Reduced tumorigenesis in p53 knockout mice exposed in utero to low-dose vitamin E.
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% all-rac-alpha-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 fetal 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 fetal 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.
Chen
Connie S
CS
Division of Biomolecular Sciences, Faculty of Pharmacy, University of Toronto, Toronto, Canada.
Squire
Jeremy A
JA
Wells
Peter G
PG
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002869:Chromosome Aberrations; D004249:DNA Damage; D019587:Dietary Supplements; D005260:Female; D016158:Genes, p53; D008431:Maternal-Fetal Exchange; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000235:genetics / Q000517:prevention & control*; D011247:Pregnancy; D011270:Pregnancy, Animal; D014810:Vitamin E / Q000494:pharmacology*
D000975:Antioxidants; D014810:Vitamin E