title: Methanol exposure does not lead to accumulation of oxidative DNA damage in bone marrow and spleen of mice, rabbits or primates.
abstract: Genotoxicity tests indicate methanol (MeOH) is not mutagenic, but a rodent study has suggested carcinogenic potential, which could result from free radical-initiated oxidative DNA damage. To investigate this possibility we treated male CD-1 mice, New Zealand white rabbits, and cynomolgus monkeys with MeOH (2.0 g/kg ip) and assessed tissue oxidative DNA damage 6 h post-dose, measured as 8-hydroxy-2'-deoxyguanosine (8-oxodG). We found no MeOH-dependent increases in 8-oxodG in bone marrow or spleen of any species. Chronic treatment of CD-1 mice with MeOH (2.0 g/kg ip) daily for 15 d also did not increase 8-oxodG levels in these organs. Further studies in the DNA repair deficient oxoguanine glycosylase 1 (Ogg1) knockout (KO) mice supported these findings. Fibroblasts from Ogg1 KO mice accumulated 8-oxodG following acute exposure to the renal carcinogen potassium bromate (KBrO(3) ; 2.0 mM) but did not accumulate 8-oxodG following exposure to 125 mM MeOH 6 h post-treatment. Ogg1 KO mice accumulated 8-oxodG in bone marrow and spleen with age but not following exposure to MeOH. In addition, free radical-mediated hydroxynonenal-histidine protein adducts were not enhanced by MeOH in primate bone marrow or spleen, or in rabbit bone marrow or mouse spleen, although modest increases were observed in rabbit spleen and mouse bone marrow. Taken together these observations suggest that MeOH exposure does not promote the accumulation of oxidative DNA damage in bone marrow and spleen, and it is unlikely that human environmental exposure to MeOH would lead to lymphomas via this mechanism.
authors.affiliation: Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Gordon P
authors.initials: GP
authors.lastname: McCallum
authors.forename: Michelle
authors.initials: M
authors.lastname: Siu
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Ondovcik
authors.forename: J Nicole
authors.initials: JN
authors.lastname: Sweeting
authors.forename: Peter G
authors.initials: PG
authors.lastname: Wells
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects*; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects*; D045647:DNA Glycosylases / Q000502:physiology; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004781:Environmental Exposure / Q000009:adverse effects*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D000432:Methanol / Q000633:toxicity*; D051379:Mice; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism; D013045:Species Specificity; D013154:Spleen / Q000187:drug effects / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D000080242:8-Hydroxy-2'-Deoxyguanosine; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse; D003849:Deoxyguanosine; D000432:Methanol