The cycad genotoxin MAM modulates brain cellular pathways involved in neurodegenerative disease and cancer in a DNA damage-linked manner.

Abstract

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.

• Authors: Glen E Kisby, Rebecca C Fry, Michael R Lasarev, Theodor K Bammler, Richard P Beyer, Mona Churchwell, Daniel R Doerge, Lisiane B Meira, Valerie S Palmer, Ana-Luiza Ramos-Crawford, Xuefeng Ren, Robert C Sullivan, Terrance J Kavanagh, Leona D Samson, Helmut Zarbl, Peter S Spencer
• Journal: PloS one (PLoS One) Vol. 6 Issue 6 Pg. e20911 ( 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21731631 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Mutagens
• Transcription Factors
• Tumor Suppressor Proteins
• Guanosine
• Methylazoxymethanol Acetate
• 6'-O-methylguanosine
• DNA Modification Methylases
• MGMT protein, mouse
• DNA Repair Enzymes
• methylazoxymethanol

Topics

• Animals
• Binding Sites
• Brain (drug effects, metabolism)
• Brain Neoplasms (metabolism, pathology)
• Cycadopsida (chemistry)
• DNA Damage
• DNA Modification Methylases (deficiency, metabolism)
• DNA Repair Enzymes (deficiency, metabolism)
• Gene Expression Profiling
• Gene Regulatory Networks (drug effects)
• Guanosine (analogs & derivatives, metabolism)
• Humans
• Liver (drug effects, metabolism)
• Male
• Methylazoxymethanol Acetate (analogs & derivatives, toxicity)
• Mice
• Mice, Inbred C57BL
• Models, Biological
• Mutagens (toxicity)
• Neurodegenerative Diseases (metabolism, pathology)
• Organ Specificity (drug effects)
• Signal Transduction (drug effects)
• Transcription Factors (metabolism)
• Transcription, Genetic (drug effects)
• Tumor Suppressor Proteins (deficiency, metabolism)