Genetic and cellular mechanisms in chromium and nickel carcinogenesis considering epidemiologic findings (original) (raw)
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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.
Molecular Mechanisms of Nickel Carcinogenesis
Annual Review of Pharmacology and Toxicology, 1991
Humans are exposed to carcinogenic nickel (Ni) compounds both occupationally and environmentally. In this paper, molecular mechanisms of nickel carcinogenesis are considered from the point-of-view of the uptake of nickel sulfide particles in cells, their dissolution and their effects on heterochromatin. Molecular mechanisms by which nickel induces gene silencing, DNA hypermethylation and inhibition of histone acetylation, will be discussed.
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.
Cancer research, 1992
As long as 60 years ago, chromium compounds and nickel refining, along with benzene and soots/tars/oils, were suspected as causing cancer in humans. Current estimates of the relative risk (observed/expected deaths) of cancer in human populations exposed to chromium compounds is 30-100 which is in the same relative risk range as auramine, benzidine, bis(chloromethyl)ether, boot/shoe manufacture, and mustard gas and is greater than the relative risk of cancer from 4-aminobiphenyl, arsenic, benzene, hematite mining, and rubber products manu facture (relative risk, 10-30). The relative risk of cancer for exposed humans from nickel refining (300+) ranks with asbes tos, furniture manufacturing, and vinyl chloride, which is greater than the relative risk (100-300) from exposure to 2-naphthylamine, isopropyl alcohol production, and soots/ tars/oils. Cadmium and nickel compounds are known animal carcinogens which are grouped with organic chemicals such as aflatoxins and benzo(a)pyrene, as probably associated with can cer in humans. Despite the fact that certain inorganic compounds have been shown to cause cancer in animals and have been identified as potent human carcinogens for over six decades, the mecha nisms by which they cause cancer are not well understood. For many years metal carcinogens were considered to be "directacting" carcinogenic agents. However, recent studies have shown that the original forms of inorganic carcinogens are rarely the forms that interact with putative cellular targets such as nucleic acids and proteins. Depending on the nature of the inorganic compound, redox reactions and/or ligand substitu tion reactions of the metal ion with cellular components can produce species that damage critical cellular molecules. There fore, it is clear that each metal compound must be considered individually. For example, carcinogenic chromium(VI) com pounds undergo redox reactions with flavoproteins, metalloproteins, thiol-containing peptides and amino acids, vitamins,
Reviews on Environmental Health, 2011
Nickel, a naturally occurring element that exists in various mineral forms, is mainly found in soil and sediment, and its mobilization is influenced by the physicochemical properties of the soil. Industrial sources of nickel include metallurgical processes such as electroplating, alloy production, stainless steel, and nickel-cadmium batteries. Nickel industries, oil-and coal-burning power plants, and trash incinerators have been implicated in its release into the environment. In humans, nickel toxicity is influenced by the route of exposure, dose, and solubility of the nickel compound. Lung inhalation is the major route of exposure for nickel-induced toxicity. Nickel may also be ingested or absorbed through the skin. The primary target organs are the kidneys and lungs. Other organs such as the liver, spleen, heart and testes may also be affected to a lesser extent. Although the most common health effect is an allergic reaction, research has also demonstrated that nickel is carcinogenic to humans. The focus of the present review is on recent research concerning the molecular mechanisms of nickel-induced genotoxicity and carcinogenicity. We first present a background on the occurrence of nickel in the environment, human exposure, and human health effects.
Recent advances in metal carcinogenicity
Pure and Applied Chemistry, 2000
The carcinogenicity of nickel, chromium, arsenic, cobalt, and cadmium compounds has long been recognized. Nevertheless, the mechanisms involved in tumor formation are not well understood. The carcinogenic potential depends on metal species; major determinants are oxidation state and solubility. Two modes of action seem to be predominant: the induction of oxidative DNA damage and the interaction with DNA repair processes, leading to an enhancement of genotoxicity in combination with a variety of DNA-damaging agents. Nucleotide excision repair (NER) is inhibited at low, non-cytotoxic concentrations of nickel(II), cadmium(II), cobalt(II), and arsenic(III); the repair of oxidative DNA base modifications is disturbed by nickel(II) and cadmium(II). One reason for repair inhibition appears to be the displacement of zinc(II) and magnesium(II). Potentially sensitive targets are so-called zinc finger structures present in several DNA repair enzymes such as the mammalian XPA protein and the ba...
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.
The Open Nutraceuticals Journal, 2010
Cancer is a leading cause of morbidity, mortality, and premature death worldwide. Certain strategies for minimizing carcinogenic factors' exposure can reduce the risk of most cancer types in human. Millions of people around the world get exposed to high levels of heavy metals in the drinking-water. Therefore, quality control in drinking-water and detection of its heavy metals is extremely critical issue in maintaining the human health. The carcinogenicity of aluminum, arsenic, chromium, nickel and selenium has been documented previously, but in scattered fashion. Trace amount of these elements entering the body via various routes can induce genetic and epigenetic alteration in different cancer related genes of somatic and stem cells, thus involving in cancer stem cell formation. Epigenetic variations in the etiology of cancer have led to increasing of cancer research studies in last recent years. Although epigenetic effects of these elements have more prominent role than their genetics effects, these elements are able to alter the pattern of cancerrelated genes' expression profiles, too. Therefore, an understanding of the underlying epigenetically mechanisms of these trace elements and the compounds, which could reduce their toxicities or the number of cancer cases due to these elements in the areas that are contaminated with these metals. Perhaps the toxic effects of these elements in many regions are predictable, but antioxidant supplements may eliminate the reactive oxygen species as leading effects of these elements. The present review article is the compilation of various studies dealt with epigenetic effects of carcinogens on human health.
A Review on Epigenetic Effect of Heavy Metal Carcinogens on Human Health
Cancer is a leading cause of morbidity, mortality, and premature death worldwide. Certain strategies for minimizing carcinogenic factors’ exposure can reduce the risk of most cancer types in human. Millions of people around the world get exposed to high levels of heavy metals in the drinking-water. Therefore, quality control in drinking-water and detection of its heavy metals is extremely critical issue in maintaining the human health. The carcinogenicity of aluminum, arsenic, chromium, nickel and selenium has been documented previously, but in scattered fashion. Trace amount of these elements entering the body via various routes can induce genetic and epigenetic alteration in different cancer related genes of somatic and stem cells, thus involving in cancer stem cell formation. Epigenetic variations in the etiology of cancer have led to increasing of cancer research studies in last recent years. Although epigenetic effects of these elements have more prominent role than their genetics effects, these elements are able to alter the pattern of cancerrelated genes’ expression profiles, too. Therefore, an understanding of the underlying epigenetically mechanisms of these trace elements and the compounds, which could reduce their toxicities or the number of cancer cases due to these elements in the areas that are contaminated with these metals. Perhaps the toxic effects of these elements in many regions are predictable, but antioxidant supplements may eliminate the reactive oxygen species as leading effects of these elements. The present review article is the compilation of various studies dealt with epigenetic effects of carcinogens on human health.