Development of a mechanistically-based genetically engineered PC12 cell system to detect p53-mediated cytotoxicity

Vliet, Erwin van; Eskes, Chantra; Stingele, Silvia; Gartlon, Joanne; Price, Anna; Farina, Massimo; Ponti, Jessica; Hartung, Thomas; Sabbioni, E.; Coecke, Sandra

doi:10.1016/j.tiv.2006.12.004

Cited by 7 publications

(4 citation statements)

References 33 publications

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“…5 ): triadimefon had a relatively modest influence on the transcriptome, compared to PBDE-99; while the latter one mainly upregulated transcripts, arsenite predominantly downregulated gene activity. However, arsenic trioxide also upregulated some transcripts and these pointed, for instance, to the activation of the p53 pathway, which has been implicated earlier in arsenite toxicity (van Vliet et al 2007 ).…”

Section: Resultsmentioning

confidence: 86%

Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration

et al. 2015

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The in vitro test battery of the European research consortium ESNATS (‘novel stem cell-based test systems’) has been used to screen for potential human developmental toxicants. As part of this effort, the migration of neural crest (MINC) assay has been used to evaluate chemical effects on neural crest function. It identified some drug-like compounds in addition to known environmental toxicants. The hits included the HSP90 inhibitor geldanamycin, the chemotherapeutic arsenic trioxide, the flame-retardant PBDE-99, the pesticide triadimefon and the histone deacetylase inhibitors valproic acid and trichostatin A. Transcriptome changes triggered by these substances in human neural crest cells were recorded and analysed here to answer three questions: (1) can toxicants be individually identified based on their transcript profile; (2) how can the toxicity pattern reflected by transcript changes be compacted/dimensionality-reduced for practical regulatory use; (3) how can a reduced set of biomarkers be selected for large-scale follow-up? Transcript profiling allowed clear separation of different toxicants and the identification of toxicant types in a blinded test study. We also developed a diagrammatic system to visualize and compare toxicity patterns of a group of chemicals by giving a quantitative overview of altered superordinate biological processes (e.g. activation of KEGG pathways or overrepresentation of gene ontology terms). The transcript data were mined for potential markers of toxicity, and 39 transcripts were selected to either indicate general developmental toxicity or distinguish compounds with different modes-of-action in read-across. In summary, we found inclusion of transcriptome data to largely increase the information from the MINC phenotypic test.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-015-1658-7) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 86%

Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration

et al. 2015

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“…Previous studies have shown that exposure to metals inducing a p53-mediated response results in increased apoptosis in the presence of p53 [14]. Based on this observation, we hypothesized that Hct116 (p53 +/+) cells would exhibit increased uranyl toxicity compared to Hct116 (p53 −/−) cells if uranyl complexes induced a p53-mediated response.…”

Section: Resultsmentioning

confidence: 92%

“…Hct116 (p53 +/+) and Hct116 (p53 −/−) cells were treated with increasing concentrations of both uranyl acetate and uranyl nitrate for 48 h. Treated cells were counted immediately after treatment as a measure of acute toxicity and colony-forming ability was determined as a measure of genotoxicity. Boric acid was chosen as a negative control as it has been shown to not induce any p53 mediated effects [14], while hydrogen peroxide was used as a positive control. Hydrogen peroxide is a well-known activator of p53 through the generation of oxidative stress and has been shown to be both genotoxic and mutagenic, making it a suitable control for p53-mediated effects.…”

Section: Resultsmentioning

confidence: 99%

“…Sodium dichromate exposure induces posttranslational phosphorylation of Ser15 and acetylation of Lys382 in p53, known signals of p53 activation. Manganese (II) chloride and cadmium sulfate initiate p53-mediated apoptotic pathways [14] and inhibit DNA synthesis in a ATM-independent manner [15], while vanadate induces cell growth arrest through a p53-mediated pathway [16]. While there is reasonable evidence to suggest a p53-mediated response to metal exposure, there remains a limited understanding of the molecular mechanism of this response.…”

Section: Introductionmentioning

confidence: 99%

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Toxicity of depleted uranium complexes is independent of p53 activity

Heintze

Aguilera

Davis

et al. 2011

Journal of Inorganic Biochemistry

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The p53 tumor suppressor protein is one of the key checkpoints in cellular response to a variety of stress mechanisms, including exposure to various toxic metal complexes. Previous studies have demonstrated that arsenic and chromium complexes are able to activate p53, but there is a dearth of data investigating whether uranium complexes exhibit similar effects. The use of depleted uranium (DU) has increased in recent years, raising concern about DU’s potential carcinogenic effects. Previous studies have shown that uranyl acetate and uranyl nitrate are capable of inducing DNA strand breaks and potentially of inducing oxidative stress through free radical generation, two potential mechanisms for activation of p53. Based on these studies, we hypothesized that either uranyl acetate or uranyl nitrate could act as an activator of p53. We tested this hypothesis using a combination of cytotoxicity assays, p53 activity assays, western blotting and flow cytometry. All of our results demonstrate that there is not a p53-mediated response to either uranyl acetate or uranyl nitrate, demonstrating that any cellular response to uranium exposure likely occurs in a p53-independent fashion under the conditions studied.

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