phases of the cell cycle In conclusion, based both on our results and on asuggests that Mn-mediated damage may be repaired review of the data from the literature, Al in thein vitro.87
1440 Human and Experimental Toxicology 30(10)Table 1. Numerical and structural chromosome aberrations and cytotoxicity of aluminum (Al), iron (Fe) and manganese(Mn)a Cycle Stages Metals G1 G1/S S 1h pulse S 6h pulse G2 SCA NCA CYT SCA NCA CYT SCA NCA CYT SCA NCA CYT SCA NCA CYT Al Fe Mn SCA: Structural Chromosome Aberrations; NCA: Numerical Chromosome Aberrations; CYT: Cytotoxicity (Mitotic Index Reduction). a Data on Lima et al.52,74,87 Statistically different from control, at all concentrations (5, 10, 15, and 25µM) Statistically different from control, at all concentrations (4.5, 9.0, and 18µM) Statistically different from control, at all concentrations (15, 20, and 25µM) Statistically different from control, at the highest concentration (25µM) cells and Mn whereas genotoxic activity can be seem around 25 mM in cultured lymphocytes and 0.05 M in bacteria. Conflicts of interest The authors declare that there are no conflicts of interest. Funding The studies conducted by our research group were sup- ported by Financiadora de Estudos e Projetos (FINEP CT-INFRA/FADESP) Grant No. 0927-03; Conselho Nacional de Desenvolvimento Cientıfico e Tecnologico ´ ´Figure 1. Damage index according to the comet test for ¸˜ (CNPq) and by Coordenacao de Aperfeicoamento de ¸aluminum (Al), iron (Fe) and manganese (Mn). Data based Pessoal de Nıvel Superior (CAPES). ´on Lima et al.52,74,87 Referencesconcentration range of 5 to 25 mM in lymphocytes, 1. Ferrer A. Metal poisoning. An Sist Sanit Navar 2003;1 mM in plant cultured cells and 34 mg/kg mice body 26: 141-153.weight, is the metal with the greatest toxicity to the 2. Rojas E, Herrera LA, Poirier LA, and Ostrosky-DNA molecule and the mitotic apparatus, followed, Wegman P. Are metals dietary carcinogens? Mut Resin decreasing order, by Fe whereas genotoxicity can 1999; 443: 157-181.be observed in the concentration range of 4.5 mM in 3. Veldman BA, Widn AM, Knoers N, Pramstra P,lymphocytes and 250 to 1000 mM in colon cancer and Horstink MW. Genetic and environmental risk
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