Utilization of DNA-protein cross-links as a biomarker of chromium exposure.

Zhitkovich, Anatoly; Voitkun, Victoria; Kluz, Tomasz; Costa, Max

doi:10.1289/ehp.98106s4969

Cited by 55 publications

(36 citation statements)

References 50 publications

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“…DNA-Protein and DNA Interstrand Cross-Links. The formation of DNA-protein cross-links (DPC) by Cr(VI) is well established in various biological systems (188,189) and in the in Vitro reactions (190). The overall yield of DPC in cells was estimated to be less than 1% of all Cr-DNA adducts, but it could be significantly higher in Vitro (133).…”

Section: Human Exposure and Carcinogenicitymentioning

confidence: 99%

Genetic and Epigenetic Mechanisms in Metal Carcinogenesis and Cocarcinogenesis: Nickel, Arsenic, and Chromium

Salnikow

Zhitkovich

2007

Chem. Res. Toxicol.

816

539

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Chronic exposure to nickel(II), chromium(VI), or inorganic arsenic (iAs) has long been known to increase cancer incidence among affected individuals. Recent epidemiological studies have found that carcinogenic risks associated with chromate and iAs exposures were substantially higher than previously thought, which led to major revisions of the federal standards regulating ambient and drinking water levels. Genotoxic effects of Cr(VI) and iAs are strongly influenced by their intracellular metabolism, which creates several reactive intermediates and byproducts. Toxic metals are capable of potent and surprisingly selective activation of stress-signaling pathways, which are known to contribute to the development of human cancers. Depending on the metal, ascorbate (vitamin C) has been found to act either as a strong enhancer or suppressor of toxic responses in human cells. In addition to genetic damage via both oxidative and nonoxidative (DNA adducts) mechanisms, metals can also cause significant changes in DNA methylation and histone modifications, leading to epigenetic silencing or reactivation of gene expression. In vitro genotoxicity experiments and recent animal carcinogenicity studies provided strong support for the idea that metals can act as cocarcinogens in combination with nonmetal carcinogens. Cocarcinogenic and comutagenic effects of metals are likely to stem from their ability to interfere with DNA repair processes. Overall, metal carcinogenesis appears to require the formation of specific metal complexes, chromosomal damage, and activation of signal transduction pathways promoting survival and expansion of genetically/epigenetically altered cells.

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Section: Human Exposure and Carcinogenicitymentioning

confidence: 99%

Genetic and Epigenetic Mechanisms in Metal Carcinogenesis and Cocarcinogenesis: Nickel, Arsenic, and Chromium

Salnikow

Zhitkovich

2007

Chem. Res. Toxicol.

816

539

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“…The greatest human exposures are from industrial uses, including chromate pigments, zinc chromate primer paints and other corrosion inhibitors, stainless steel machining and welding, chrome plating, leather tanning, and others. These industrial uses also result in the annual release of more than 10 5 tons of Cr, and Cr has become a contaminant of significant concern at many sites in the United States (Gadd and White, 1993;Zhitkovich et al, 1998;EPA, 1999).…”

Section: Introductionmentioning

confidence: 99%

Hexavalent chromium causes the oxidation of thioredoxin in human bronchial epithelial cells

2008

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Hexavalent chromium [Cr(VI)] species such as chromates are cytotoxic. Inhalational exposure is a primary concern in many Cr-related industries and their immediate environments, and bronchial epithelial cells are directly exposed to inhaled Cr(VI). Chromates are readily taken up by cells and are reduced to reactive Cr species which may also result in the generation of reactive oxygen species (ROS). The thioredoxin (Trx) system has a key role in the maintenance of cellular thiol redox balance and is essential for cell survival. Cells normally maintain the cytosolic (Trx1) and mitochondrial (Trx2) thioredoxins largely in the reduced state. Redox western blots were used to assess the redox status of the thioredoxins in normal human bronchial epithelial cells (BEAS-2B) incubated with soluble Na 2 CrO 4 or insoluble ZnCrO 4 for different periods of time. Both chromates caused a doseand time-dependent oxidation of Trx2 and Trx1. Trx2 was more susceptible in that it could all be converted to the oxidized form, whereas a small amount of reduced Trx1 remained even after prolonged treatment with higher Cr concentrations. Only one of the dithiols, presumably the active site, of Trx1 was oxidized by Cr(VI). Cr(VI) did not cause significant GSH depletion or oxidation indicating that Trx oxidation does not result from a general oxidation of cellular thiols. With purified Trx and thioredoxin reductase (TrxR) in vitro, Cr(VI) also resulted in Trx oxidation. It was determined that purified TrxR has pronounced Cr(VI) reducing activity, so competition for electron flow from TrxR might impair its ability to reduce Trx. The in vitro data also suggested some direct redox interaction between Cr(VI) and Trx. The ability of Cr(VI) to cause Trx oxidation in cells could contribute to its cytotoxic effects, and could have important implications for cell survival, redoxsensitive cell signaling, and the cells' tolerance of other oxidant insults.

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“…Environmental exposure to Cr is also of increasing concern. Greater than 10 5 tons of Cr are released annually into the environment, and Cr is a significant contaminant at many sites across the U.S.A., including at hundreds of Superfund sites [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Reduction of hexavalent chromium by human cytochrome b5: Generation of hydroxyl radical and superoxide

Borthiry

Antholine

Kalyanaraman

et al. 2007

Free Radical Biology and Medicine

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The reduction of hexavalent chromium, Cr(VI), can generate reactive Cr intermediates and various types of oxidative stress. The potential role of human microsomal enzymes in free radical generation was examined using reconstituted proteoliposomes (PLs) containing purified cytochrome b 5 and NADPH:P450 reductase. Under aerobic conditions, the PLs reduced Cr(VI) to Cr(V) which was confirmed by ESR using isotopically pure 53 Cr(VI). When 5-Diethoxyphos-phoryl-5-methyl-1-pyrroline-N-oxide (DEPMPO) was included as a spin trap, a very prominent signal for the hydroxyl radical (HO • ) adduct was observed as well as a smaller signal for the superoxide (O 2 •− ) adduct. These adducts were observed even at very low Cr(VI) concentrations (10 μM). NADPH, Cr(VI), O 2 and the PLs were all required for significant HO • generation. Superoxide dismutase eliminated the O 2 • − adduct and resulted in a 30% increase in the HO • adduct. Catalase largely diminished the HO • adduct signal indicating its dependence on H 2 O 2 . Some sources of catalase were found to have Cr(VI)-reducing contaminants which could confound results, but a source of catalase free of these contaminants was used for these studies. Exogenous H 2 O 2 was not needed, indicating that it was generated by the PLs. Adding exogenous H 2 O 2 , however, did increase the amount of DEPMPO/ HO • adduct. The inclusion of formate yielded the carbon dioxide radical adduct of DEPMPO, and experiments with dimethylsulfoxide (DMSO) plus the spin trap α-phenyl-N-tert-butylnitrone (PBN) yielded the methoxy and methyl radical adducts of PBN, confirming the generation of HO • . Quantification of the various species over time was consistent with a stoichiometric excess of HO • relative to the net amount of Cr(VI) reduced. This also represents the first demonstration of a role for cytochrome b 5 in the generation of HO • . Overall, the simultaneous generation of Cr(V) and H 2 O 2 by the PLs and the resulting generation of HO • at low Cr(VI) concentrations could have important implications for Cr(VI) toxicity.

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Utilization of DNA-protein cross-links as a biomarker of chromium exposure.

Cited by 55 publications

References 50 publications

Genetic and Epigenetic Mechanisms in Metal Carcinogenesis and Cocarcinogenesis: Nickel, Arsenic, and Chromium

Genetic and Epigenetic Mechanisms in Metal Carcinogenesis and Cocarcinogenesis: Nickel, Arsenic, and Chromium

Hexavalent chromium causes the oxidation of thioredoxin in human bronchial epithelial cells

Reduction of hexavalent chromium by human cytochrome b5: Generation of hydroxyl radical and superoxide

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