ArticleEnvironmental health perspectives2016
Different ATM Signaling in Response to Chromium(VI) Metabolism via Ascorbate and Nonascorbate Reduction: Implications for in Vitro Models and Toxicogenomics.
Article in Environmental health perspectives, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 24 citations in OpenAlex.
- Hexavalent-Chromium-Induced Disruption of Mitochondrial Dynamics and Apoptosis in the Liver via the AMPK-PGC-1α Pathway in Ducks.International journal of molecular sciences · 2023Article
- ATR activation by Cr-DNA damage is a major survival response establishing late S and G2 checkpoints after Cr(VI) exposure.Toxicology and applied pharmacology · 2023Article
- Chemical mechanisms of DNA damage by carcinogenic chromium(VI).Advances in pharmacology (San Diego, Calif.) · 2023Article
- Ascorbate: antioxidant and biochemical activities and their importance for in vitro models.Archives of toxicology · 2021Review
- Nuclear and Cytoplasmic Functions of Vitamin C.Chemical research in toxicology · 2020Review
- A Novel Transcriptome Integrated Network Approach Identifies the Key Driver lncRNA Involved in Cell Cycle With Chromium (VI)-Treated BEAS-2B Cells.Frontiers in genetics · 2020Article
- Vitamin C increases DNA breaks and suppresses DNA damage-independent activation of ATM by bleomycin.Free radical biology & medicine · 2019Article
- Vitamin C as a Modulator of the Response to Cancer Therapy.Molecules (Basel, Switzerland) · 2019Review
- Toxicological Antagonism among Welding Fume Metals: Inactivation of Soluble Cr(VI) by Iron.Chemical research in toxicology · 2018Article
- Tdp1 processes chromate-induced single-strand DNA breaks that collapse replication forks.PLoS genetics · 2018Article
- Variation in Extracellular Detoxification Is a Link to Different Carcinogenicity among Chromates in Rodent and Human Lungs.Chemical research in toxicology · 2017Article
- Nickel-induced HIF-1α promotes growth arrest and senescence in normal human cells but lacks toxic effects in transformed cells.Toxicology and applied pharmacology · 2017Article
- High-Throughput Screening Data Interpretation in the Context of In Vivo Transcriptomic Responses to Oral Cr(VI) Exposure.Toxicological sciences : an official journal of the Society of Toxicology · 2017Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
backgroundCarcinogenic hexavalent chromium [Cr(VI)] requires cellular reduction to generate DNA damage. Metabolism of Cr(VI) by its principal reducer ascorbate (Asc) lacks a Cr(V) intermediate, which is abundant in reactions with a minor reducing agent, glutathione. Cultured cells are widely used in mechanistic studies of Cr(VI) toxicity; however, they typically contain < 1% of normal Asc levels. Asc deficiency is also expected to diminish protection against reactive oxygen species.
objectivesWe assessed how the presence of Asc in cells affects their stress signaling and survival responses to chromate.
methodsWe investigated the effects of Asc restoration in human lung H460 cells and normal human lung fibroblasts on the activation and functional role of ATM kinase, which controls DNA damage responses involving several hundreds of proteins.
resultsTreatment of standard cultures with Cr(VI) strongly activated ATM, as indicated by its automodification at Ser1981 and by phosphorylation of checkpoint kinase 2 (CHK2) and chromatin/transcription regulator KRAB-associated protein 1 (KAP1). Confirming the importance of activated ATM, its inhibition impaired replication recovery and clonogenic survival. In contrast, fully Asc-restored cells lacked ATM activation by Cr(VI), and ATM silencing produced no significant effects on p53 stabilization, apoptosis, replication recovery, or clonogenic survival. Dose dependence studies found a close correlation between ATM activation and the extent of Cr(VI) reduction by glutathione.
conclusionsAsc restoration in cultured cells dramatically altered their stress responses to Cr(VI) by preventing activation of the oxidant-sensitive ATM network. We suggest that toxicogenomic and other cell response-based approaches likely underestimate Cr(VI) genotoxicity when standard ATM-activating carcinogens are used as references. CITATION: Luczak MW, Green SE, Zhitkovich A. 2016. Different ATM signaling in response to chromium(VI) metabolism via ascorbate and nonascorbate reduction: implications for in vitro models and toxicogenomics. Environ Health Perspect 124:61-66; http://dx.doi.org/10.1289/ehp.1409434.
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