Increased Levels of Inosine in a Mouse Model of Inflammation
One possible mechanism linking inflammation with cancer involves the generation of reactive oxygen, nitrogen, and halogen species by activated macrophages and neutrophils infiltrating sites of infection or tissue damage, with these chemical mediators causing damage that ultimately leads to cell deat...
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| Format: | Article |
| Language: | en_US |
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American Chemical Society
2014
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| Online Access: | http://hdl.handle.net/1721.1/88702 https://orcid.org/0000-0002-5811-6853 https://orcid.org/0000-0003-0011-3067 https://orcid.org/0000-0002-4607-5337 |
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| author | Prestwich, Erin Mangerich, Aswin Pang, Bo McFaline, Jose Luis Lonkar, Pallavi Sullivan, Matthew R. Trudel, Laura J. Taghizedeh, Koli Dedon, Peter C. |
| author2 | Massachusetts Institute of Technology. Center for Environmental Health Sciences |
| author_facet | Massachusetts Institute of Technology. Center for Environmental Health Sciences Prestwich, Erin Mangerich, Aswin Pang, Bo McFaline, Jose Luis Lonkar, Pallavi Sullivan, Matthew R. Trudel, Laura J. Taghizedeh, Koli Dedon, Peter C. |
| author_sort | Prestwich, Erin |
| collection | MIT |
| description | One possible mechanism linking inflammation with cancer involves the generation of reactive oxygen, nitrogen, and halogen species by activated macrophages and neutrophils infiltrating sites of infection or tissue damage, with these chemical mediators causing damage that ultimately leads to cell death and mutation. To determine the most biologically deleterious chemistries of inflammation, we previously assessed products across the spectrum of DNA damage arising in inflamed tissues in the SJL mouse model nitric oxide overproduction (Pang et al. (2007) Carcinogenesis28, 1807−1813). Among the anticipated DNA damage chemistries, we observed significant changes only in lipid peroxidation-derived etheno adducts. We have now developed an isotope-dilution, liquid chromatography-coupled, tandem quadrupole mass spectrometric method to quantify representative species across the spectrum of RNA damage products predicted to arise at sites of inflammation, including nucleobase deamination (xanthosine and inosine), oxidation (8-oxoguanosine), and alkylation (1,N6-ethenoadenosine). Application of the method to the liver, spleen, and kidney from the SJL mouse model revealed generally higher levels of oxidative background RNA damage than was observed in DNA in control mice. However, compared to control mice, RcsX treatment to induce nitric oxide overproduction resulted in significant increases only in inosine and only in the spleen. Further, the nitric oxide synthase inhibitor, N-methylarginine, did not significantly affect the levels of inosine in control and RcsX-treated mice. The differences between DNA and RNA damage in the same animal model of inflammation point to possible influences from DNA repair, RcsX-induced alterations in adenosine deaminase activity, and differential accessibility of DNA and RNA to reactive oxygen and nitrogen species as determinants of nucleic acid damage during inflammation. |
| first_indexed | 2024-09-23T11:09:21Z |
| format | Article |
| id | mit-1721.1/88702 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:09:21Z |
| publishDate | 2014 |
| publisher | American Chemical Society |
| record_format | dspace |
| spelling | mit-1721.1/887022022-09-27T17:31:34Z Increased Levels of Inosine in a Mouse Model of Inflammation Prestwich, Erin Mangerich, Aswin Pang, Bo McFaline, Jose Luis Lonkar, Pallavi Sullivan, Matthew R. Trudel, Laura J. Taghizedeh, Koli Dedon, Peter C. Massachusetts Institute of Technology. Center for Environmental Health Sciences Massachusetts Institute of Technology. Department of Biological Engineering Prestwich, Erin Mangerich, Aswin Pang, Bo McFaline, Jose Luis Lonkar, Pallavi Sullivan, Matthew R. Trudel, Laura J. Taghizedeh, Koli Dedon, Peter C. One possible mechanism linking inflammation with cancer involves the generation of reactive oxygen, nitrogen, and halogen species by activated macrophages and neutrophils infiltrating sites of infection or tissue damage, with these chemical mediators causing damage that ultimately leads to cell death and mutation. To determine the most biologically deleterious chemistries of inflammation, we previously assessed products across the spectrum of DNA damage arising in inflamed tissues in the SJL mouse model nitric oxide overproduction (Pang et al. (2007) Carcinogenesis28, 1807−1813). Among the anticipated DNA damage chemistries, we observed significant changes only in lipid peroxidation-derived etheno adducts. We have now developed an isotope-dilution, liquid chromatography-coupled, tandem quadrupole mass spectrometric method to quantify representative species across the spectrum of RNA damage products predicted to arise at sites of inflammation, including nucleobase deamination (xanthosine and inosine), oxidation (8-oxoguanosine), and alkylation (1,N6-ethenoadenosine). Application of the method to the liver, spleen, and kidney from the SJL mouse model revealed generally higher levels of oxidative background RNA damage than was observed in DNA in control mice. However, compared to control mice, RcsX treatment to induce nitric oxide overproduction resulted in significant increases only in inosine and only in the spleen. Further, the nitric oxide synthase inhibitor, N-methylarginine, did not significantly affect the levels of inosine in control and RcsX-treated mice. The differences between DNA and RNA damage in the same animal model of inflammation point to possible influences from DNA repair, RcsX-induced alterations in adenosine deaminase activity, and differential accessibility of DNA and RNA to reactive oxygen and nitrogen species as determinants of nucleic acid damage during inflammation. National Cancer Institute (U.S.) (CA116318) National Cancer Institute (U.S.) (CA026731) National Institute of Environmental Health Sciences (Bioanalytical Facilties Core of the MIT Center for Environmental Health Sciences (ES002109)) National Institute of Environmental Health Sciences (5T32-ES007020-34 NIEHS Training Grant in Environmental Toxicology) German Academic Exchange Service (Fellowship) 2014-08-14T20:22:29Z 2014-08-14T20:22:29Z 2013-04 2012-11 Article http://purl.org/eprint/type/JournalArticle 0893-228X 1520-5010 http://hdl.handle.net/1721.1/88702 Prestwich, Erin G., Aswin Mangerich, Bo Pang, Jose L. McFaline, Pallavi Lonkar, Matthew R. Sullivan, Laura J. Trudel, Koli Taghizedeh, and Peter C. Dedon. “Increased Levels of Inosine in a Mouse Model of Inflammation.” Chemical Research in Toxicology 26, no. 4 (April 15, 2013): 538–546. https://orcid.org/0000-0002-5811-6853 https://orcid.org/0000-0003-0011-3067 https://orcid.org/0000-0002-4607-5337 en_US http://dx.doi.org/10.1021/tx300473n Chemical Research in Toxicology Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Chemical Society PMC |
| spellingShingle | Prestwich, Erin Mangerich, Aswin Pang, Bo McFaline, Jose Luis Lonkar, Pallavi Sullivan, Matthew R. Trudel, Laura J. Taghizedeh, Koli Dedon, Peter C. Increased Levels of Inosine in a Mouse Model of Inflammation |
| title | Increased Levels of Inosine in a Mouse Model of Inflammation |
| title_full | Increased Levels of Inosine in a Mouse Model of Inflammation |
| title_fullStr | Increased Levels of Inosine in a Mouse Model of Inflammation |
| title_full_unstemmed | Increased Levels of Inosine in a Mouse Model of Inflammation |
| title_short | Increased Levels of Inosine in a Mouse Model of Inflammation |
| title_sort | increased levels of inosine in a mouse model of inflammation |
| url | http://hdl.handle.net/1721.1/88702 https://orcid.org/0000-0002-5811-6853 https://orcid.org/0000-0003-0011-3067 https://orcid.org/0000-0002-4607-5337 |
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