Recent advances in metal carcinogenicity (original) (raw)
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Carcinogenesis, 1997
radical attack, has been observed after treatment of isolated 1 To whom correspondence should be addressed calf thymus DNA with nickel(II) and H 2 O 2 (6) and of isolated Compounds of nickel(II) and cadmium(II) are carcinogenic human chromatin with nickel(II) in the absence or presence to humans and to experimental animals. One frequently of H 2 O 2 (7). The formation of 7,8-dihydro-8-oxoguanine discussed mechanism involved in tumor formation is an (8-hydroxyguanine*) was further enhanced when nickel(II) increase in reactive oxygen species by both metals with the was complexed to heterochromatic proteins (8). An increase subsequent generation of oxidative DNA damage. In the in oxidative DNA damage by nickel(II) has also been detected present study we used human HeLa cells to investigate the in experimental animals. An elevated level of 8-hydroxypotential of nickel(II) and cadmium(II) to induce DNA guanine was induced in rat kidney cells after a single i.p. lesions typical for oxygen free radicals in intact cells and injection of nickel acetate (9), and the extent was considerably the effect on their repair. As indicators of oxidative DNA higher after the administration of nickel(II)-histidine (10). damage, we determined the frequencies of DNA strand Nevertheless, data supporting the induction of oxidative DNA breaks and of lesions recognized by the bacterial formdamage in mammalian cells in culture are still missing.
Carcinogenesis, 2000
environmental hazards. From epidemiological studies and/or animal experiments it is well known that compounds of and Andrea Hartwig 1, 4 chromium, arsenic, cadmium, nickel and cobalt are carcinocells in culture. Nevertheless, these metal compounds enhance Netherlands the genotoxic effects of different mutagens such as UVC radiation, X-rays, benzo[a]pyrene, cis-diamminedichloroplatinum(II) (cisplatin) or DNA alkylating agents (1) and inhibit DNA repair processes. Nucleotide excision repair (NER), Even though not mutagenic, compounds of the carcinogenic which is involved in the removal of DNA damage induced by metals nickel, cadmium, cobalt and arsenic have been a variety of environmental mutagens including UV light, shown previously to inhibit nucleotide excision repair and aromatic amines and polyaromatic hydrocarbons, is inhibited base excision repair at low, non-cytotoxic concentrations.
Interference by toxic metal compounds with isolated zinc finger DNA repair proteins
Toxicology Letters, 2000
Compounds of nickel, cadmium, cobalt and arsenic have been shown previously to inhibit DNA repair processes at low concentrations. In the present study we investigated whether this repair inhibition may be caused by the displacement of zinc in zinc finger structures of DNA repair proteins. As models, the bacterial formamidopyrimidine-DNA glycosylase (Fpg) and the mammalian XPA protein were applied. Both proteins were inhibited by Cd(II) and Cu(II). Hg(II) strongly inhibited the Fpg protein, but did not affect the XPA protein. In contrast, the XPA protein was disturbed by Co(II) and Ni(II), while the activity of the Fpg protein was not reduced. Neither protein was inhibited by As(III) or Pb(II). Thus, each zinc finger protein appears to have its own structural features and sensitivities towards toxic metal ions. Furthermore, each metal exerts specific mechanisms leading to DNA repair inhibition.
Chemical Research in Toxicology, 2008
Chronic exposure to nickel(II), chromium(VI), or inorganic arsenic (iAs) has long been known to increase cancer incidence among affected individuals. Recent epidemiological studies have found that carcinogenic risks associated with chromate and iAs exposures were substantially higher than previously thought, which led to major revisions of the federal standards regulating ambient and drinking water levels. Genotoxic effects of Cr(VI) and iAs are strongly influenced by their intracellular metabolism, which creates several reactive intermediates and byproducts. Toxic metals are capable of potent and surprisingly selective activation of stress-signaling pathways, which are known to contribute to the development of human cancers. Depending on the metal, ascorbate (vitamin C) has been found to act either as a strong enhancer or suppressor of toxic responses in human cells. In addition to genetic damage via both oxidative and nonoxidative (DNA adducts) mechanisms, metals can also cause significant changes in DNA methylation and histone modifications, leading to epigenetic silencing or reactivation of gene expression. In vitro genotoxicity experiments and recent animal carcinogenicity studies provided strong support for the idea that metals can act as cocarcinogens in combination with nonmetal carcinogens. Cocarcinogenic and comutagenic effects of metals are likely to stem from their ability to interfere with DNA repair processes. Overall, metal carcinogenesis appears to require the formation of specific metal complexes, chromosomal damage, and activation of signal transduction pathways promoting survival and expansion of genetically/epigenetically altered cells. Contents 1. Introduction 28 2. Nickel 28 2.1. Human Exposure and Carcinogenicity 28 2.2. Genetic and Epigenetic Changes 29 2.3. Activation of Hypoxic Signaling 29 2.4. Ni(II) as a Cocarcinogen 31 3. Arsenic 31 3.1. Human Exposure and Carcinogenicity 31 3.2. Increased Cellular Proliferation 32 3.3. Apoptotic Effects of Arsenite Exposure and NF-kB Signaling Pathway 33 3.4. Genetic and Epigenetic Changes 33 3.5. Metabolic Changes 33 3.6. Arsenic as a Cocarcinogen 34 4. Chromium 34 4.1. Human Exposure and Carcinogenicity 34 4.2. Cr(VI) Metabolism and DNA Damage 35 4.
Carcinogenic metal compounds: recent insight into molecular and cellular mechanisms
Archives of Toxicology, 2008
Mechanisms of carcinogenicity are discussed for metals and their compounds, classiWed as carcinogenic to humans or considered to be carcinogenic to humans: arsenic, antimony, beryllium, cadmium, chromium, cobalt, lead, nickel and vanadium. Physicochemical properties govern uptake, intracellular distribution and binding of metal compounds. Interactions with proteins (e.g., with zinc Wnger structures) appear to be more relevant for metal carcinogenicity than binding to DNA. In general, metal genotoxicity is caused by indirect mechanisms. In spite of diverse physicochemical properties of metal compounds, three predominant mechanisms emerge: (1) interference with cellular redox regulation and induction of oxidative stress, which may cause oxidative DNA damage or trigger signaling cascades leading to stimulation of cell growth; (2) inhibition of major DNA repair systems resulting in genomic instability and accumulation of critical mutations; (3) deregulation of cell proliferation by induction of signaling pathways or inactivation of growth controls such as tumor suppressor genes. In addition, speciWc metal compounds exhibit unique mechanisms such as interruption of cell-cell adhesion by cadmium, direct DNA binding of trivalent chromium, and interaction of vanadate with phosphate binding sites of protein phosphatases.
Advances in Carcinogenic Metal Toxicity and Potential Molecular Markers
International Journal of Molecular Sciences, 2011
Metal compounds such as arsenic, cadmium, chromium, cobalt, lead, mercury, and nickel are classified as carcinogens affecting human health through occupational and environmental exposure. However, the underlying mechanisms involved in tumor formation are not well clarified. Interference of metal homeostasis may result in oxidative stress which represents an imbalance between production of free radicals and the system's ability to readily detoxify reactive intermediates. This event consequently causes DNA damage, lipid peroxidation, protein modification, and possibly symptomatic effects for various diseases including cancer. This review discusses predominant modes of action and numerous molecular markers. Attention is paid to metal-induced generation of free radicals, the phenomenon of oxidative stress, damage to DNA, lipid, and proteins, responsive signal transduction pathways with major roles in cell growth and development, and roles of antioxidant enzymatic and DNA repair systems. Interaction of non-enzymatic antioxidants (carotenoids, flavonoids, glutathione, selenium, vitamin C, vitamin E, and others) with cellular oxidative stress markers (catalase, glutathione peroxidase, and superoxide dismutase) as well as certain regulatory factors, including AP-1, NF-κB, Ref-1, and p53 is also reviewed. Dysregulation of protective pathways, including cellular antioxidant network against free radicals as well as DNA repair deficiency is related to oncogenic stimulation. These observations provide evidence that emerging oxidative OPEN ACCESS stress-responsive regulatory factors and DNA repair proteins are putative predictive factors for tumor initiation and progression.
Carcinogenesis, 2017
The heavy metal nickel is a known carcinogen, and occupational exposure to nickel compounds has been implicated in human lung and nasal cancers. Unlike many other environmental carcinogens, however, nickel does not directly induce DNA mutagenesis, and the mechanism of nickel-related carcinogenesis remains incompletely understood. Cellular nickel exposure leads to signaling pathway activation, transcriptional changes and epigenetic remodeling, processes also impacted by hypoxia, which itself promotes tumor growth without causing direct DNA damage. One of the mechanisms by which hypoxia contributes to tumor growth is the generation of genomic instability via downregulation of high-fidelity DNA repair pathways. Here, we find that nickel exposure similarly leads to down-regulation of DNA repair proteins involved in homology-dependent DNA double-strand break repair (HDR) and mismatch repair (MMR) in tumorigenic and non-tumorigenic human lung cells. Functionally, nickel induces a defect in HDR capacity, as determined by plasmid-based host cell reactivation assays, persistence of ionizing radiation-induced DNA double-strand breaks and cellular hypersensitivity to ionizing radiation. Mechanistically, we find that nickel, in contrast to the metalloid arsenic, acutely induces transcriptional repression of HDR and MMR genes as part of a global transcriptional pattern similar to that seen with hypoxia. Finally, we find that exposure to low-dose nickel reduces the activity of the MLH1 promoter, but only arsenic leads to long-term MLH1 promoter silencing. Together, our data elucidate novel mechanisms of heavy metal carcinogenesis and contribute to our understanding of the influence of the microenvironment on the regulation of DNA repair pathways.
Modulation of DNA repair processes by arsenic and selenium compounds
Toxicology, 2003
Nickel, cadmium, cobalt and arsenic compounds are well known carcinogens to humans and experimental animals. In addition to the induction of mainly oxidative DNA damage, they interfere with nucleotide and base excision repair (BER) at low, non-cytotoxic concentrations. In case of arsenic, an inactivation of DNA repair has also been observed for the trivalent and pentavalent methylated metabolites, with the strongest effects exerted by MMA(III) and DMA(III). As potential molecular targets, interactions with so-called zinc finger proteins involved in DNA repair and/or DNA damage signaling have been identified. For example, arsenite suppresses poly(ADP-ribosyl)ation at extremely low, environmentally relevant concentrations. Also, Fpg and XPA involved in BER and NER, respectively, are inactivated by arsenite, MMA(III) and DMA(III). Nevertheless, an interaction with the zinc finger structures of DNA repair proteins may also occur by essential trace elements such as certain selenium compounds, which appear to exert anticarcinogenic properties at low concentrations but may compromise genetic stability at higher concentrations.
Heterochromatinization as a Potential Mechanism of Nickel-Induced Carcinogenesis
Biochemistry, 2009
Epigenetics refers to heritable patterns of gene expression that do not depend on alterations of the genomic DNA sequence. Nickel compounds have demonstrated carcinogenicity without any associated mutagenesis, suggesting that its mechanism of carcinogenesis is epigenetic in nature. One such potential mechanism is the heterochromatinization of chromatin within a region of the genome containing a gene sequence, inhibiting any further molecular interactions with that underlying gene sequence and effectively inactivating that gene. We report here the observation, by atomic force microscopy and circular dichroism spectropolarimetry, that nickel ion (Ni 2+) condenses chromatin to a greater extent than the natural divalent cation of the cell, magnesium ion (Mg 2+). In addition, we use a model experimental system that incorporates a transgene, the bacterial xanthine guanine phosphoribosyl transferase gene (gpt) differentially near to, and far away from, a heterochromatic region of the genome, in two cell lines, the Chinese hamster V79-derived G12 and G10 cells, respectively, to demonstrate by DNase I protection assay that nickel treatement protects the gpt gene sequence from DNase I exonuclease digestion in the G12 cells, but not in the G10 cells. We conclude that condensation of chromatin by nickel is a potential mechanism of nickel-mediated gene regulation.