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.
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.
Branda
Richard F
RF
Department of Medicine, University of Vermont, Burlington, VT 05405, United States. rbranda@zoo.uvm.edu
O'Neill
J Patrick
JP
Brooks
Elice M
EM
Powden
Cheryl
C
Naud
Shelly J
SJ
Nicklas
Janice A
JA
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity; D003114:Colony-Forming Units Assay; D045647:DNA Glycosylases / Q000172:deficiency* / Q000235:genetics; D005494:Folic Acid Deficiency / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D008297:Male; D008741:Methyl Methanesulfonate / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation; D013154:Spleen / Q000187:drug effects / Q000473:pathology
D018906:Antineoplastic Agents, Alkylating; D009153:Mutagens; D008741:Methyl Methanesulfonate; D007041:Hypoxanthine Phosphoribosyltransferase; C021565:3-methyladenine-DNA glycosylase; D045647:DNA Glycosylases