Genomic and proteomic profiling of responses to toxic metals in human lung cells.

Andrew, Angeline S.; Warren, Amy J.; Barchowsky, Aaron; Temple, Kaili A; Klei, Linda R.; Soucy, Nicole V.; O’Hara, Kimberley A.; Hamilton, Joshua W.

doi:10.1289/ehp.111-1241504

Cited by 196 publications

(68 citation statements)

References 47 publications

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“…A similar observation was reported following arsenic exposure in a human lung cell line. At low concentrations, the arsenic response was distinct but a higher dose caused a very different gene expression profile composed of mostly general stress response genes (12). Another study in rainbow trout fry reported similar gene expression profiles in response to high doses of four different toxicants ( -naphthoflavone ( NF), Cd, CCl4, and pyrene).…”

Section: Resultsmentioning

confidence: 99%

Gene Expression Profiling in Daphnia magna Part I: Concentration-Dependent Profiles Provide Support for the No Observed Transcriptional Effect Level

Poynton

Loguinov

Varshavsky

et al. 2008

Environ. Sci. Technol.

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Ecotoxicogenomic approaches to environmental monitoring provide holistic information, offer insight into modes of action, and help to assess the causal agents and potential toxicity of effluents beyond the traditional end points of death and reproduction. Recent investigations of toxicant exposure indicate dose-dependent changes are a key issue in interpreting genomic studies. Additionally, there is interest in developing methods to integrate gene expression studies in environmental monitoring and regulation, and the No Observed Transcriptional Effect Level (NOTEL) has been proposed as a means for screening effluents and unknown chemicals for toxicity. However, computational methods to determine the NOTEL have yet to be established. Therefore, we examined effects on gene expression in Daphnia magna following exposure to Cu, Cd, and Zn over a range of concentrations including a tolerated, a sublethal, and a nearly acutely toxic concentration. Each concentration produced a distinct gene expression profile. We observed differential expression of a very few genes at tolerated concentrations that were distinct from the expression profiles observed at concentrations associated with toxicity. These results suggest that gene expression analysis may offer a strategy for distinguishing toxic and nontoxic concentrations of metals in the environment and provide support for a NOTEL for metal exposure in D. magna. Mechanistic insights could be inferred from the concentration-dependent gene expression profiles including metal specific effects on disparate metabolic processes such as digestion, immune response, development and reproduction, and less specific stress responses at higher concentrations.

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Section: Resultsmentioning

confidence: 99%

Gene Expression Profiling in Daphnia magna Part I: Concentration-Dependent Profiles Provide Support for the No Observed Transcriptional Effect Level

Poynton

Loguinov

Varshavsky

et al. 2008

Environ. Sci. Technol.

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“…As mentioned previously, it has been reported that carcinogenic metals including Cd and Ni exhibited different patterns of gene expressions and had different carcinogenic mechanisms [Bartosiewicz et al, 2001;Andrew et al, 2003]. Hence, the gene alterations that were considered to be associated with carcinogenesis have not been shown directly.…”

Section: Discussionmentioning

confidence: 99%

“…Bartosiewicz et al [2001] have shown that cadmium chroride, Benzo[a]pyrene, and trichloroethylene exhibited different patterns of gene expression in the livers of exposed mice. Likewise, Andrew et al [2003] reported that cadmium chloride, sodium dichromate, and nickel subsulfide altered only a few genes that overlapped with DNA-cross-linker mitomycin C in human lung cells. Thus, these metals induced quite different gene expression patterns from the ones genotoxic and nongenotoxic carcinogens did, indicating a different class of carcinogen.…”

Section: Introductionmentioning

confidence: 97%

Comparison of gene expression profiles in HepG2 cells exposed to arsenic, cadmium, nickel, and three model carcinogens for investigating the mechanisms of metal carcinogenesis

Kawata

Shimazaki

Okabe

2008

Environ and Mol Mutagen

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Carcinogenesis is an important chronic toxicity of metals and metalloids, although their mechanisms of action are still unclear. Comparison of gene expression patterns induced by carcinogenic metals, metalloids, and model carcinogens would give an insight into understanding of their carcinogenic mechanisms. In this study, we examined the gene expression alteration in human hepatoma cell line, HepG2, after exposing to two metals (cadmium and nickel), a metalloid (arsenic), and three model carcinogenic chemicals N-dimethylnitrosoamine (DMN), 12-O-tetradecanoylphorbol-13-acetate (TPA), and tetrachloroethylene (TCE) using DNA microarrays with 8,795 human genes. Of the genes altered by As, Cd, and Ni exposures, 31-55% were overlapped with those altered by three model carcinogenic chemical exposures in our experiments. In particular, the metals and metalloid shared certain characteristics with TPA and TCE in remarkable upregulations of the genes associated with progression of cell cycle, which might play a central role in As, Cd, and Ni carcinogenesis. This characteristic of gene expression alteration was partially counteracted by intracellular accumulation of vitamin C in Asexposed cells, whereas the number of cell-cycle associated genes was increased in Cd-and Niexposed cells. In our experimental conditions, ROS might have an accelerative effect on the cell proliferation mechanisms of As, but have an inhibitory effect on those of other two heavy metals. Furthermore, based on the results of Q-PCR, the oncogene PTTG1, which was upregulated by all carcinogenic chemical exposures in the array experiments, might be a useful biomarker for evaluation of the carcinogenesis of inorganic carcinogens. Environ. Mol. Mutagen. 50:46-59, 2009.

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“…The c-Jun N-terminal kinase (JNK) is selectively activated in A549 cells by 10 μM Cr(VI), and pre-exposure of cells to N-acetylcysteine prevents this activation [68]. This level of Cr(VI) is also sufficient to alter the expression of dozens of genes [88] and to induce apoptosis in BEAS-2B (normal human bronchial epithelial) cells [89], and it causes extensive cell death in primary human fibroblasts [90].…”

Section: Discussionmentioning

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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Genomic and proteomic profiling of responses to toxic metals in human lung cells.

Cited by 196 publications

References 47 publications

Gene Expression Profiling in Daphnia magna Part I: Concentration-Dependent Profiles Provide Support for the No Observed Transcriptional Effect Level

Gene Expression Profiling in Daphnia magna Part I: Concentration-Dependent Profiles Provide Support for the No Observed Transcriptional Effect Level

Comparison of gene expression profiles in HepG2 cells exposed to arsenic, cadmium, nickel, and three model carcinogens for investigating the mechanisms of metal carcinogenesis

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

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