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Kazimierz S Kasprzak - One of the best experts on this subject based on the ideXlab platform.
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effects of ascorbic acid on carcinogenicity and acute toxicity of Nickel Subsulfide and on tumor transplants growth in gulonolactone oxidase knock out mice and wild type c57bl mice
Toxicology and Applied Pharmacology, 2011Co-Authors: Kazimierz S Kasprzak, Bhalchandra A Diwan, Monika Kaczmarek, Daniel Logsdon, Mathew J Fivash, Konstantin SalnikowAbstract:The aim of this study was to test a hypothesis that ascorbate depletion could enhance carcinogenicity and acute toxicity of Nickel. Homozygous L-gulono- -lactone oxidase gene knock-out mice (Gulo-/- mice) unable to produce ascorbate and wild-type C57BL mice (WT mice) were injected intramuscularly with carcinogenic Nickel Subsulfide (Ni₃S₂), and observed for the development of injection site tumors for 57 weeks. Small pieces of one of the induced tumors were transplanted subcutaneously into separate groups of Gulo-/- and WT mice and the growth of these tumors was measured for up to 3 months. The two strains of mice differed significantly with regard to (1) Ni₃S₂ carcinogenesis: Gulo-/- mice were 40% more susceptible than WT mice; and (2) transplanted tumors development: Gulo-/- mice were more receptive to tumor growth than WT mice, but only in terms of a much shorter tumor latency; later in the exponential phase of growth, the growth rates were the same. And, with adequate ascorbate supplementation, the two strains were equally susceptible to acute toxicity of Ni₃S₂. Statistically significant effects of dietary ascorbate dosing levels were the following: (1) reduction in ascorbate supplementation increased acute toxicity of Ni₃S₂ in Gulo-/- mice; (2) ascorbate supplementation extended the latency of transplanted tumors in WT mice. In conclusion, the lack of endogenous ascorbate synthesis makes Gulo-/- mice more susceptible to Ni₃S₂ carcinogenesis. Dietary ascorbate tends to attenuate acute toxicity of Ni₃S₂ and to extend the latency of transplanted tumors. The latter effects may be of practical importance to humans and thus deserve further studies.
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metallothionein i ii double knockout mice are no more sensitive to the carcinogenic effects of Nickel Subsulfide than wild type mice
International Journal of Toxicology, 2005Co-Authors: Michael P Waalkes, Kazimierz S Kasprzak, Bhalchandra A DiwanAbstract:Metallothionein (MT) is a high-affinity metal-binding protein thought to mitigate the toxicity of various metals. MT may limit the toxicity of a metal by direct binding or through action as an antioxidant for metals that generate reactive oxygen species. Nickel compounds have carcinogenic potential in humans and animals, possibly by production of oxidative stress. The impact of MT deficiency on the carcinogenic effects of Nickel is unknown. Thus, groups (n = 25) of male MT-I/II double knockout (MT-null) or MT wild-type (WT) mice were exposed to a single treatment of Nickel (0.5 or 1.0 mg Ni3S2/site, intramuscularly, [i.m.], into both hind legs), or left untreated (control) and observed over the next 104 weeks. There were no differences in the incidence of spontaneous tumors in MT-null and WT mice. Nickel induced injection site fibrosarcomas in a dose-related fashion to a similar extent in both WT and MT-null mice. Nickel-treatment had no effect on total lung tumor incidence, although some phenotypic-speci...
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relative susceptibilities of c57bl6 c57bl6 c3hhe f1 and c3hhe mice to acute toxicity and carcinogenicity of Nickel Subsulfide
Toxicology, 1996Co-Authors: Ricardo E Rodriguez, Manoj Misra, Bhalchandra A Diwan, Charles W Riggs, Kazimierz S KasprzakAbstract:Abstract The aim of this study was to compare susceptibility of mice of different strains to the toxicity and carcinogenicity of Nickel Subsulfide (Ni3S2), a water insoluble compound suspected to damage cells through oxidative mechanisms. Groups of 30 male mice of each strain, C57BL/6 (C57BL), ( C57BL /6 × C3H He )F1 (B6C3F1), and C3H He (C3H), were injected with single doses of 0.5–10 mg of Ni3S2/site into the thigh muscle and observed for up to 78 weeks. The highest Ni3S2 dose was lethal within 1 week to C57BL (93%) > B6C3F1 (80%) > C3H (53%) mice. The most susceptible C57BL mice also had the most severe necrotic/inflammatory kidney damage, compared with that in the other mice. The final incidence of local sarcomas at the 5 mg Ni3S2 dose was: C3H (97%) > B6C3F1 (76%) > C57BL (40% of mice at risk, i.e. those surviving at least 25 weeks; P
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enhanced generation of hydroxyl radical and sulfur trioxide anion radical from oxidation of sodium sulfite Nickel ii sulfite and Nickel Subsulfide in the presence of Nickel ii complexes
Environmental Health Perspectives, 1994Co-Authors: Xianglin Shi, N S Dalal, Kazimierz S KasprzakAbstract:Electron spin resonance (ESR) spin trapping was utilized to investigate the generation of free radicals from oxidation of sodium sulfite, Nickel(II) sulfite, and Nickel Subsulfide (Ni3S2) by ambient oxygen or H2O2 at pH 7.4. The spin trap used was 5,5-dimethyl-1-pyrroline-N-oxide (DMPO). Under ambient oxygen, a solution of sodium sulfite alone generated predominantly sulfur trioxide anion radical (.SO3-) due to the autoxidation of sulfite. Addition of Nickel(II) chloride [Ni(II)] enhanced the .SO3- yield about 4-fold. Incubation of sulfite with Ni(II) in the presence of chelators such as tetraglycine, histidine, beta-alanyl-3-methyl-L-histidine (anserine), beta--L-histidine (carnosine), gamma-aminobutyryl-L-histidine (homocarnosine), glutathione, and penicillamine did not have any significant effect on that enhancement. In contrast, albumin, and especially glycylglycylhistidine (GlyGlyHis), augmented the enhancing effect of Ni(II) by factors of 1.4 and 4, respectively. Computer simulation analysis of the spin-adduct spectrum and formate scavenging experiment showed that the mixture of sodium sulfite, Ni(II), and GlyGlyHis generated both hydroxyl (.OH) radical and .SO3- radical, in the ratio of approximately 1:2. The free-radical spin adduct intensity reached its saturation level in about 5 min. The yield of the radical adducts could be slightly reduced by deferoxamine and very strongly reduced by diethylenetriaminepentaacetic acid (DTPA). Aqueous suspensions of sparingly soluble Nickel(II) sulfite in the presence of air and GlyGlyHis generated surface-located .SO3- and .OH radicals. The same radicals were generated in Ni3S2 suspension in the presence of GlyGlyHis and H2O2, indicating sulfite production by oxidation of the sulfide moiety of this compound.(ABSTRACT TRUNCATED AT 250 WORDS)
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ggt to gtt transversions in codon 12 of the k ras oncogene in rat renal sarcomas induced with Nickel Subsulfide or Nickel Subsulfide iron are consistent with oxidative damage to dna
Cancer Research, 1992Co-Authors: Kathleen G Higinbotham, Bhalchandra A Diwan, Kazimierz S Kasprzak, Jerry M Rice, Carl D Reed, Alan O PerantoniAbstract:Abstract Nickel is a toxic, mutagenic, and carcinogenic metal of significant occupational and environmental concern. Although several cellular targets of Nickel have been identified, considerable evidence suggests that it can act indirectly upon DNA by inducing the formation of oxidized purines or pyrimidines that constitute promutagenic lesions. In this study, we examined Nickel Subsulfide (Ni3S2)- or Ni3S2/iron-induced renal sarcomas in F344 rats for the presence of transforming mutations in the K-ras oncogene. Selective oligonucleotide hybridization analysis of K-ras gene sequences amplified by polymerase chain reaction revealed that 1 of 12 primary tumors induced with Ni3S2 and 7 of 9 primary tumors induced with Ni3S2/iron contained exclusively GGT to GTT activating mutations in codon 12. These mutations are consistent with the known ability of Nickel, in the presence of an oxidizing agent, to catalyze formation of 8-hydroxydeoxyguanosine, which in turn promotes misincorporation of dATP opposite the oxidized guanine residue. The presence of GGT to GTT transversions was confirmed by direct sequencing of the polymerase chain reaction products. Sequencing also revealed that there were no transforming mutations in codons 13 or 59–61. Additionally, a direct correlation between shortened tumor latency and the presence of activating ras mutations was noted. These results show that, in rat kidney, Ni3S2 can induce transforming mutations that are consistent with the ability of Nickel to produce oxidative lesions and that iron, which exacerbates the extent of cellular oxidative damage, can enhance the frequency of these transforming mutations.
Janet M. Benson - One of the best experts on this subject based on the ideXlab platform.
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pulmonary toxicity of Nickel Subsulfide in f344 n rats exposed for 1 22 days
Toxicology, 1995Co-Authors: Janet M. Benson, A. F. Eidson, Yung-sung Cheng, Fletcher F. Hahn, Rogene F Henderson, John A. PickrellAbstract:Abstract Repeated inhalation of Nickel Subsulfide (Ni 3 S 2 ) by F344/N rats for 3 months results in chronic active inflammation in the lung and atrophy of the olfactory epithelium. The primary purpose of this study was to determine early responses of the respiratory tract to inhaled Ni 3 S 2 in rats and to track the course of development of such lesions in rats exposed for up to 22 days. A secondary purpose was to obtain an improved estimate of the half-time for clearance of Ni from Ni 3 S 2 -exposed lungs. Groups of F344/N rats were exposed to 0, 0.6 or 2.5 mg Ni 3 S 2 /m 3 , 6 h/day for 1–22 days. Histopathological changes in nose and lung, as well as biochemical and cytological changes in lung, as measured in bronchoalveolar lavage fluid (BALF) and lung tissue, alveolar macrophage (AM) viability and Ni concentration in lung were evaluated. Inflammatory lung lesions in rats exposed to 2.5 mg Ni 3 S 2 /m 3 peaked in intensity after 4 days of exposure. Minimal degeneration of the olfactory epithelium was noted in the 2.5 mg Ni 3 S 2 /m 3 -exposed rats after day 4 of exposure, with atrophy of the olfactory epithelium occurring in rats killed at 22 days. Lactate dehydrogenase, β-glucuronidase and total protein in BALF were significantly elevated within 7 days of exposure while alkaline phosphatase activity was significantly depressed. AM viability was significantly reduced after 2 days of exposure. Concentrations of Ni in lung increased rapidly during the first 7 days of exposure, but more slowly thereafter. Lung burden data from this and a previous study suggest a clearance half-time for Ni of 3.5–8 days. Results indicate that Ni 3 S 2 is relatively soluble in lung and inhalation of concentrations near the current Threshold Limit Value of 1 mg Ni/m 3 can produce detrimental changes in the respiratory tract of rats after only a few days of exposure.
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Comparative carcinogenic effects of Nickel Subsulfide, Nickel oxide, or Nickel sulfate hexahydrate chronic exposures in the lung.
Cancer research, 1995Co-Authors: June K. Dunnick, Janet M. Benson, Fletcher F. Hahn, Michael R. Elwell, Ann E. Radovsky, Kristan J. Nikula, Edward B. Barr, Charles H. HobbsAbstract:Abstract The relative toxicity and carcinogenicity of Nickel sulfate hexahydrate (NiSO 4 ·6H 2 O), Nickel Subsulfide (Ni 3 S 2 ), and Nickel oxide (NiO) were studied in F344/N rats and B6C3F 1 mice after inhalation exposure for 6 h/day, 5 days/week, for 2 years. Nickel Subsulfide (0.15 and 1 mg/m 3 ) and Nickel oxide (1.25 and 2.5 mg/m 3 ) caused an exposure-related increased incidence of alveolar/bronchiolar neoplasms and adrenal medulla neoplasms in male and female rats. Nickel oxide caused an equivocal exposure-related increase in alveolar/bronchiolar neoplasms in female mice. No exposure-related neoplastic responses occurred in rats or mice exposed to Nickel sulfate or in mice exposed to Nickel Subsulfide. These findings are consistent with results from other studies, which show that Nickel Subsulfide and Nickel oxide reach the nucleus in greater amounts than the do water-soluble Nickel compounds such as Nickel sulfate. It has been proposed that the more water-insoluble particles are phagocytized, whereas the vacuoles containing Nickel migrate to the nuclear membrane, where they release Nickel ions that effect DNA damage. The findings from these experimental studies show that chronic exposure to Nickel can cause lung neoplasms in rats, and that this response is related to exposure to specific types of Nickel compounds.
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fate of inhaled Nickel oxide and Nickel Subsulfide in f344 n rats
Inhalation Toxicology, 1994Co-Authors: Janet M. Benson, Yung-sung Cheng, Charles H. Hobbs, June K. Dunnick, Edward B. Barr, William E Bechtold, William Eastin, Christopher H Kennedy, Kirk R MaplesAbstract:AbstractThe fates of inhaled Nickel oxide (NiO, green oxide calcined at 1200°C) and Nickel Subsulfide (Ni3S2), two occupationally relevant Nickel compounds, have been studied in male F344/N rats. Groups of rats underwent pernasal exposure to 9.9 mg NiO/m3 or to 5.7 mg Ni3S2/m3 for 70 and 120 min, respectively. The activity median aerodynamic diameters (geometric standard deviation) of the NiO and Ni3S2 aerosols were 1.3 μm (2.0) and 1.3 μm (1.5), respectively. End points evaluated included total and regional respiratory tract deposition of the aerosols, lung clearance of deposited material, distribution of solubilized material to extrarespiratory tract tissue, and pathways of Ni excretion from the body. The fractions of the inhaled NiO and Ni3S2 aerosols that deposited in the respiratory tract were 0.11 and 0.13, respectively. The fractions of the inhaled aerosol that deposited in the lungs were 0.05 for both aerosols. Inhaled NiO cleared slowly from the lungs, with a half-life of approximately 120 days. ...
Charles H. Hobbs - One of the best experts on this subject based on the ideXlab platform.
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Comparative carcinogenic effects of Nickel Subsulfide, Nickel oxide, or Nickel sulfate hexahydrate chronic exposures in the lung.
Cancer research, 1995Co-Authors: June K. Dunnick, Janet M. Benson, Fletcher F. Hahn, Michael R. Elwell, Ann E. Radovsky, Kristan J. Nikula, Edward B. Barr, Charles H. HobbsAbstract:Abstract The relative toxicity and carcinogenicity of Nickel sulfate hexahydrate (NiSO 4 ·6H 2 O), Nickel Subsulfide (Ni 3 S 2 ), and Nickel oxide (NiO) were studied in F344/N rats and B6C3F 1 mice after inhalation exposure for 6 h/day, 5 days/week, for 2 years. Nickel Subsulfide (0.15 and 1 mg/m 3 ) and Nickel oxide (1.25 and 2.5 mg/m 3 ) caused an exposure-related increased incidence of alveolar/bronchiolar neoplasms and adrenal medulla neoplasms in male and female rats. Nickel oxide caused an equivocal exposure-related increase in alveolar/bronchiolar neoplasms in female mice. No exposure-related neoplastic responses occurred in rats or mice exposed to Nickel sulfate or in mice exposed to Nickel Subsulfide. These findings are consistent with results from other studies, which show that Nickel Subsulfide and Nickel oxide reach the nucleus in greater amounts than the do water-soluble Nickel compounds such as Nickel sulfate. It has been proposed that the more water-insoluble particles are phagocytized, whereas the vacuoles containing Nickel migrate to the nuclear membrane, where they release Nickel ions that effect DNA damage. The findings from these experimental studies show that chronic exposure to Nickel can cause lung neoplasms in rats, and that this response is related to exposure to specific types of Nickel compounds.
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fate of inhaled Nickel oxide and Nickel Subsulfide in f344 n rats
Inhalation Toxicology, 1994Co-Authors: Janet M. Benson, Yung-sung Cheng, Charles H. Hobbs, June K. Dunnick, Edward B. Barr, William E Bechtold, William Eastin, Christopher H Kennedy, Kirk R MaplesAbstract:AbstractThe fates of inhaled Nickel oxide (NiO, green oxide calcined at 1200°C) and Nickel Subsulfide (Ni3S2), two occupationally relevant Nickel compounds, have been studied in male F344/N rats. Groups of rats underwent pernasal exposure to 9.9 mg NiO/m3 or to 5.7 mg Ni3S2/m3 for 70 and 120 min, respectively. The activity median aerodynamic diameters (geometric standard deviation) of the NiO and Ni3S2 aerosols were 1.3 μm (2.0) and 1.3 μm (1.5), respectively. End points evaluated included total and regional respiratory tract deposition of the aerosols, lung clearance of deposited material, distribution of solubilized material to extrarespiratory tract tissue, and pathways of Ni excretion from the body. The fractions of the inhaled NiO and Ni3S2 aerosols that deposited in the respiratory tract were 0.11 and 0.13, respectively. The fractions of the inhaled aerosol that deposited in the lungs were 0.05 for both aerosols. Inhaled NiO cleared slowly from the lungs, with a half-life of approximately 120 days. ...
June K. Dunnick - One of the best experts on this subject based on the ideXlab platform.
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Comparative carcinogenic effects of Nickel Subsulfide, Nickel oxide, or Nickel sulfate hexahydrate chronic exposures in the lung.
Cancer research, 1995Co-Authors: June K. Dunnick, Janet M. Benson, Fletcher F. Hahn, Michael R. Elwell, Ann E. Radovsky, Kristan J. Nikula, Edward B. Barr, Charles H. HobbsAbstract:Abstract The relative toxicity and carcinogenicity of Nickel sulfate hexahydrate (NiSO 4 ·6H 2 O), Nickel Subsulfide (Ni 3 S 2 ), and Nickel oxide (NiO) were studied in F344/N rats and B6C3F 1 mice after inhalation exposure for 6 h/day, 5 days/week, for 2 years. Nickel Subsulfide (0.15 and 1 mg/m 3 ) and Nickel oxide (1.25 and 2.5 mg/m 3 ) caused an exposure-related increased incidence of alveolar/bronchiolar neoplasms and adrenal medulla neoplasms in male and female rats. Nickel oxide caused an equivocal exposure-related increase in alveolar/bronchiolar neoplasms in female mice. No exposure-related neoplastic responses occurred in rats or mice exposed to Nickel sulfate or in mice exposed to Nickel Subsulfide. These findings are consistent with results from other studies, which show that Nickel Subsulfide and Nickel oxide reach the nucleus in greater amounts than the do water-soluble Nickel compounds such as Nickel sulfate. It has been proposed that the more water-insoluble particles are phagocytized, whereas the vacuoles containing Nickel migrate to the nuclear membrane, where they release Nickel ions that effect DNA damage. The findings from these experimental studies show that chronic exposure to Nickel can cause lung neoplasms in rats, and that this response is related to exposure to specific types of Nickel compounds.
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fate of inhaled Nickel oxide and Nickel Subsulfide in f344 n rats
Inhalation Toxicology, 1994Co-Authors: Janet M. Benson, Yung-sung Cheng, Charles H. Hobbs, June K. Dunnick, Edward B. Barr, William E Bechtold, William Eastin, Christopher H Kennedy, Kirk R MaplesAbstract:AbstractThe fates of inhaled Nickel oxide (NiO, green oxide calcined at 1200°C) and Nickel Subsulfide (Ni3S2), two occupationally relevant Nickel compounds, have been studied in male F344/N rats. Groups of rats underwent pernasal exposure to 9.9 mg NiO/m3 or to 5.7 mg Ni3S2/m3 for 70 and 120 min, respectively. The activity median aerodynamic diameters (geometric standard deviation) of the NiO and Ni3S2 aerosols were 1.3 μm (2.0) and 1.3 μm (1.5), respectively. End points evaluated included total and regional respiratory tract deposition of the aerosols, lung clearance of deposited material, distribution of solubilized material to extrarespiratory tract tissue, and pathways of Ni excretion from the body. The fractions of the inhaled NiO and Ni3S2 aerosols that deposited in the respiratory tract were 0.11 and 0.13, respectively. The fractions of the inhaled aerosol that deposited in the lungs were 0.05 for both aerosols. Inhaled NiO cleared slowly from the lungs, with a half-life of approximately 120 days. ...
Peter Schmezer - One of the best experts on this subject based on the ideXlab platform.
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Nickel Subsulfide is genotoxic in vitro but shows no mutagenic potential in respiratory tract tissues of bigblue rats and muta mouse mice in vivo after inhalation
Mutation Research-genetic Toxicology and Environmental Mutagenesis, 1998Co-Authors: Claudia Mayer, R G Klein, H Wesch, Peter SchmezerAbstract:Abstract Carcinogenic Nickel compounds are known to induce promutagenic DNA lesions such as DNA strand breaks and DNA adducts in cultured mammalian cells. In standard mutation assays, in contrast, they were found to be either inactive or weakly active. In our in vitro mutation studies in a lacI transgenic embryonic fibroblast cell line, Nickel Subsulfide (Ni 3 S 2 ) increased mutation frequency up to 4.5-fold. We subsequently applied the comet assay and transgenic rodent mutation assays to investigate the DNA damaging effect and mutagenic potential of Nickel Subsulfide in target cells of carcinogenesis. A 2-h in vitro treatment of freshly isolated mouse nasal mucosa and lung cells with Nickel Subsulfide clearly induced DNA fragmentation in a concentration dependent manner. The strong effect was not seen in the same cell types following inhalative treatment of mice and rats, leading only in the mouse nasal mucosa to high DNA damage. When the same inhalative treatment was applied to lacZ and lacI transgenic mice and rats, the spontaneous mutation frequency of these target genes in the respiratory tissues was not increased. These results support a recently proposed non-genotoxic model of Nickel carcinogenesis, which acts through gene silencing via DNA methylation and chromatin condensation. This model may also explain our in vitro mutation data in the lacI transgenic cell line, in which Nickel Subsulfide increased mutation frequency, but in about one-third of the mutants, molecular analysis did not reveal any DNA sequence change in the coding region of the lacI gene despite of the phenotypic loss of its function.