PMID- 16401638
OWN - NLM
STAT- MEDLINE
DCOM- 20060822
LR  - 20071115
IS  - 0143-3334 (Print)
IS  - 0143-3334 (Linking)
VI  - 27
IP  - 7
DP  - 2006 Jul
TI  - Enhanced tumorigenesis in p53 knockout mice exposed in utero to high-dose vitamin 
      E.
PG  - 1358-68
AB  - The limited antioxidative capacity of the embryo and fetus may increase their 
      risk for cancer initiation and/or promotion by reactive oxygen species 
      (ROS)-mediated oxidative DNA damage and/or signaling. To determine if cancer can 
      originate in utero, a high dietary dose of the antioxidant vitamin E (VE) (10% 
      dl-alpha-tocopherol-acetate) was given to cancer-prone p53 knockout mice 
      throughout pregnancy. Although reducing fetal death (P < 0.05), in utero exposure 
      to VE enhanced postnatal tumorigenesis in both +/- (P < 0.04) and -/- (P < 
      0.0008) p53-deficient offspring. VE did not alter maternal weights, offspring p53 
      genotypic distribution or tumor spectrum. Constitutive embryonic DNA oxidation in 
      untreated -/- p53 embryos [gestational day (GD) 13] was higher than in +/- and 
      +/+ p53 littermates (P < 0.05). VE reduced DNA oxidation in -/- p53 embryos (P < 
      0.05) without affecting +/- and +/+ p53 littermates. VE had contrasting, 
      tissue-dependent effects on fetal (GD 19) DNA oxidation, with reductions in -/- 
      and +/- p53-deficient fetal brains (P < 0.01), increases in skin (P < 0.05) and 
      no effect in liver and thymus. The 250-fold increase in dietary VE levels 
      produced only 1.6-6.3-fold, tissue-dependent increases in tissue concentrations. 
      The greatest increase, in fetal skin, correlated with increased DNA oxidation in 
      that tissue in -/- and +/- p53-deficient fetuses and enhanced tumorigenesis in 
      these genotypes. These results show that some cancers may originate in utero and 
      the risk can be enhanced by embryonic and fetal exposure to high dietary levels 
      of VE. The elevated DNA oxidation in some tissues of untreated -/- p53 offspring 
      suggests that ROS may contribute to their higher baseline tumor incidence. The 
      limited and tissue-dependent disposition of VE indicates substantial conceptal 
      regulation. The similarly selective and contrasting effects of VE on DNA 
      oxidation may contribute to its controversial protective efficacy and suggest 
      that its effects on tumorigenesis are cell-specific, possibly in high doses 
      involving a pro-oxidative mechanism.
FAU - Chen, Connie S
AU  - Chen CS
AD  - Faculty of Pharmacy and Department of Pharmacology, University of Toronto, 
      Toronto, Ontario, Canada, M5S 2S2.
FAU - Wells, Peter G
AU  - Wells PG
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20060109
PL  - England
TA  - Carcinogenesis
JT  - Carcinogenesis
JID - 8008055
RN  - 0 (Antioxidants)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 1406-18-4 (Vitamin E)
RN  - 9007-49-2 (DNA)
SB  - IM
MH  - Animals
MH  - Antioxidants/administration & dosage/*adverse effects/pharmacokinetics
MH  - DNA/drug effects
MH  - DNA Damage/drug effects
MH  - Dietary Supplements
MH  - Dose-Response Relationship, Drug
MH  - Embryo, Mammalian
MH  - Female
MH  - Genotype
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Neoplasms/*chemically induced
MH  - Oxidation-Reduction
MH  - Pregnancy
MH  - Prenatal Exposure Delayed Effects
MH  - Tissue Distribution
MH  - Tumor Suppressor Protein p53/*deficiency/genetics
MH  - Vitamin E/administration & dosage/*adverse effects/pharmacokinetics
EDAT- 2006/01/13 09:00
MHDA- 2006/08/23 09:00
CRDT- 2006/01/13 09:00
PHST- 2006/01/13 09:00 [pubmed]
PHST- 2006/08/23 09:00 [medline]
PHST- 2006/01/13 09:00 [entrez]
AID - bgi325 [pii]
AID - 10.1093/carcin/bgi325 [doi]
PST - ppublish
SO  - Carcinogenesis. 2006 Jul;27(7):1358-68. doi: 10.1093/carcin/bgi325. Epub 2006 Jan 
      9.