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The Cycad Genotoxin MAM Modulates Brain Cellular Pathways Involved in Neurodegenerative Disease and Cancer in a DNA Damage-Linked Manner
Methylazoxymethanol (MAM), the genotoxic metabolite of the cycad azoxyglucoside cycasin, induces genetic alterations in bacteria, yeast, plants, insects and mammalian cells, but adult nerve cells are thought to be unaffected. We show that the brains of adult C57BL6 wild-type mice treated with a sing...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3121718/ https://www.ncbi.nlm.nih.gov/pubmed/21731631 http://dx.doi.org/10.1371/journal.pone.0020911 |
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author | Kisby, Glen E. Fry, Rebecca C. Lasarev, Michael R. Bammler, Theodor K. Beyer, Richard P. Churchwell, Mona Doerge, Daniel R. Meira, Lisiane B. Palmer, Valerie S. Ramos-Crawford, Ana-Luiza Ren, Xuefeng Sullivan, Robert C. Kavanagh, Terrance J. Samson, Leona D. Zarbl, Helmut Spencer, Peter S. |
author_facet | Kisby, Glen E. Fry, Rebecca C. Lasarev, Michael R. Bammler, Theodor K. Beyer, Richard P. Churchwell, Mona Doerge, Daniel R. Meira, Lisiane B. Palmer, Valerie S. Ramos-Crawford, Ana-Luiza Ren, Xuefeng Sullivan, Robert C. Kavanagh, Terrance J. Samson, Leona D. Zarbl, Helmut Spencer, Peter S. |
author_sort | Kisby, Glen E. |
collection | PubMed |
description | Methylazoxymethanol (MAM), the genotoxic metabolite of the cycad azoxyglucoside cycasin, induces genetic alterations in bacteria, yeast, plants, insects and mammalian cells, but adult nerve cells are thought to be unaffected. We show that the brains of adult C57BL6 wild-type mice treated with a single systemic dose of MAM acetate display DNA damage (O (6)-methyldeoxyguanosine lesions, O (6)-mG) that remains constant up to 7 days post-treatment. By contrast, MAM-treated mice lacking a functional gene encoding the DNA repair enzyme O (6)-mG DNA methyltransferase (MGMT) showed elevated O (6)-mG DNA damage starting at 48 hours post-treatment. The DNA damage was linked to changes in the expression of genes in cell-signaling pathways associated with cancer, human neurodegenerative disease, and neurodevelopmental disorders. These data are consistent with the established developmental neurotoxic and carcinogenic properties of MAM in rodents. They also support the hypothesis that early-life exposure to MAM-glucoside (cycasin) has an etiological association with a declining, prototypical neurodegenerative disease seen in Guam, Japan, and New Guinea populations that formerly used the neurotoxic cycad plant for food or medicine, or both. These findings suggest environmental genotoxins, specifically MAM, target common pathways involved in neurodegeneration and cancer, the outcome depending on whether the cell can divide (cancer) or not (neurodegeneration). Exposure to MAM-related environmental genotoxins may have relevance to the etiology of related tauopathies, notably, Alzheimer's disease. |
format | Online Article Text |
id | pubmed-3121718 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-31217182011-06-30 The Cycad Genotoxin MAM Modulates Brain Cellular Pathways Involved in Neurodegenerative Disease and Cancer in a DNA Damage-Linked Manner Kisby, Glen E. Fry, Rebecca C. Lasarev, Michael R. Bammler, Theodor K. Beyer, Richard P. Churchwell, Mona Doerge, Daniel R. Meira, Lisiane B. Palmer, Valerie S. Ramos-Crawford, Ana-Luiza Ren, Xuefeng Sullivan, Robert C. Kavanagh, Terrance J. Samson, Leona D. Zarbl, Helmut Spencer, Peter S. PLoS One Research Article Methylazoxymethanol (MAM), the genotoxic metabolite of the cycad azoxyglucoside cycasin, induces genetic alterations in bacteria, yeast, plants, insects and mammalian cells, but adult nerve cells are thought to be unaffected. We show that the brains of adult C57BL6 wild-type mice treated with a single systemic dose of MAM acetate display DNA damage (O (6)-methyldeoxyguanosine lesions, O (6)-mG) that remains constant up to 7 days post-treatment. By contrast, MAM-treated mice lacking a functional gene encoding the DNA repair enzyme O (6)-mG DNA methyltransferase (MGMT) showed elevated O (6)-mG DNA damage starting at 48 hours post-treatment. The DNA damage was linked to changes in the expression of genes in cell-signaling pathways associated with cancer, human neurodegenerative disease, and neurodevelopmental disorders. These data are consistent with the established developmental neurotoxic and carcinogenic properties of MAM in rodents. They also support the hypothesis that early-life exposure to MAM-glucoside (cycasin) has an etiological association with a declining, prototypical neurodegenerative disease seen in Guam, Japan, and New Guinea populations that formerly used the neurotoxic cycad plant for food or medicine, or both. These findings suggest environmental genotoxins, specifically MAM, target common pathways involved in neurodegeneration and cancer, the outcome depending on whether the cell can divide (cancer) or not (neurodegeneration). Exposure to MAM-related environmental genotoxins may have relevance to the etiology of related tauopathies, notably, Alzheimer's disease. Public Library of Science 2011-06-23 /pmc/articles/PMC3121718/ /pubmed/21731631 http://dx.doi.org/10.1371/journal.pone.0020911 Text en This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. |
spellingShingle | Research Article Kisby, Glen E. Fry, Rebecca C. Lasarev, Michael R. Bammler, Theodor K. Beyer, Richard P. Churchwell, Mona Doerge, Daniel R. Meira, Lisiane B. Palmer, Valerie S. Ramos-Crawford, Ana-Luiza Ren, Xuefeng Sullivan, Robert C. Kavanagh, Terrance J. Samson, Leona D. Zarbl, Helmut Spencer, Peter S. The Cycad Genotoxin MAM Modulates Brain Cellular Pathways Involved in Neurodegenerative Disease and Cancer in a DNA Damage-Linked Manner |
title | The Cycad Genotoxin MAM Modulates Brain Cellular Pathways Involved in Neurodegenerative Disease and Cancer in a DNA Damage-Linked Manner |
title_full | The Cycad Genotoxin MAM Modulates Brain Cellular Pathways Involved in Neurodegenerative Disease and Cancer in a DNA Damage-Linked Manner |
title_fullStr | The Cycad Genotoxin MAM Modulates Brain Cellular Pathways Involved in Neurodegenerative Disease and Cancer in a DNA Damage-Linked Manner |
title_full_unstemmed | The Cycad Genotoxin MAM Modulates Brain Cellular Pathways Involved in Neurodegenerative Disease and Cancer in a DNA Damage-Linked Manner |
title_short | The Cycad Genotoxin MAM Modulates Brain Cellular Pathways Involved in Neurodegenerative Disease and Cancer in a DNA Damage-Linked Manner |
title_sort | cycad genotoxin mam modulates brain cellular pathways involved in neurodegenerative disease and cancer in a dna damage-linked manner |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3121718/ https://www.ncbi.nlm.nih.gov/pubmed/21731631 http://dx.doi.org/10.1371/journal.pone.0020911 |
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