Dietary restriction during murine development provides protection against MNU-induced mutations

Naoko Shima, Roy R. Swiger, John A. Heddle

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19 Scopus citations


The developmental stage is the most rapid period for the accumulation of somatic mutations. Epidemiological studies have also suggested a significant role of early life for cancer susceptibility, showing a protective effect of modest dietary restriction early in life. To determine if mutation rate, diet, and cancer risk are related, we have investigated the effect of dietary restriction on somatic mutations early in life. The diet of mouse dams was restricted during pregnancy and lactation by 10% from ad libitum control. F1 pups (SWR x Muta(TM) Mouse) were weaned at 3 weeks of age. Pups from dams that were on a restricted diet were kept under dietary restriction (40% until 5 weeks of age and then 20% until sacrifice). Only females from litters of seven or eight were used in this study. A portion of pups from both groups were treated with N-methyl-N-nitrosourea (MNU, 50 mg/kg, i.p.) at 5 weeks of age and all mice were sacrificed at 10 weeks of age. The frequency of induced mutations was reduced by about 30% at the three loci studied, lacZ (P = 0.028) and cII (P = 0.042) and Dlb-1 (P = 0.032) in the small intestine in the restricted group. A similar decrease in the lacZ mutant frequency was observed in the bone marrow, but the results did not reach statistical significance (P = 0.074). Few differences in the lacZ mutant frequency were observed in the colon and the mammary epithelium, but variability of the mutant frequencies was such that an effect of similar magnitude could not be excluded statistically. Analysis of 47 cII mutants revealed that the majority of MNU-induced mutations were G:C to A:T transition at non-CpG sites, with no difference in the mutation spectrum between the two dietary groups. (C) 2000 Published by Elsevier Science B.V.

Original languageEnglish (US)
Pages (from-to)189-200
Number of pages12
JournalMutation Research - Genetic Toxicology and Environmental Mutagenesis
Issue number2
StatePublished - Oct 31 2000

Bibliographical note

Funding Information:
We thank Covance Laboratories Inc. for granting permission to cross Muta™Mouse to obtain F 1 . This work was funded by the Cancer Research Society Inc. in Canada. N.S. is supported by a fellowship from the Japan Society for the Promotion of Science. We are also grateful to Beichen Sun and Jennifer Moody for their help to Lee Wong for sequencing cII mutants, and to Joel Shore for statistical advice.


  • CII
  • Dlb-1
  • LacZ
  • Somatic mutation


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