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

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

Research output: Contribution to journalArticle

26 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere20911
JournalPloS one
Volume6
Issue number6
DOIs
StatePublished - Jun 29 2011

Fingerprint

Neurodegenerative diseases
Cycadopsida
cycasin
Mutagens
neurodegenerative diseases
lesions (animal)
Neurodegenerative Diseases
DNA damage
DNA Damage
Brain
brain
neoplasms
Cycasin
DNA
Guam
Neoplasms
New Guinea
mice
methyltransferases
cells

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Kisby, G. E., Fry, R. C., Lasarev, M. R., Bammler, T. K., Beyer, R. P., Churchwell, M., ... Spencer, P. S. (2011). The cycad genotoxin MAM modulates brain cellular pathways involved in neurodegenerative disease and cancer in a DNA damage-linked manner. PloS one, 6(6), [e20911]. https://doi.org/10.1371/journal.pone.0020911
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. In: PloS one. 2011 ; Vol. 6, No. 6.
@article{aeff50a696cb4725a2e67e7e695580f2,
title = "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.",
author = "Kisby, {Glen E.} and Fry, {Rebecca C.} and Lasarev, {Michael R.} and Bammler, {Theodor K.} and Beyer, {Richard P.} and Mona Churchwell and Doerge, {Daniel R.} and Meira, {Lisiane B.} and Palmer, {Valerie S.} and Ramos-Crawford, {Ana Luiza} and Xuefeng Ren and Sullivan, {Robert C.} and Kavanagh, {Terrance J.} and Samson, {Leona D.} and Helmut Zarbl and Spencer, {Peter S.}",
year = "2011",
month = "6",
day = "29",
doi = "10.1371/journal.pone.0020911",
language = "English (US)",
volume = "6",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "6",

}

Kisby, GE, Fry, RC, Lasarev, MR, Bammler, TK, Beyer, RP, Churchwell, M, Doerge, DR, Meira, LB, Palmer, VS, Ramos-Crawford, AL, Ren, X, Sullivan, RC, Kavanagh, TJ, Samson, LD, Zarbl, H & Spencer, PS 2011, 'The cycad genotoxin MAM modulates brain cellular pathways involved in neurodegenerative disease and cancer in a DNA damage-linked manner', PloS one, vol. 6, no. 6, e20911. https://doi.org/10.1371/journal.pone.0020911

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.

In: PloS one, Vol. 6, No. 6, e20911, 29.06.2011.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The cycad genotoxin MAM modulates brain cellular pathways involved in neurodegenerative disease and cancer in a DNA damage-linked manner

AU - Kisby, Glen E.

AU - Fry, Rebecca C.

AU - Lasarev, Michael R.

AU - Bammler, Theodor K.

AU - Beyer, Richard P.

AU - Churchwell, Mona

AU - Doerge, Daniel R.

AU - Meira, Lisiane B.

AU - Palmer, Valerie S.

AU - Ramos-Crawford, Ana Luiza

AU - Ren, Xuefeng

AU - Sullivan, Robert C.

AU - Kavanagh, Terrance J.

AU - Samson, Leona D.

AU - Zarbl, Helmut

AU - Spencer, Peter S.

PY - 2011/6/29

Y1 - 2011/6/29

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=79959569353&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79959569353&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0020911

DO - 10.1371/journal.pone.0020911

M3 - Article

C2 - 21731631

AN - SCOPUS:79959569353

VL - 6

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 6

M1 - e20911

ER -