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...
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| Format: | Article |
| Language: | en_US |
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Public Library of Science
2011
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| Online Access: | http://hdl.handle.net/1721.1/65888 https://orcid.org/0000-0002-7112-1454 |
| _version_ | 1826206331518844928 |
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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. |
| author2 | Massachusetts Institute of Technology. Center for Environmental Health Sciences |
| author_facet | Massachusetts Institute of Technology. Center for Environmental Health Sciences 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 | MIT |
| 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 (O6-methyldeoxyguanosine lesions, O6-mG) that remains constant up to 7 days post-treatment. By contrast, MAM-treated mice lacking a functional gene encoding the DNA repair enzyme O6-mG DNA methyltransferase (MGMT) showed elevated O6-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. |
| first_indexed | 2024-09-23T13:27:28Z |
| format | Article |
| id | mit-1721.1/65888 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T13:27:28Z |
| publishDate | 2011 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | mit-1721.1/658882022-09-28T14:23:30Z 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. Massachusetts Institute of Technology. Center for Environmental Health Sciences Massachusetts Institute of Technology. Department of Biological Engineering Samson, Leona D. Samson, Leona D. Fry, Rebecca C. 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 (O6-methyldeoxyguanosine lesions, O6-mG) that remains constant up to 7 days post-treatment. By contrast, MAM-treated mice lacking a functional gene encoding the DNA repair enzyme O6-mG DNA methyltransferase (MGMT) showed elevated O6-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. National Institute of Environmental Health Sciences (ES11384 ) National Institute of Environmental Health Sciences (ES11399) National Institute of Environmental Health Sciences (ES011387) National Institute of Environmental Health Sciences (ES07033) 2011-09-19T15:11:45Z 2011-09-19T15:11:45Z 2011-06 2011-01 Article http://purl.org/eprint/type/JournalArticle 1932-6203 http://hdl.handle.net/1721.1/65888 Kisby, Glen E. et al. “The Cycad Genotoxin MAM Modulates Brain Cellular Pathways Involved in Neurodegenerative Disease and Cancer in a DNA Damage-Linked Manner.” Ed. Mel B. Feany. PLoS ONE 6 (2011): e20911. https://orcid.org/0000-0002-7112-1454 en_US http://dx.doi.org/10.1371/journal.pone.0020911 PLoS ONE Creative Commons Attribution http://creativecommons.org/licenses/by/2.5/ application/pdf Public Library of Science PLoS |
| spellingShingle | 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 |
| url | http://hdl.handle.net/1721.1/65888 https://orcid.org/0000-0002-7112-1454 |
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