Metal toxicity

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Abstract

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Gregor Grass

Gregor Grass, Oberregierungsrat, Bundeswehr Institute of Microbiology. Gregor Grass has worked as a tenured senior research scientist at the Bundeswehr Institute of Microbiology (Munich, Germany) since 2011. He is interested in how bacteria acquire essential transition metals and in systems involved in metal detoxification. Currently, his research focuses on the antimicrobial mode-of-action of metallic copper and biodefense issues. Gregor studied Biology at the Martin-Luther-University (MLU, Halle, Germany). He completed his PhD in microbiology in 2000 and then worked as a postdoctoral fellow with Chris Rensing in Tucson, AZ. In 2002, Gregor become an independent non tenure-track group leader at MLU before temporarily accepting a position as assistant professor at the University of Nebraska-Lincoln in 2008.

Ludger Rensing

Ludger Rensing obtained his PhD in zoology at the University of Göttingen in 1960 where he subsequently worked as an assistant and associate professor until 1976. He then became a full professor in cell and molecular biology at the University of Bremen. He spent two years (1962–64) as a postdoc in the laboratory of Prof. C. S. Pittendrigh at Princeton University and a sabbatical (1978–79) with Prof. W. Hastings at Harvard. His research focus during that time was the analysis of circadian rhythms while he later concentrated on the molecular mechanisms during stress reactions in fungal and mammalian cells (book: “Man under Stress” [in German], Akademischer Verlag/Elsevier, Heidelberg).

Christopher Rensing

Christopher Rensing, Associate Professor of Microbiology, University of Arizona. Chris Rensing studied and obtained his PhD at the Freie Universität Berlin and later Martin-Luther Universität Halle-Wittenberg supervised by Dietrich Nies in 1996. He then joined Barry Rosen’s lab at Wayne State University in Detroit as a postdoctoral fellow mainly working on the biochemical characterization of two metal-transporting P-type ATPases, ZntA and CopA. In 1999, he accepted a faculty position at the University of Arizona and in 2007 was promoted to associate professor. His research is looking at different aspects of metal–microbe interactions, encompassing both environmental as well as medical microbiology.

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Faster, more efficient enzymes can help organisms gain a competitive edge in the evolutionary race. It is therefore not surprising that in 30–45% of all enzymes the rather limited chemical reactivity of the amino acid side chains is enhanced by the superior reactivity of transition metal cofactors. Which metal was employed for improving cellular metabolism depended on the catalyzed reaction and the bioavailability of different metals. This has not been a one-time event but rather a long process, since the solubility and accessibility of various metals has changed over the course of Earth's history.

For example, iron was very accessible in early Earth under anaerobic, reducing conditions. This is probably the reason why many cytoplasmic metallo-enzymes in bacteria and archaea are iron enzymes. As the concentration of oxygen increased, iron precipitated and in turn, oxidized copper and zinc became much more accessible and were increasingly used as enzyme cofactors.

However, the usage of the multitude of transition metals makes the presence of homeostasis systems necessary both for uptake and detoxification. Functions of these systems have previously been reviewed in great detail. In contrast, there are gaps in our knowledge regarding exactly how metals are toxic and what the cellular targets of metal-mediated damage are. In fact, many false claims, half truths and results from poorly designed experiments have been published and new ones pop-up from time to time. It is thus no wonder that is quite a challenge to separate the wheat from the chaff. This, in our opinion, justified a fresh and revised look at metal toxicity.

The special issue was organized into distinct subchapters covering a wide range of pro- and eukaryotic organismal or cellular systems, essential and purely toxic as well as ionic, metallic or nanoparticle forms of metals.

Toxicity of different metals and metalloids in bacteria and eukaryotes

This central subchapter features reviews covering recent advances in our understanding of the biological role of biometals as well as new findings on chromium and arsenic toxicity. Lee Macomber and Robert Hausinger (DOI: 10.1039/c1mt00063b) present an extensive review on the understudied aspect of nickel toxicity in microorganisms; they propose four main mechanisms of nickel toxicity. Additionally, nickel homeostasis and resistance is explored in bacteria. Christopher Dupont et al. (DOI: 10.1039/c1mt00107h) attempt to correlate changes in copper availability in the Earth's history with increased usage of copper and development of copper resistance mechanisms. Protozoan predation is also introduced as a possible evolutionary pressure influencing the widespread occurrence of copper resistance determinants in bacteria and archaea. Frederic Barras and Marc Fontecave describe targets of cobalt toxicity and resistance mechanisms in Escherichia coli and Salmonella enterica (DOI: 10.1039/c1mt00099c). An interesting aspect in nickel, cobalt and copper toxicity is that all of these transition metals negatively affect Fe–S enzymes. There are many pathways for how this could occur, for example iron shortage, direct iron replacement and subsequent degradation of iron–sulfur clusters, oxidative stress and decreased sulfur supply. However, individual metals have different properties e.g. Cu(I) is a much stronger soft metal than either cobalt or nickel, so the effect on selected targets has to be different. This will be an area of interest in future research.

Nickel has no known biological role in human metabolism and is thus for us a toxic biometal. As a mode-of-action, Ni(II)-dependent peptide-bond hydrolysis is considered a causative factor in nickel-mediated toxicity and eventually carcinogenesis. Ewa Kurowska et al. (DOI: 10.1039/c1mt00081k) suggest that sequence specificity within zinc finger domains of various human transcription factors contain such nickel hydrolytic patterns leading to damage in crucial regulatory circuits in cellular physiology.

Nutritional sciences might benefit from the interesting review of David Eide (DOI: 10.1039/c1mt00064k). The author describes how zinc might indirectly improve the antioxidant response acting as a starting point for future experiments and leading to improved nutritional approaches. The one fact that is for certain in yeast is that zinc deficiency and antioxidant response are linked through the Zap1 transcription factor. Sara Holland and Simon Avery (DOI: 10.1039/c1mt00059d) take a careful look at how excess chromate can lead to sulfur deprivation and subsequent oxidative damage and disease. Chromate is not only taken up by sulfate transporters but once in the cell can lead to oxidative stress and competition between sulfate and chromate. All these factors would be able to contribute to chromate toxicity. Toby Rossman and Catherine Klein (DOI: 10.1039/c1mt00074h) try to solve the apparent contradiction that arsenic can cause oxidative DNA damage without forming adducts with DNA. Here, epigenetic effects as a future field in arsenic toxicity are also introduced.

Metal recognition and transport

Joshua Klein and Oded Lewinson (DOI: 10.1039/c1mt00073j) do an excellent job summarizing the currently available structural information on transition metal transporting efflux P1B-ATPases and ABC transporters involved in transition metal uptake. Recently, it became increasingly clear that metal homeostasis affects the interaction between host and symbiont. The authors show how metal transporters are important for bacterial virulence.

Toxicity of nanoparticles and nanoshells

Nanoparticles have recently received considerable attention for their potential application in industry and medical science. Currently, however, there is considerable public concern about safe use of these materials e.g., in skin care products or as food additives. Aspects of the cytotoxicity exerted by different nanoparticles and also nanoshells, the latter being employed in biomedical imaging and therapy, are presented in three articles. For example, platinum nanoparticles appear metabolically inert and did not drive any cellular stress markers as shown by Masanori Horie et al. (DOI: 10.1039/c1mt00060h). Philip Moos et al. focus on the transcriptional response of human cell lines to ZnO nanoparticles (DOI: 10.1039/c1mt00061f). These cells responded similarly to the nanoparticles as when challenged with soluble zinc salts. Zinc homeostasis factors were up-regulated but changes in expression of chaperonins and other protein folding genes were also observed. Lastly, Vimal Swarup et al. revealed that coating of gold nanoshells with polyethyleneglycol resulted in diminished redox stress-mediated cytotoxicity when compared to plain nanoshells (DOI: 10.1039/c1mt00089f).

Cell biology and metal toxicity

From the very beginning of cellular life about 4 billion years ago organisms have been confronted with stressors of various kinds such as heat, osmotic stressors, radiation and toxic substances. The latter included various metals of different charges and concentrations. Living systems adapted to these stressors during evolution—in the case of metals by developing specific transport mechanisms, metal binding proteins or proteins that make use of metals as functional elements. However, metals also have toxic capacities depending on concentration, exposure time and molecular properties. This is comprehensively shown in the critical review by Steve Pappas ‘Toxic elements in tobacco and in cigarette smoke: inflammation and sensitization’ (DOI: 10.1039/c1mt00066g). Tobacco leaves contain different metals and metalloids—largely depending on the soil on which the plants were grown and on the fertilizers applied. In humans toxic effects such as inflammation, sensitization and cancer are due to the amount of metals and the duration of tissue exposure. This all contributes to the pathologies observed as a consequence of smoking and the use of smokeless tobacco.

Another way in which chronic exposure to metals can lead to chronic inflammation and cancer is shown by the contribution of Marisa Freitas and Eduardo Fernandes ‘Zinc, cadmium and nickel increase the activation of NF-κB and the release of cytokines from THP-1 monocytic cells’ (DOI: 10.1039/c1mt00050k). These metals increase the activity of NF-κB by means of oxidants, while activated NF-κB induces the release of the chemokine IL-8, in case of cadmium also the release of proinflammatory cytokines such as IL-6 and TNF-α. Chronic release of these cytokines may cause chronic inflammation and eventually cancer.

Metals such as cisplatin (cis-diaminedichloroplatinum II) on the other hand have been used as anti-cancer chemotherapeutic DNA crosslinking agents which ultimately lead to apoptosis of cancer cells. There are, however, severe side effects of cisplatin, which limits its use. In view of these side effects substances have been developed which lower the side effects on normal tissues but still have the desired effects on cancer cells. The paper by Yuji Wang et al. (DOI: 10.1039/c1mt00013f) describes the development and application of such a protective drug. It consists of a glucosyl tail, an amino acid side chain and a dithiocarbamate group. The drug's evaluation on tumor-bearing mice demonstrated constantly lower tumor weights and a considerable decrease in adverse side effects of cisplatin.

The review by Leonid Breydo and Vladimir Uversky (DOI: 10.1039/c1mt00106j) highlights the role of metal ion binding in the aggregation pathways of intrinsically disordered proteins. Intrinsically disordered proteins are involved in various human neurodegenerative diseases such as Alzheimer's, Parkinson's or prion disease. It can be expected that further investigating the involvement of metal ions in these processes may not only lead to a better molecular understanding of the diseases but may also open pathways to new protective strategies.

Recent progress in methods and approaches

Scientific progress is intimately linked to the development of technical advances and new methods to study phenomena such as metal toxicity. This is impressively demonstrated by Sean Booth et al. (DOI: 10.1039/c1mt00070e) in a critical review of the possibilities of studying metal toxicity via a systems biology view of the influence of metals on metabolism hence metabolomics.

The chemical form of a metal can greatly influence its toxicity and a well known example is elemental and methylmercury. Graham George et al. (DOI: 10.1039/c1mt00077b) used spectroscopic methods such as X-ray absorption spectroscopy and especially near-edge X-ray absorption fine structure to show that the predominant form of mercury in skeletal muscle of whales resembled that of fish.

Conclusion

Our intention in this special issue is to provide researchers and students with a broad sample of reviews and original papers on this topic. There are recurring themes such as metal dependent degradation of iron–sulfur clusters in enzymes as one target of toxicity. However, with new methods the field of metal toxicity is just beginning to open up. Therefore, perhaps most importantly, we believe this will also be an opportunity for the new student or postdoctoral fellow to get an excellent head-start for exploring this exciting research field.

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