The effect of dietary folic acid deficiency on the cytotoxic and mutagenic responses to methyl methanesulfonate in wild-type and in 3-methyladenine DNA glycosylase-deficient Aag null mice

Mutat Res. 2007 Feb 3;615(1-2):12-7. doi: 10.1016/j.mrfmmm.2006.09.007. Epub 2007 Jan 4.


Folic acid deficiency (FA-) augments DNA damage caused by alkylating agents. The role of DNA repair in modulating this damage was investigated in mice. Weanling wild-type or 3-methyladenine glycosylase (Aag) null mice were maintained on a FA- diet or the same diet supplemented with folic acid (FA+) for 4 weeks. They were then treated with methyl methanesulfonate (MMS), 100mg/kg i.p. Six weeks later, spleen cells were collected for assays of non-selected and 6-thioguanine (TG) selected cloning efficiency to measure the mutant frequency at the Hprt locus. In wild-type mice, there was no significant effect of either MMS treatment or folate dietary content on splenocyte non-selected cloning efficiency. In contrast, non-selected cloning efficiency was significantly higher in MMS-treated Aag null mice than in saline treated controls (diet-gene interaction variable, p=0.04). The non-selected cloning efficiency was significantly higher in the FA+ diet than in the FA- diet group after MMS treatment of Aag null mice. Mutant frequency after MMS treatment was significantly higher in FA- wild-type and Aag null mice and in FA+ Aag null mice, but not in FA+ wild-type mice. For the Aag null mice, mutant frequency was higher in the FA+ mice than in the FA- mice after either saline or MMS treatment. These studies indicate that in wild-type mice treated with MMS, dietary folate content (FA+ or FA-) had no effect on cytotoxicity, but FA- diet increased DNA mutation frequency compared to FA+ diet. In Aag null mice, FA- diet increased the cytotoxic effects of alkylating agents but decreased the risk of DNA mutation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents, Alkylating / toxicity
  • Colony-Forming Units Assay
  • DNA Glycosylases / deficiency*
  • DNA Glycosylases / genetics
  • Folic Acid Deficiency / genetics*
  • Folic Acid Deficiency / metabolism*
  • Folic Acid Deficiency / pathology
  • Hypoxanthine Phosphoribosyltransferase / genetics
  • Male
  • Methyl Methanesulfonate / toxicity*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutagens / toxicity*
  • Mutation
  • Spleen / drug effects
  • Spleen / pathology


  • Antineoplastic Agents, Alkylating
  • Mutagens
  • Methyl Methanesulfonate
  • Hypoxanthine Phosphoribosyltransferase
  • 3-methyladenine-DNA glycosylase
  • DNA Glycosylases