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

The developmental stage is the most rapid period for the accumulation of so matic mutations. Epidemiological studies have also suggested a significant role of early life for cancer susceptibility, showing a protective effect o f modest dietary restriction early in life. To determine if mutation rate, diet, and cancer risk are related, we have investigated the effect of dieta ry restriction on somatic mutations early in life. The diet of mouse dams w as restricted during pregnancy and lactation by 10% from ad Libitum control . F-1 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 lit ters 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 frequenc y 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 int estine in the restricted group. A similar decrease in the lacZ mutant frequ ency was observed in the bone marrow, but the results did not reach statist ical 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 n ot 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 sit es, with no difference in the mutation spectrum between the two dietary gro ups. (C) 2000 Published by Elsevier Science B.V.