Additionally, oxidation of iron in IRP-1 results in inactivation of aconitase. This in turn should inhibit the tricarboxylic acid cycle and affect levels of 2 oxoglutarate 2OG , a cofactor of hydroxylases. This will impair the accessibility of DNA for transcription factors and, as the result, affect gene expression. Figure 2. Schematic representation of major cellular interactions of tri- and pentavalent arsenic. Both forms, tri- or pentavalent arsenic, can enter cells.
This will result in modification of protein function and retention of arsenic inside the cell. Arsenic methylation can deplete S -adenosylmethionine, which serves as a universal donor of the methyl group. As a result, DNA or histone methylation pattern may be changed. The repair of this damage may also be inhibited by arsenic. NIH Publication 07—, Figure 3.
Figure 4. Figure 5. Figure 6. Selection model of Cr VI carcinogenesis. Research by K. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U. We thank Dr. Kasprzak for the critical reading of the manuscript.
Handbook on the Toxicology of Metals
View Author Information. Phone: Fax: Cite this: Chem. ACS AuthorChoice. Article Views Altmetric -. Citations PDF KB. Abstract High Resolution Image. The ability of some metal compounds to cause cancers in exposed workers has been known for a long time, with early documented cases dating back to the 19th century. Massive growth of manufacturing and other economic activities in the major industrialized countries has been accompanied by parallel increases in the large-scale consumption of nonferrous metals, some of which are now recognized human carcinogens. High-volume utilization and poor practices in the disposal of metal-containing waste products created numerous sources of heavy environmental contamination, including some of the largest toxic sites known as Superfund sites in the U.
Toxic metals represent the ultimate form of persistent environmental pollutants because they are chemically and biologically indestructible. Despite well-recognized carcinogenic potentials of such toxic metals as chromium, nickel, and metalloid arsenic, the molecular mechanisms underlying their cell-transforming ability remain poorly understood.
Carcinogenic metals are typically weak mutagens, and with the exception of chromium, they do not form DNA adducts, which represent a key initiating event in the cancer-inducing activity of organic carcinogens. A long-held view that elevated production of reactive oxygen species is the main pathway in metal carcinogenicity is clearly at odds with data on weak or no mutagenicity of most metals. This perspective will summarize the most recent development in the field of metal carcinogenicity and cocarcinogenicity with special emphasis on the roles of activated signaling pathways, epigenetic changes, and DNA repair processes.
Nickel II is a toxic and carcinogenic metal 1. It is used in modern industry with other metals to form alloys to produce coins, jewelry, and stainless steel as well as for nickel plating and manufacturing Ni-Cd batteries. Among new applications, it is important to note its role as a catalyst for the production of carbon nanoparticles. This new technology increases consumption and contamination with nickel compounds.
Workers are exposed at different stages of processing of nickel-containing products. The most important route of human exposure to nickel is inhalation. This exposure has long been known to cause acute respiratory symptoms, ranging from mild irritation and inflammation of respiratory system to bronchitis, pulmonary fibrosis, asthma, and pulmonary edema 2.
Additionally, nickel exposure also may cause cardiovascular and kidney diseases, as well as allergic dermatitis. However, nickel carcinogenic activity represents the most serious concerns. Nickel II exerts its carcinogenic activity most likely through nongenotoxic mechanisms. Because of a fast clearance from the exposed tissues, which limits cellular uptake, water-soluble Ni II compounds possess lower toxic and carcinogenic potential as compared to semisoluble compounds such as nickel subsulfide 1. Possible mechanisms of nickel carcinogenesis have been discussed in a number of comprehensive reviews 1, Epidemiological studies have clearly implicated Ni II compounds as human carcinogens on the basis of an increased mortality from respiratory tract malignancies in refinery workers chronically exposed to nickel-containing dusts and fumes 7, 8.
Other health effects of inhalation exposure to soluble and insoluble nickel compounds are reported in a number of recent publications 2, 4, Acute lung injury following nickel exposure was demonstrated in mice and rats In various animal models, chronic exposure to nickel compounds induces tumors at virtually any site of administration 1, 3. Nickel compounds efficiently transform rodent and human cells in vitro All Ni II compounds were recognized as human carcinogens Group 1 , and metallic nickel is classified as possibly carcinogenic to humans Group 2B The purpose of this perspective is to re-evaluate existing hypotheses on the basis of recently obtained data.
Although various potentially mutagenic DNA lesions have been shown to occur following nickel exposure, the actual mutagenic activity of nickel compounds observed in most of the mutational systems examined thus far from Salmonella to mammalian cells in vitro has been low Thus, it may be suggested that nickel-induced mutagenic activity is not the primary cause in nickel-induced carcinogenesis. Indeed, the experiments with the SHE system have provided confirmatory evidence that cell immortalization can occur as an indirect consequence of carcinogen exposure following an induced high frequency change in the treated population, rather than through direct targeted mutagenesis Additionally, no increase of ouabain-resistant or 6-thioguanine-resistant colonies has been found in human diploid fibroblasts even at concentrations of Ni 3 S 2 that increased the frequency of anchorage-independence by fold Changes in DNA methylation leading to the inactivation of gene expression following the exposure to nickel compounds were initially found using the transgenic E.
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Although the mechanisms by which nickel induces DNA hypermethylation in cultured cells are presently unknown, a possible model includes the ability of nickel to substitute for magnesium, increase chromatin condensation and trigger de novo DNA methylation Changes in DNA methylation can also be observed in vivo in nickel-induced tumors. The hypermethylation of the promoter of the tumor suppressor gene p16 was observed in all tumors. Fhit is another tumor suppressor gene silenced by nickel exposure both in vitro and in vivo Fhit is a tumor suppressor gene whose expression is frequently reduced or lost in tumors and premalignant lesions.
In addition to gene silencing by DNA methylation, the suppressive effects of nickel on histone H4 acetylation in vitro in both yeast and mammalian cells have been reported 30, Acetylation of lysine 12 and 16 in yeast was more strongly affected than lysine 5 and 8, and it was proposed that nickel binding to histidine 18 in histone H4 may be responsible for this effect The loss of histone acetylation and DNA methylation worked together in gpt gene silencing in G12 transgenic cell line by nickel 32, In human lung cells exposed to soluble nickel compounds, three major changes in histone modifications were observed: i loss of acetylation of H2A, H2B, H3, and H4; ii increases of H3K9 dimethylation; and iii substantial increases in the ubiquitylation of H2A and H2B 28, The acetylation of the core histone N-terminal tail domains is recognized as a highly conserved mechanism for regulating chromatin functional states.
Biochemical data supports a correlation between histone acetylation and gene activation, suggesting that histone acetylation acts to enhance the access of transcription-associated proteins to DNA. Conversely, histone methylation results in more compacted chromatin and gene silencing. If gene silencing mediated by histone modification plays a role in nickel-induced cell transformation, then the reactivation of these genes may reverse this effect.
Indeed, recent experiments showed that the exposure of nickel-transformed cells to the histone deacetylase inhibitor trichostatin A TSA resulted in the appearance of a significant number of revertants measured by their inability to grow in soft agar Low levels of histone acetylation in nickel-exposed cells may result from low levels of acetyl CoA, which is a universal donor of acetyl group. This may occur because the conversion of pyruvate into acetyl-CoA is blocked by the enzyme pyruvate dehydrogenase kinase Figure 1.
Taken together, these data suggest that epigenetic changes probably are more important for nickel-induced toxic and carcinogenic effects than mutational changes. High Resolution Image. Nickel is not an essential metal ion in mammalian cells. Therefore, no specific proteins involved in uptake, intracellular distribution, or storage of nickel ions are known that may be commonly up-regulated by nickel exposure. Thus, no characteristic to nickel exposure pattern of gene expression was expected. Remarkably, nickel exposure produces a rather specific pattern of gene expression, which is similar to the response to hypoxia Under normoxic conditions, this protein is virtually undetectable in most cells but can accumulate following exposure to proteasomal inhibitors, such as lactacystin or MG These data were mainly supported by the finding that ferritin disappeared and IRP1 was activated in nickel-exposed cells However, the oxidation of iron in iron—sulfur clusters could produce the same result Figure 1.
Modest changes in intracellular iron levels in nickel-exposed cells support this notion Recently, we showed that the depletion of intracellular ascorbate by Ni II may lead to the inhibition of prolyl hydroxylases 39, These enzymes are members of the Fe II -, 2-oxoglutarate 2OG -, and ascorbate-dependent family of dioxygenases. Ascorbate plays an important role in the reduction of enzyme-bound iron, which is vital for maintaining hydroxylase activity. The active role of ascorbate in the hydroxylase reactions may explain the controversy about the role of ROS in HIF-1 activation and reconcile previously obtained data.
Indeed, ROS may deplete through oxidation a variety of reducing molecules. However, since only ascorbate is capable of maintaining iron in the reduced state, its presence is critical for hydroxylase activity. This results in the inactivation of the hydroxylases and produces a phenotype observed in hypoxic cells or in cells with mutated VHL 61, Thus, exposure of cells to Ni II most likely results in the oxidation of intracellular iron followed by the induction of HIF-1 and activation expression of hypoxia-inducible genes The activation of hypoxic signaling pathway and switch of cellular metabolism to a state that mimics permanent hypoxia may be a part of nickel-induced carcinogenesis 39, 64, Hypoxia is common in tumors because the tumor body is growing faster than the blood vessels growing into it.
It may promote tumor progression via activation of genes coding for proteins, enabling cells to overcome nutritive deprivation and to escape from the hostile metabolic microenvironment Stimulation of angiogenesis through up-regulation of VEGF and other growth factors involved in building new blood vessels is also an important part of the survival program.
Additionally, cellular responses to hypoxic stress include inhibition of cell proliferation and, when cell damage is irreversible, apoptosis. The activation of HIF-1 transcription factor and modification of histones may represent a molecular basis for cellular adaptation in growing tumors. The selection theory seems to explain the low mutagenic but high transforming activity of nickel compounds However, one may suggest that for successful cell transformation an additional mutagenic DNA damage event is required.
Nickel compounds were shown to act synergistically with many mutagenic carcinogens in enhancing cell transformation both in vitro and in vivo A single i. These tumors occurred only in coexposed rats. A growing body of evidence indicates that nickel enhances the cytotoxicity and genotoxicity of DNA-damaging agents through inhibition of DNA repair. Thus, exposure to particulate black NiO and soluble NiCl 2 affected the removal of DNA adducts formed by benzo[ a ]pyrene in human lung cells 69, Nickel inhibits the repair of O 6-methylguanine and N 7-methylguanine induced by treatment with N -methyl- N -nitrosourea in Chinese hamster ovary cells Nickel blocks the removal of cyclobutane pyrimidine dimers produced by UV light exposure in HeLa cells More recently, a new class of DNA repair enzymes has been found.
In the presence of oxygen, these enzymes can specifically hydroxylate alkyl groups on 1-methyladenine and 3-methylcytosine The requirement of iron for the reaction as well as inhibition of hydroxylase activity in crude cell extracts by iron chelators suggested that these enzymes are iron- and ascorbate-dependent. The activity of these enzymes, similar to protein hydroxylases, depends on iron oxidation status and may be inhibited by nickel exposure. These results indicate that the nucleotide and base excision repair pathway is affected by water-soluble and particulate nickel compounds and provide further evidence that DNA repair inhibition may be one of the mechanisms involved in nickel cocarcinogenic activity.
In addition to the inhibition of DNA repair, epigenetic changes induced by nickel compounds should be taken into consideration. It is noteworthy that in animals nickel-induced carcinogenesis is known to be tissue, strain, and species-dependent 1. This suggests that genetic predispositions, including variations in the expression of genes involved in the metabolism of antioxidants, most likely glutathione and vitamin C, in different species and strains of animals, may also play an important role in nickel carcinogenesis It is conceivable that similar genetic predispositions take place in human populations.
In conclusion, carcinogenic nickel produces significant alterations in cellular metabolism, which include, but are not limited to stimulation of glycolytic activity, alteration of iron homeostasis, depletion of ascorbate, and hypoxic stress. These effects of nickel exposure are summarized in Figure 1. It is clear that such metabolic alterations will lead to the modulation of gene expression through epigenetic changes. A coexposure with genotoxic carcinogens may exacerbate nickel effects. Arsenic is an environmental contaminant, which can be found in the soil, water, and airborne particles as the result of both natural and human activities 77, Epidemiological studies have confirmed that exposure to arsenic and its compounds can have adverse effects on human health.
Inhaling arsenic can cause lung carcinomas, while ingestion in food or water, can provoke skin, respiratory system, liver and bladder tumors as well as diabetes and cardiovascular and neurological diseases Humans are clearly more sensitive to inorganic arsenic carcinogenesis than animals.
In rodents, it has proven difficult to induce tumors after inorganic arsenic exposure alone, making it problematic, in the absence of an animal model, to study mechanisms of arsenic carcinogenesis The increase in cancer risk observed in epidemiological studies is attributed mainly to the exposure to inorganic arsenite, which is more toxic than arsenate 80, This may be due to a better cellular uptake of arsenite, which, at equimolar concentration, is accumulated in many cell types much faster as compared with arsenate.
Inside the cell, arsenate may be reduced to arsenite. Glutathione seems to play an important role in arsenate reduction and detoxification through conjugation 82 Figure 2. After ingestion, arsenic is rapidly excreted, primarily through urine, mainly in the form methylated arsenic metabolites These methylated metabolites are produced in vivo by conjugation using S -adenosylmethionine as the methyl donor 82, The methyltransferases involved in the process are not yet characterized.
The levels of S -adenosylmethionine are important in arsenic metabolism since a low intake of dietary methyl groups, that is, low dietary content of methionine or folate deficiency, results in lower arsenic methylation Since methylated species are excreted much faster than inorganic arsenic species, it is conceivable that methylation represents a part of detoxification program. Pentavalent arsenicals were not shown to be a carcinogenic risk to humans at typical environmental exposures. However, dimethylarsinic acid DMA V is carcinogenic at high doses to the rat urinary bladder but not in mice The carcinogenic mode of action involves cytotoxicity followed by regenerative cell proliferation.
Thus, these data indicate that methylated forms of arsenic may be potentially more dangerous than nonmethylated ones. This, however, will require further investigations. It is noteworthy, that arsenicals administered to the rat may also bind to a specific cysteine in the hemoglobin alpha chain as DMA III , regardless of the arsenical being administered.
Hemoglobin binding is responsible for the greater accumulation of arsenic species in rat blood than in human or mouse blood. The significance of this modification is not clear; however, it is conceivable that this may be the reason that the rat is one of the few arsenic carcinogenic animal models available at present. In cell and animal models, arsenite and perhaps some methylated metabolites may activate signal transduction pathways, which enhance cell proliferation, reduce antiproliferative signaling or inhibit differentiation, and override checkpoints controlling cell division after genotoxic insult 87, In animals treated with arsenite, hyperplasia is seen in the urinary bladder epithelium and in skin 89, In a human uroepithelial cell line, arsenic activates EGFR and ERK in a ligand-independent manner, which does not involve autophosphorylation Tyr Activation of growth factor receptors regulates G 1 phase cyclins and associated cyclin-dependent kinases cdks.
Cyclin D1 is one of the cyclins up-regulated by arsenite exposure 93, Cyclin D1 has a very short half-life, and its protein levels depend on phosphorylation by a number of kinases, including extracellular signal-related kinases ERKs , phosphotidylinositol 3-kinase PI3K , and IKK. Initially, in human fibroblasts, it was found that long-term and low-dose but not short-term, high-dose exposure to arsenite resulted in increased expression of cyclin D1 However, it was later shown that even 12 h of exposure to low-dose arsenite caused cyclin D1 up-regulation in human keratinocytes Low concentrations of arsenite also disrupt p53 function, which results in down-regulation of p21 in response to genotoxic stress Murine fibroblasts chronically exposed to low concentrations of arsenite show increased proliferative response to epidermal growth factor EGF and increased expression of c-myc and E2F-1 positive growth regulators Thus, exposure to arsenite results in the stimulation of cell-cycle progression, especially G 1 -S transition.
Down-regulation of p53 function suggests that in the presence of arsenic cells may enter the cell cycle with unrepaired DNA lesions. Arsenic trioxide is an effective treatment for acute promyelocytic leukemia APL The APL patients resistant to all-trans retinoic acid and other types of chemotherapy can still respond to arsenic trioxide. In vitro studies showed that at micromolar concentration arsenic trioxide triggers APL cell apoptosis. Lower doses of arsenic were shown to induce differentiation of leukemic cells.
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Both apoptosis and cell differentiation are important factors of arsenic therapeutic effect. Thus, therapeutic effect of arsenic is mediated through down-regulation of an important antiapoptotic transcription factor NF-kB. The effect of arsenite on NF-kB was extensively studied in vitro. The experimental findings, however, are contradictory. In some instances, the exposure to arsenite up-regulated NF-kB In others, the exposure to arsenite down-regulated NF-kB , This controversy could be explained by the use of different cell models as well as by different time and doses of treatment.
Thus, low-dose and short-term of treatment with sodium arsenite could activate NF-kB DNA binding, whereas chronic exposure to 0. Arsenic is known to induce deletion mutations and chromosomal alterations, such as aberrations, aneuploidy, and sister-chromatid exchanges, but not point mutations In spite of its low mutagenic activity, arsenic has high transforming activity Among genetic changes, it is also important to note that arsenic exposure can cause gene amplification.
Thus, two arsenic salts, sodium arsenite and sodium arsenate, were shown to induce a high frequency of methotrexate-resistant 3T6 cells The resistance was due to the amplification of the dihydrofolate reductase gene. The ability of arsenic to induce gene amplification may relate to its carcinogenic effects in humans since amplification of oncogenes is observed in many human tumors.
A large body of evidence has been accumulated over the last 10 years suggesting that epigenetic changes are important in arsenic carcinogenesis. Thus, exposure to arsenic can induce both DNA hypomethylation and hypermethylation. DNA methylation changes are typically observed in cancer, in which global methylation is reduced, but some gene-specific promoter methylation is increased The exposure of human lung adenocarcinoma A cells to arsenite results in increased cytosine methylation in the p53 promoter Both hypo and hypermethylation of different genes was found in human kidney cells treated with arsenite in vitro Global DNA hypomethylation and evidence of depressed levels of S -adenosyl-methionine and decreased DNA methyltransferase activity were found in rat liver epithelial cell line following chronic exposure to low levels of arsenic This reduced or lost expression was the result of hypermethylation of these genes.
Significant DNA hypermethylation of the promoter region of p53 gene was observed in the DNA of arsenic-exposed humans compared to that in control subjects This hypermethylation showed a dose—response relationship. Furthermore, hypermethylation of the p53 gene was also observed in arsenic-induced skin cancer patients compared to that in subjects having skin cancer unrelated to arsenic, though not at a significant level. However, a small subgroup of cases showed hypomethylation with high arsenic exposure. Significant hypermethylation of the gene p16 was also observed in cases of arsenicosis caused by high levels of arsenic.
Thus, the ability of arsenic to alter DNA methylation in humans may be important in carcinogenesis. Unlike nickel, exposure to arsenite does not cause methylation and silencing of the transgenic E. Arsenite was shown to inhibit pyruvate dehydrogenase PD activity through binding to vicinal dithiols in pure enzyme and tissue extract.
However, more recently, it was shown that arsenite may cause oxidation and inactivation of PD by ROS, which inactivates an enzyme This can occur at a much lower concentration than that needed for direct binding of arsenite to the critical thiols. In contrast, pretreatment with the thiol antioxidants glutathione or N -acetylcysteine completely abrogated both effects, whereas a potentiation was observed by the depletion of intracellular glutathione.
Further studies, however, did not confirm transcriptional up-regulation of hypoxic genes. Arsenic reduction and methylation is aimed to detoxify and excrete this toxic metalloid from cells. The complex relationship between glutathionylation and methylation of arsenic was investigated recently. It was suggested that As-GSH complexes are substrates for arsenic methyltransferase; therefore, all observed products are components of the arsenic metabolic pathway 82, At low nonmutagenic concentrations, arsenite can enhance the mutagenicity of other carcinogens, probably by interfering with DNA repair Arsenic inhibits the repair of DNA adducts caused by benzopyrene in rats In mice, arsenite can enhance the carcinogenicity of ultraviolet radiation UV , No tumors appeared in any organs in control mice or in mice given arsenite alone.
The molecular mechanism for tumor formation involves reduction in the repair rate of photoadducts and inhibition of apoptosis , Recently, it has been shown that a short period of maternal exposure to inorganic arsenic in the drinking water results in multitissue carcinogenesis in the adult offspring For example, prenatally exposed female C3H offspring showed dose-related increases in ovarian tumors and lung carcinoma and in proliferative lesions tumors plus preneoplastic hyperplasia of the uterus and oviduct. In addition, prenatal arsenic plus postnatal exposure to the tumor promoter, O -tetradecanoyl phorbolacetate TPA in C3H mice produced excess lung tumors in both sexes and liver tumors in females.
In CD1 mice, additional postnatal treatment with diethylstilbestrol or tamoxifen after prenatal arsenic exposure induces urinary bladder transitional cell proliferative lesions, including carcinoma and papilloma, and enhances the carcinogenic response in the liver of both sexes. These data provide convincing evidence that arsenic is a transplacental carcinogen and cocarcinogen in mice with the ability to target tissues of potential human relevance, such as the urinary bladder, lung, and liver. In conclusion, arsenic is acting as a nongenotoxic carcinogen mainly via alterations in DNA methylation Figure 2.
It cannot be excluded that arsenic may also cause alterations in histone methylation, although this has not been shown yet. Because of its inhibitory effects on DNA repair, arsenic acts as a very efficient cocarcinogen. Cr and its compounds have a long history of industrial uses in the manufacture of a large number of high-volume products, such as stainless steel and pressure-treated wood. Occupational exposure to Cr is found among approximately half a million industrial workers in the United States and several million worldwide , Environmental exposure likely impacts millions of people drinking Cr-containing water, residing in the vicinity of numerous toxic sites, and various industrial users of Cr products.
The presence of Cr in urban particulate matter and emissions from automobile catalytic converters leads to exposure by very large segments of populations in densely populated areas. Cr 0 is usually present in its metallic form, which typically occurs in alloys with other metals, particularly Fe and Co. Cr III is thermodynamically stable, and it is the final oxidative form found in all biological systems. Depending on the nature of the counter ion, the solubility of Cr VI compounds varies from very high salts with alkali metals to moderate salts of Ca, Mg, Sr, and Zn to very low barium and lead salts.
The highest exposure to Cr VI occurs in chromate manufacturing, chrome plating, ferrochrome production, and stainless steel welding. Welders employed in construction and small car repair shops are at particular risk of heavy exposure because of the absence or practical difficulties in the installation of exhaust systems for removal of Cr VI -containing fumes from the breathing area.
Occupational exposure to Cr VI compounds but not other oxidative forms of Cr is a well-documented cause of respiratory cancers 21, , Cr VI -associated neoplasms are typically located in the lung, but risk of nasal cancers is also significantly increased In parallel with epidemiological findings, recent studies in cells cultured under more biologically relevant conditions found a much greater potential for Cr VI to cause chromosomal damage and mutations than it was previously thought.
Although a frequently referenced review by IARC in 21 found stronger evidence for the carcinogenicity of less soluble chromates, specifically for salts with moderate solubility, the follow-up epidemiological studies clearly showed that human exposure to soluble chromates also significantly increased the risk of lung cancer , A recently released draft of the NTP report 2 on testing of dichromate in drinking water contains clear evidence of its carcinogenicity in the oral cavity and small intestine.
While NTP studies have not found evidence for systemic cancers following the ingestion of dichromate, exposed animals showed clear signs of toxicity in the liver and other internal organs, indicating the ability of toxic Cr VI to avoid detoxification in the GI tract and enter systemic circulation. Sustained elevation of Cr levels in red blood cells of human volunteers following ingestion of Cr VI -laced water is also consistent with the absorption of significant amounts of Cr VI into the blood Insoluble salts of lead and barium chromates were negative in the implantation model of lung carcinogenesis , and epidemiological data for their carcinogenicity are also not as strong as those for other chromates However, considering that soluble chromates were also negative in the implantation model but are now confirmed as carcinogenic, it is prudent to consider all chromates as equally carcinogenic.
Squamous cell carcinoma is the most common form of lung malignancies in chromate workers, and the majority of tumors were located in the central part of the lung Interestingly, Cr VI exposure was associated with the development of multiple tumors in several subjects, pointing to the potential existence of individual susceptibility factors in Cr-induced carcinogenesis. Squamous cell carcinoma appears to develop from dysplastic lesions over a relatively short period of about one year The location of lung tumors corresponds to the sites of Cr accumulation, with bronchial bifurcations exhibiting the highest Cr levels in ex-workers who had been exposed to soluble chromates Long-term retention of Cr in the bronchial tissue primarily occurred in the stroma , probably reflecting a faster clearance of Cr from the more rapidly renewable bronchial epithelia.
Suppressed mucus flow, delaying effective clearance of chromate particles, could be another contributing factor since chronic exposure to respiratory toxicants causes the loss of cilia near bifurcations Lung-deposition profiles of Cr from particles of lower solubility chromates are currently unknown, but they are expected to show the same pattern of hotspots.
Although the majority of lung cancers were found among chromate workers who smoked , , this may simply reflect a fact that the majority of workers were smokers. Smoking does not affect Cr accumulation in the lung , and chromate exposure was clearly established as an independent risk factor for lung cancer Molecular features of chromate and smoking-associated cancers are very different section 4.
Chromates are isostructural with physiological sulfate and phosphate ions, and because of this molecular mimicry, Cr VI readily enters cells through the sulfate channels Human and other mammalian cells are capable of massive accumulation of Cr VI , with cellular levels 10—20 times above those outside the cell within 3 h , A h long incubation can lead to fold or higher accumulations When this occurs extracellularly, reduction acts as the detoxification process because of the production of poorly permeable Cr III complexes Figure 4. Inside the cell, Cr VI reduction is the activation event that is responsible for the generation of genotoxic damage and other forms of toxicity.
Unlike the majority of other human pro-carcinogens, Cr VI metabolism in mammalian cells does not require any enzymes and relies on the direct electron transfer from ascorbate and nonprotein thiols, such as glutathione and cysteine In contrast to the millimolar levels of ascorbate in cells in vivo e. Thus, unless cellular ascorbate levels are restored to normal, typical cell cultures provide a nonphysiological model of Cr VI metabolism, which has recently been found to underestimate the genotoxic and mutagenic abilities of Cr VI The end-product of Cr VI metabolism in all biological systems is always Cr III , but the reduction process can also generate variable amounts of Cr V , Cr IV , and organic radicals depending on the reducer and the ratio of reactants The presence of Cr V was only detectable when high concentrations of the reactants were used and ascorbate was present at nonphysiological or lower ratio to Cr VI.
While the presence of small amounts of short-lived Cr V at higher than 2-fold ratio of ascorbate to Cr VI cannot be excluded because of the technical limitations of the employed spin resonance spectroscopy approaches, it is doubtful that environmental levels of Cr VI will be sufficient to produce significant quantities of Cr V in cells with millimolar ascorbate concentrations. The first step in the reduction of Cr VI by physiological concentrations of cysteine proceeds primarily through one electron transfer , which explains a strong signal for Cr V in Cr VI -cysteine reactions The initial electron transfer reaction in the glutathione-driven reductions is predominanatly a two-electron process , but the production of Cr V -glutathione species is also readily detectable , , In vitro reduction reactions also generate large amounts of Cr III complexes containing two molecules of the unoxidized reducer , Small Cr-DNA adducts are the most abundant form of Cr VI -induced genetic lesions in mammalian cells , and they were found to be responsible for all mutagenic damage generated during Cr VI reduction with cysteine and ascorbate Binary adducts are only weakly mutagenic , , and their existence in cells is uncertain because of the presence of numerous Cr III -binding small molecules.
Ternary Cr-DNA adducts can be disrupted during DNA isolation , which produces binary adducts and further complicates the assessment of the real levels of these small adducts. All ternary adducts were much more mutagenic than binary adducts, and ascorbate-Cr-DNA cross-links were the most potent premutagenic Cr-DNA modifications , Binary adducts can also be generated in the direct reaction of newly formed Cr III with DNA , , , but the possibility that a fraction of binary adducts results from the reaction of intermediate Cr forms, particularly Cr IV , cannot be excluded.
Both types of adducts are substrates for nucleotide excision repair NER in human and hamster cells, as evidenced by the persistence of total adducts and increased toxicity and mutagenicity of Cr-DNA damage in NER-deficient cells. The availability of sensitive methodologies led to the frequent use of DPC measurements as a biomarker of Cr VI exposure in humans , and aquatic species The biological significance and repair of Cr-induced DPC remain largely unknown; however, a very large size of these lesions would likely represent a major obstacle for the replication and transcription processes.
The presence of interstrand DNA cross-links have been detected only under certain in vitro conditions , , , and on the basis of the severe steric restrictions for the intercalation of octahedral Cr III complexes, it was argued that interstrand cross-links were probably produced by Cr III oligomers If formed, the interstrand cross-link would represent a potent block for cellular DNA replication. The presence of single-strand breaks SSB in chromate-treated cells in culture and in animal tissues has been reported in several studies that used standard detection assays for the quantitation of these DNA lesions.
While the results of these and related studies showed clear positive responses, the reliance of all of the employed methodologies alkali elution, alkaline unwinding assay, and alkaline single cell electrophoresis on DNA unwinding in strongly alkali conditions raises a major concern as to whether the recorded data measured genuine SSB or breaks that were artifacts of the alkaline assay conditions. Cr-DNA phosphate adducts , similar to other modifications of DNA phosphate groups, make phosphodiester linkages unstable under alkaline conditions, causing breaks.
In fact, this property of alkylphosphotriesters has long been used for their quantitation in cellular DNA The production of SSB was inhibited by the addition of catalase and iron chelators or by elevation of glutathione levels. These results along with the oxygen dependence of SSB induction in glutathione—chromate mixtures led to the suggestion that SSB were caused by oxidizing species generated in the reaction of Cr V with H 2 O 2 The ability of Cr V to act as a catalyst in Fenton-like reactions with H 2 O 2 has been well established , The source of H 2 O 2 in vitro has been traced to Fe contamination, particularly in the stock preparations of the reducers , , Since ascorbate-driven reductions generate minimal if any Cr V at biologically relevant conditions , then the formation of SSB in ascorbate-supplemented cells should be very low.
In support of this suggestion, in vitro reactions of Cr VI with 0. Cytogenetic studies in Cr VI -exposed cells in culture and in vivo have long reported findings, such as increased frequencies of chromosomal breaks , and micronuclei , consistent with the induction of DNA double-strand breaks DSB. However, it is only very recently that more direct evidence for the formation of DSB in Cr VI -treated human cells has been obtained , , DSB were produced via an indirect mechanism, which required the passage of cells through S-phase and the participation of mismatch repair proteins.
A more detailed discussion of this phenomenon is presented in section 4.
Damage to the base component of DNA can involve either loss of bases i. In vitro studies of Cr VI reductions with ascorbate and glutathione showed that the formation of abasic sites closely mirrored the yield of SSB and required the same reactive species , Similarly to SSB, when iron-free reaction conditions were used, no abasic sites were observed , Given the parallel production of both types of backbone damage, cellular conditions permitting the induction of SSB should also lead to the concomitant production of abasic sites.
No direct measurements of abasic sites in Cr VI -treated human cells have yet been done. Administration of Cr VI to animals with different tissue levels of ascorbate failed to induce the formation of 8-oxoG , which is the most widely used indicator of the oxidative insult on DNA.
However, Slade et al. Thus, it appears that guanine oxidation can occur during Cr VI reduction, but its main product was different from that typically expected for the oxidant-producing reactions. Apart from potentially significant differences in the reaction conditions, the discrepancy between the lack of mutagenic responses in shuttle-vector plasmids treated with Cr VI -ascorbate in phosphate buffer , and the production of spiroiminodihydantoin in PBS buffer may be related to either a weak mutagenicity of this lesion or its rapid repair in human cells.
Determination of spiroiminodihydantoin and other advanced oxidation products of guanine in ascorbate-complemented human cells would be very useful to clarify their importance in genotoxic effects of Cr VI. Cr VI -associated carcinogenesis differs from malignant processes involved in smoking-induced lung tumors by its very low frequency of mutational inactivation of p53 Thus, the Cr VI -activated malignant process proceeds through a completely different pathway despite that fact the majority of lung cancers were found among chromate workers who were smokers One interesting feature of Cr VI -associated cancers was the presence of microsatellite instability , which indicates a complete loss of functional mismatch repair MMR , In Cr-induced cancers, microsatellite instability was associated with the loss of expression of MLH1 , which is one of the essential MMR proteins.
The absence of MMR leads to the inability of cells to correct replication errors, and these cells exhibit times higher mutation rates at their chromosomal genes, but the frequency of mutagenic events is even greater in the areas of simple nucleotide repeats known as microsatellites.
Thus, chromate-associated cancer cells express the mutator phenotype caused by the loss of the major mutation avoidance system, MMR. Once cells inactivated MMR, the subsequent acquisition of mutations in the critical growth-controlling genes is greatly accelerated since these cells maintain high rates of random mutagenesis and no longer need continuous exposure to Cr VI for additional mutagenic events.
Then the question arises as to how and why Cr VI selectively leads to the appearance of this specific form of genomic instability, which is uncommon for other lung carcinogens. MMR-deficient mouse and human cells have recently been found to be resistant to apoptosis and clonogenic lethality of Cr VI , Thus, MMR acted as the aberrant repair process, generating genotoxic damage rather than eliminating it.
The potentiating effects of MMR were most strongly pronounced in cells supplemented with physiological levels of ascorbate , Apoptotic responses and clonogenic lethality induced by Cr VI in human cells with normal or low ascorbate concentrations did not require the involvement of p53 , In addition to the promotion of chromosomal breaks via the activation of abnormal MMR, ascorbate was also a very potent enhancer of mutagenic activity of Cr VI The ascorbate—Cr-DNA adduct is a unique form of DNA damage induced during Cr VI metabolism by vitamin C , and they were highly mutagenic during the replication of shuttle-vectors in human cells MMR-promoted DSB were preferentially found in the G2 phase of the cell cycle, irrespective of doses, postexposure time, and type of cells , A combination of these findings led to the model that highly mutagenic adducts such as ascorbate—Cr-DNA cross-links induce mismatches during the replication of damaged DNA and that these compound lesions mismatches at the site of Cr adducts then lead to abnormal MMR In this scenario, premutagenic adducts induce mutations and also promote larger chromosomal abnormalities deletions and translocations resulting from the error-prone repair of DSB through a nonhomologous end-joining process.
Exposure of human cells to Cr VI is known to induce a series of gross chromosomal alterations, particularly in telomerase-negative primary cells This model postulates that chronic exposure to toxic doses of Cr VI results in the selective outgrowth of resistant clones that lack MMR. Once a population of these cells emerged, the subsequent exposure to Cr VI may no longer be necessary for the generation of additional mutations needed for the further progression of initiated cells because MMR-null cells have very high rates of spontaneous mutagenesis.
Since p53 plays no significant role in the toxicity of Cr VI at biologically relevant doses , , there is no selective pressure to inactivate this tumor suppressor, and this could be the main reason why Cr-induced tumors retained wild-type p Overall, Cr VI carcinogenesis can be envisioned as a deadly combination of Cr-DNA damage processed by MMR into chromosomal abnormalities at low Cr VI doses and elimination of cells with an intact mutation avoidance mechanism at higher doses. Paradoxically, intracellular ascorbate is a very potent stimulator of both processes, leading to genomic instability in Cr VI -exposed cells , While there are well-documented situations of human exposure to Cr VI as a single agent, such as those encountered in chromate production, the majority of other occupational and probably all environmental exposures are actually coexposures with other carcinogens.
Two examples of common coexposures are stainless steel welders and Cr VI -exposed workers who are also smokers. The possibility of cocarcinogenesis has been discussed for a long time, but the underlying considerations were largely theoretical, and only recently has chromate cocarcinogenesis been demonstrated in animal studies and the likely underlying mechanistic basis emerged. Two reports from Costa and colleagues , provided strong experimental data demonstrating that Cr VI can act as a potent cocarcinogen for UV-induced skin tumors.
In both studies, the presence of Cr VI in drinking water caused dose-dependent increases in the frequency of skin tumors in UV-irradiated hairless mice. Cr VI alone produced no tumors, indicating that it acted a strong enhancer of UV-initiated tumorigenesis. Supplementation with vitamin E or selenomethionine had no effect on Cr VI -mediated enhancement of skin carcinogenesis , suggesting that cocarcinogenic effects were not oxidant-mediated.
While the evidence for Cr-UV cocarcinogenesis in mouse skin is very clear , , whether Cr VI reached skin cells through systemic distribution after the ingestion of Cr VI -laced water or whether skin was exposed to Cr VI externally remains uncertain. The inability to repair UV-induced DNA damage leads to a dramatically increased risk of skin cancer and is the cause of xeroderma pigmentosum syndrome The reported comutagenicity of Cr VI and UV , which offers further support for the biological plausibility of Cr-UV cocarcinogenesis, can be explained by the same mechanism involving the competition for NER factors.
Tobacco smoking and Cr VI exposure represent another potential case for synergistic tumorigenesis. Smoking is very common among chromate-exposed workers, and DNA adducts formed by polycyclic aromatic hydrocarbons, which are one of the main groups of tobacco-derived mutagens, are repaired by NER Interestingly, Cr VI appears to cause a selective increase in the number of BPDE adducts at the mutational hotspots of p53 in smoking-induced lung cancer: codons , , and These sites are likely to be repair coldspots, which would make them particularly sensitive to decreased NER because of the competition with Cr-DNA adducts.
Although the majority of lung cancer cases among Cr VI -exposed workers were smokers , the interaction between smoking and Cr VI remained statistically uncertain because of the small number of cancer cases among nonsmokers. Cr VI and smoking-induced cancers also have different spectra of inactivated tumor-suppressors. While p53 mutations caused by activated polycyclic aromatic hydrocarbons and other mutagens are very common in tobacco-associated lung cancers , the majority of lung cancers in chromate workers retained wild-type p53 and instead inactivated the expression of MLH1 mismatch repair protein , , These major molecular differences provide further support for epidemiological findings that despite its potential for cocarcinogenesis, Cr VI can act as a potent lung carcinogen by itself Elsevier Science B.
A review. Human exposure to highly nickel-polluted environments, such as those assocd. Among them are skin allergies, lung fibrosis, and cancer of the respiratory tract. The exact mechanisms of nickel-induced carcinogenesis are not known and have been the subject of numerous epidemiol. These mechanisms are likely to involve genetic and epigenetic routes. The present review provides evidence for the genotoxic and mutagenic activity of Ni II particularly at high doses. Such doses are best delivered into the cells by phagocytosis of sparingly sol.
Broad spectrum of epigenetic effects of nickel includes alteration in gene expression resulting from DNA hypermethylation and histone hypoacetylation, as well as activation or silencing of certain genes and transcription factors, esp. The investigations of the pathogenic effects of nickel greatly benefit from the understanding of the chem. Many pathogenic effects of nickel are due to the interference with the metab. Research in this field allows for identification of putative Ni II targets relevant to carcinogenesis and prediction of pathogenic effects caused by exposure to nickel.
Ultimately, the investigations of nickel carcinogenesis should be aimed at the development of treatments that would inhibit or prevent Ni II interactions with crit. A review with 33 refs. Topics of discussion include: history, toxicol. A total of 18 Ni compds. The carcinogenic activities of particulate Ni compds. New York Academy of Sciences. DNA methylation and histone modification promote changes in chromatin structure that may affect gene expression in a heritable manner without directly altering the genome.
As such, these phenomena are considered to be epigenetic in nature and are believed to contribute to the normal processes of human development but also to aberrant disease states such as cancer. Epigenetic processes probably contribute mechanistically to toxicant-induced changes in gene expression and cancer. Nickel is a potent human carcinogen that has been shown to alter DNA methylation patterns and affect histone acetylation status. Both of these changes are assocd. The two processes probably occur in concert in mammalian cells.
However, in yeast cells, DNA methylation is absent, and nickel is capable of regulating gene expression through changes in acetylation of the lysine residues in the N terminal tail of histone H4. Arsenic is another important environmental carcinogen, and it is methylated during its metab. Hence, it was proposed that arsenic metab. However, the data concerning DNA methylation changes following arsenic exposure are equivocal, leading researchers to propose that DNA hypo- and hypermethylation are both important in the development of arsenic-induced cancers.
Heightened awareness by toxicologists of the importance of epigenetics in normal human development and in carcinogenesis should lead to the identification of other toxicants that manifest their effects, at least in part, via epigenetic mechanisms. Nickel is a widely distributed metal that is industrially applied in many forms. Accumulated epidemiol. Although the mol.
The present review summarizes the current knowledge on the mol. The increasing utilization of heavy metals in modern industries leads to an increase in the environmental burden. Nickel represents a good example of a metal whose use is widening in modern technologies. As the result of accelerated consumption of nickel-containing products nickel compounds are released to the environment at all stages of production and utilization.
Their accumulation in the environment may represent a serious hazard to human health. Among the known health related effects of nickel are skin allergies, lung fibrosis, variable degrees of kidney and cardiovascular system poisoning and stimulation of neoplastic transformation. The mechanism of the latter effect is not known and is the subject of detailed investigation. This review provides an analysis of the current state in the field. British journal of cancer , 24 4 , ISSN: Men employed in a nickel refinery in South Wales were investigated to determine whether the specific risks of developing carcinoma of the bronchi and nasal sinuses, which had been associated with the refining of nickel, are still present.
The data obtained were also used to compare the effect of age at exposure on susceptibility to cancer induction and to determine the rate of change of mortality after exposure to a carcinogenic agent had ceased. Eight hundred and forty five men were studied who had been employed in the industry for at least 5 years and whose first employment was in or before April All but 27 3.
Altogether of the men had died: from lung cancer and 39 from nasal cancer. In men employed before , deaths from lung cancer varied from about 5 to 10 times the numbers that would have been expected from the corresponding national mortality rates, while the deaths from nasal cancer varied from about to times the expected numbers. Among men first employed in or after there were 8 deaths from lung cancer against 6.
The death rate from causes other than cancer was similar to that experienced by men in the same geographical area irrespective of their date of first employment. Susceptibility to the induction of nasal cancer increased with age at first exposure, but susceptibility to the induction of lung cancer varied irregularly. The trends in susceptibility showed some similarity to the trends in the national mortality among men employed at similar ages. It is suggested that susceptibility to cancer induction is determined by the amount of previous exposure to other agents. The risk of developing nasal cancer persisted with little change 15 to 42 years after the carcinogen was eliminated whereas the risk of developing lung cancer decreased.
If the effects of cigarette smoking and the specific occupational hazard interact, the reduction in the risk of lung cancer could be due to the differential elimination of heavy cigarette smokers. Google Scholar There is no corresponding record for this reference. Haber, L. Regulatory Toxicology and Pharmacology , 31 2, Pt. Academic Press. A substantial body of occupational epidemiol. However, due to coexposure of these populations to sol. Results of parenteral assays follow a similar pattern, but provide evidence of weak carcinogenicity of sol. Kinetic factors also indicate that exposure to sol.
Overall, the authors conclude that the carcinogenic activity of insol. The overall data suggest a nonlinear dose-response relationship for carcinogenicity, but the data are insufficient to det. Under the U. A ref. American journal of epidemiology , 12 , ISSN: The International Agency for Research on Cancer has classified nickel compounds as carcinogenic to humans, but it is still not known with certainty which forms of nickel pose the risk.
In a case-control study of Norwegian nickel-refinery workers, the authors examined dose-related associations between lung cancer and cumulative exposure to four forms of nickel: water-soluble, sulfidic, oxidic, and metallic. A job-exposure matrix was based on personal measurements of total nickel in air and quantification of the four forms of nickel in dusts and aerosols. The nickel exposures were moderately to highly correlated. A general rise in risk from other types of nickel could not be excluded, but no further dose-dependent increase was seen.
Smoking was a weak to moderate confounder. The study suggests an important role of water-soluble nickel species in nickel-related cancer. A review concerning the role metals play in the pulmonary effects assocd. Topics discussed include: welding process description; exposure concns. Health Perspect. National Institute of Environmental Health Sciences. A review with refs.
In recent years the greatest progress in our understanding of pneumoconioses, other than those produced by asbestos, silica, and coal, has been in the arena of metal-induced parenchymal lung disorders. Inhalation of metal dusts and fumes can induce a wide range of lung pathol. The emphasis of this update is on parenchymal diseases caused by metal inhalation, including granulomatous disease, giant cell interstitial pneumonitis, chem.
The clin. Metal fume fever, an inhalation fever syndrome attributed to exposure to a no. Advances in our knowledge of antigen-specific immunol. Other metals such as cadmium and mercury induce nonspecific damage, probably by initiating prodn. Future research needs include development of biol. Exposure concns. For each compd. For Ni3S2, mortality was seen in mice but not in rats at the highest exposure concn.
No mortality was seen after NiO exposure. Lesions of the lung and nasal cavity were seen in both rats and mice after exposure to NiSO4. Lesions of the lung were seen primarily at the highest exposure concns. The amt. Based on these 2-wk studies, the toxicity ranking was NiSO4. Dunnick, J. No exposure-related effects on mortality and only minor effects on body wt. The most sensitive parameter for Ni toxicity was histopathol. There was an exposure-related increase in lung wt. No nasal lesions were seen after NiO exposure. Lymphoid hyperplasia of the bronchial lymph nodes developed in animals exposed to all three Ni compds.
The order of toxicity corresponded to the water soly. Dunnick, June K. American Association for Cancer Research. Nickel subsulfide 0. Preserved meat such as bacon, sausages, and ham increases the risk while a diet high in fresh fruit and vegetables may reduce the risk. The risk also increases with age. From Wikipedia, the free encyclopedia. IUPAC definition. Carcinogenicity : Ability or tendency to produce cancer. Note: In general, polymers are not known as carcinogens or mutagens, however, residual monomers or additives can cause genetic mutations. Main article: radiation-induced cancer.
Main article: Tobacco and health. History of cancer Mutagen Possible carcinogen Safe handling of carcinogens Teratogen. Cancer Science. PLoS Medicine. Journal of Gastrointestinal Cancer. Pure and Applied Chemistry. Abstract No. Work was done while employed by Dept. April International Journal of Occupational and Environmental Health.
Retrieved Cancer Research. Oxford: Nov 18, Canadian Journal of Public Health. National Cancer Institute. Retrieved 23 June Page no. Archived from the original on Cadmium and cancer". Sigel ed. Cadmium: From Toxicology to Essentiality. Metal Ions in Life Sciences. Archived from the original Press release on June 12, Retrieved June 12, Rowland and Patricia W. Durbin, Robbins Basic Pathology. Philadelphia: Saunders. Cancer and aging as consequences of un-repaired DNA damage. Clark Chen Ed. International Journal of Cancer. Food and Chemical Toxicology. The New England Journal of Medicine.
Chemical Research in Toxicology. Journal of the National Cancer Institute. World Journal of Gastroenterology. Archives of Toxicology. Infection and Immunity. Redox Report. Cancer Research UK. Cancer-causing materials and agents carcinogens. Cancer Cancer cells. Overview of tumors , cancer and oncology C00—D48 , — Hyperplasia Cyst Pseudocyst Hamartoma. Carcinoma Sarcoma Blastoma Papilloma Adenoma. Precancerous condition Paraneoplastic syndrome. Research Index of oncology articles History Cancer pain Cancer and nausea.
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Cancer Sites Associated with Occupational Exposures : OSH Answers
Leukemia Hodgkin's lymphoma. Missile fuel Lightweight alloys Aerospace applications Nuclear reactors. Yellow pigments Phosphors Solders Batteries Metal paintings and coatings. Lung  Bladder . Exhaust gas from engines. Ripening agent for fruits and nuts Rocket propellant Fumigant for foodstuffs and textiles Sterilant for hospital equipment. Nickel plating Ferrous alloys Ceramics Batteries Stainless-steel welding byproduct. Uranium decay Quarries and mines Cellars and poorly ventilated places.
Refrigerant Production of polyvinyl chloride Adhesive for plastics Former use in pressurized containers. Bone they are bone seekers Liver.