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 (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.

Neurotoxicity may be an overlooked consequence of benzo[a]pyrene exposure that is relevant to human health risk assessment

“…This comparison could then be anchored to the traditional assays, measuring the risk for the two adverse outcomes. If the conclusion of Kisby and co-workers [41] can be extrapolated to BaP-mediated neurotoxicity and DNA damage is, indeed, an important component of the neurotoxic MOA of BaP, future studies should explore whether genotoxins, in general, are also neurotoxins.…”

“…This has led to the hypothesis that neuronal degeneration arises as a result of progressive accumulation of unrepaired DNA lesions [40]. As we describe briefly in Section 3.2, it has been suggested that cancer and neurodegenerative disease are ''two sides of the same coin'' and the ultimate outcome depends on the presence or absence of active division within the exposed tissues (e.g., hepatocytes vs. non-dividing, post-mitotic neurons [41]). This hypothesis has been supported by the finding that DNA repair-deficient adult C57BL6 mice challenged with a genotoxic compound show perturbed gene expression in the brain that is related to both cancer and neurodegenerative/neurodevelopmental disorders [41].…”

“…As we describe briefly in Section 3.2, it has been suggested that cancer and neurodegenerative disease are ''two sides of the same coin'' and the ultimate outcome depends on the presence or absence of active division within the exposed tissues (e.g., hepatocytes vs. non-dividing, post-mitotic neurons [41]). This hypothesis has been supported by the finding that DNA repair-deficient adult C57BL6 mice challenged with a genotoxic compound show perturbed gene expression in the brain that is related to both cancer and neurodegenerative/neurodevelopmental disorders [41]. To determine if neurotoxicity and carcinogenicity may be the ''two sides of the same coin'' for BaP as well, the comparison of gene expression profiles, especially for the DNA damage/repair pathway genes of brain and peripheral tissues that are at risk for ''neurotoxicity'' and carcinogenesis, respectively, should be conducted.…”

“…It has been suggested that the mechanisms leading to longlasting consequences of human and rodent exposure to environmental genotoxins are related to the stimulation of neuronal mRNA expression of tau, which triggers taupathy, a slowlyprogressing disease related to atypical Parkinsonism and Alzheimer's dementia [41]. Moreover, as described above, it has been suggested that cancer and neurodegenerative disease are different outcomes of similar perturbations as certain genotoxins (e.g., methylazoxymethanol (MAM)) target cell signalling pathways that are common to neurodegeneration and cancer and the outcome depends on the presence (cancer) or absence (neurodegeneration) of active cell division [41].…”

“…Moreover, as described above, it has been suggested that cancer and neurodegenerative disease are different outcomes of similar perturbations as certain genotoxins (e.g., methylazoxymethanol (MAM)) target cell signalling pathways that are common to neurodegeneration and cancer and the outcome depends on the presence (cancer) or absence (neurodegeneration) of active cell division [41]. Shared signalling pathways that are associated with MAM-induced colon cancer and brain diseases include transforming growth factor-beta (TGF-beta), wingless and proto-oncogene Int-1 (Wnt), and mitogen-activated protein kinase (MAPK) [41].…”