methylazoxymethanol and Brain-Neoplasms

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.

Topics: Animals; Binding Sites; Brain; Brain Neoplasms; Cycadopsida; DNA Damage; DNA Modification Methylases; DNA Repair Enzymes; Gene Expression Profiling; Gene Regulatory Networks; Guanosine; Humans; Liver; Male; Methylazoxymethanol Acetate; Mice; Mice, Inbred C57BL; Models, Biological; Mutagens; Neurodegenerative Diseases; Organ Specificity; Signal Transduction; Transcription Factors; Transcription, Genetic; Tumor Suppressor Proteins

Mutations in the region corresponding to the N-terminal phosphorylation sites (codons 1-51) of the rat beta-catenin gene (Ctnnb1) were investigated in rat colon tumors induced by 1-hydroxyanthraquinone (1-HA) plus methylazoxymethanol (MAM) acetate, by using polymerase chain reaction (PCR)-single-strand conformation polymorphism (SSCP) analysis. The beta-catenin gene was also screened for mutations in rat brain and oral tumors induced by ethyl nitrosourea (ENU) and 4-nitroquinoline 1-oxide (4-NQO), respectively. In colon tumors, beta-catenin gene mutations were found in two of three adenomas (67%) and 26 of 28 adenocarcinomas (93%), with a total incidence of 90% (28 of 31 adenomas plus adenocarcinomas). Eight (29%) were (34)G-->T (second position), eight (29%) were (32)G-->A (first position), five (18%) were (34)G-->A (first position), five (18%) were (41)C-->T (second position), one (4%) was (34)G-->A (second position), and one (4%) was (32)A-->G (second position), mutations, resulting in the substitutions of Gly(34)-->Val, Asp(32)-->Asn, Gly(34)-->Arg, Thr(41)-->Ile, Gly(34)-->Glu, and Asp(32)-->Gly, respectively. The (34)G-->T (second position) mutations found in this study were unique compared to those found in other carcinogen-induced rat colon carcinogenesis models. In contrast, beta-catenin gene mutations were not found in either the brain or oral tumors. These results suggest that mutations in the beta-catenin gene in rat tumors occur in specific tissues or organ sites and in a carcinogen-specific manner. Thus, the mutation spectrum in the beta-catenin gene is organ- and chemical carcinogen-specific.

Topics: 4-Nitroquinoline-1-oxide; Animals; Anthraquinones; beta Catenin; Brain Neoplasms; Carcinogens; Colonic Neoplasms; Cytoskeletal Proteins; Genetic Markers; Male; Methylazoxymethanol Acetate; Mouth Neoplasms; Mutation; Nitrosourea Compounds; Organ Specificity; Polymerase Chain Reaction; Quinolones; Rats; Rats, Inbred F344; Trans-Activators