Genetic and Epigenetic Mechanisms in Metal Carcinogenesis and Cocarcinogenesis: Nickel, Arsenic, and Chromium (original) (raw)
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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.
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...
Environmental Health Perspectives, 1994
Carcinogenic arsenic, nickel, and chromium compounds induced morphological and neoplastic transformation but no mutation to ouabain resistance in 10T1/2 mouse embryo cells; lead chromate also did not induce mutation to ouabain or 6-thioguanine resistance in Chinese hamster ovary cells. The mechanism of metal-induced morphological transformation was likely not due to the specific base substitution mutations measured in ouabain resistance mutation assays, and for lead chromate, likely not due to this type of base substitution mutation or to frameshift mutations. Preliminary data indicate increases in steady-state levels of c-myc RNA in arsenic-, nickel-, and chromium-transformed cell lines. We also showed that carcinogenic nickel, chromium, and arsenic compounds and N-methyl-N-nitro-N-nitrosoguanidine (MNNG) induced stable anchorage independence (Al) in diploid human fibroblasts (DHF) but no focus formation or immortality. Nickel subsulfide and lead chromate induced Al but not mutation to 6-thioguanine resistance. The mechanism of induction of Al by metal salts in DHF was likely not by the type of base substitution or frameshift mutations measured in these assays. MNNG induced Al, mutation to 6-thioguanine resistance, and mutation to ouabain resistance,and might induce Al by base substitution or frameshift mutations. Dexamethasone, aspirin, and salicylic acid inhibited nickel subsulfide, MNNG, and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced Al in DHF, suggesting that arachidonic acid metabolism and oxygen radical generation play a role in induction of Al. We propose that nickel compounds stimulate arachidonic acid metabolism, consequent oxygen radical generation, and oxygen radical attack upon DNA. Intracellular reduction of Cr(VI) to Cr(V) or other species that generate oxygen radicals leads to Cr(V) or oxygen radical attack upon DNA. Arsenite causes chromosome breaks. We propose that arsenic, nickel, and chromium compounds then cause small deletions or mutations in the 5' or 3' regulatory regions of the c-myc and other protooncogenes, resulting in stabilization of c-myc RNA and higher steady-state levels of c-myc RNA and protein. We also postulate that nickel-induced oxygen radical generation, Cr(V) ions or oxygen radicals generated by chromium, and arsenite induce inactivating mutations or deletions in tumor suppressor genes. Arsenic, nickel, or chromium compound-induced neoplastic transformation is postulated to proceed through a combination of activation of c-myc and/or other protooncogenes and inactivation of tumor suppressor.-Environ Health Perspect 102(Suppl 3):119-125 (1994).
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.
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.
Toxicological Sciences, 2001
The purpose of the present study was to investigate the mechanism of cross-tolerance to nickel in arsenic-transformed cells. Chronic arsenite-exposed (CAsE) cells (TRL 1215 cells, which had been continuously exposed to 0.5 M arsenite for 20 or more weeks) and control TRL 1215 cells were both exposed to nickel for 24 h, and cell viability was determined by metabolic integrity. The LC 50 for nickel was 608 ؎ 32 M in CAsE cells as compared to 232 ؎ 16 M in control cells, a 2.6-fold increase. CAsE and control cells were treated with 200 M nickel for 4 h and cellularfree radical production was measured using ESR spectrometry.
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.
Journal of Public Health Student Capstones, 2023
Exposure to inorganic arsenic (iAs) is a global public health concern. It is believed that the dysregulation of epigenetic mechanisms contributes and plays a major role in arsenic-associated adverse health effects. The present authors have already conducted a systematic review that summarized the findings of arsenic-induced epigenetic disruptions from in vitro and animal studies. In recent years, an increasing number of studies have been conducted with humans becoming available. In order to further clarify the association between arsenic exposure and epigenetic modifications, the authors reviewed the effects of arsenic on epigenetic mechanisms, including DNA methylation, histone post-translational modifications, and altered microRNA (miRNA) levels in studies conducted in human populations. Our systematic review reveals that in humans exposed to arsenic, global DNA methylation appears to increase, which is contrary to in vitro and the majority of animal studies. Specific genes that were identified as having their methylation profile altered by exposure to arsenic were associated with various cancer and noncancer diseases. The histone modifications post-arsenic exposure in humans are more diverse and amino acid-specific. Arsenic exposure changes the expression of specific miRNAs in human studies. Overall, it is consistent that exposure to arsenic leads to alterations of epigenetic mechanisms in almost all human studies; however, current studies do not seem to identify conserved epigenetic biomarkers across studies. Further studies are warranted with standardized study design, clearly defined outcomes of health effects, and measurements of arsenic exposure.
Metallomics, 2012
The complex process of carcinogenesis begins with transformation of a single cell to favor aberrant traits such as loss of contact inhibition and unregulated proliferation-features found in every cancer. Despite cancer's widespread prevalence, the early events that initiate cancer remain elusive, and without knowledge of these events cancer prevention is difficult. Here we show that exposure to As, Cr, Ni, or Vanadium (V) promotes changes in gene expression that occur in conjunction with aberrant growth. We exposed immortalized human bronchial epithelial cells to one of four metals/metalloid for four to eight weeks and selected transformed clonal populations based upon anchorage independent growth of single cells in soft agar. We detected a metalspecific footprint of cancer-related gene expression that was consistent across multiple transformed clones. These gene expression changes persisted in the absence of the progenitor metal for numerous cell divisions. Our results show that even a brief exposure to a carcinogenic metal may cause many changes in gene expression in the exposed cells, and that from these many changes, the specific change(s) that each metal causes that initiate cancer likely arise.