Reduced tumorigenesis in p53 knockout mice exposed in utero to low-dose vitamin E

Abstract

Background: The limited antioxidative capacity of the fetus renders it more susceptible to reactive oxygen species (ros), and possibly to ros-mediated cancer initiation or promotion in utero. Methods: To test this hypothesis, pregnant cancer-prone p53 knockout mice were prenatally supplemented with a low dietary dose of the antioxidant vitamin e (ve) (0.1% a//-/-ac-α- tocopherol-acetate), and the homozygous (-/-) and heterozygous (+/-) p53-deficient and wild-type (+/+) offspring were examined for ve levels, oxidative dna damage, chromosomal stability, cellular viability and postnatal tumorigenesis. Results: In utero exposure to ve reduced spontaneous postnatal tumorigenesis in p53 +/- Offspring, and increased ve levels and reduced fet al dna oxidation in some but not all tissues of p53-deficient fetuses. Survival of ve- Exposed p53 +/- Offspring at the end of the study was double that of the +/- Controls (45% vs 23%). In primary culture of skin fibroblasts from ve-exposed fetuses, ve did not alter chromosomal ploidy, but reduced cell death, indicating that its protective effect did not involve chromosomal stability. Conclusions: The tissue-selective increase in fet al ve levels and reduced dna oxidation, together with a concomitant reduction in postnatal tumorigenesis, suggest that in utero oxidative stress contributes to some postnatal cancers, and the risk can be reduced by maternal dietary supplementation with low-dose ve. © 2009 american cancer society.