A teratologic suppressor role for p53 in benzo(a)pyrene–treated transgenic p53-deficient mice

Abstract

DNA damage may mediate birth defects caused by many drugs and environmental chemicals, therefore p53, a tumour suppressor gene that facilitates DNA repair, may be critically embryoprotective. We have studied the effects of the environmental teratogen, benzo[a]pyrene, on pregnant heterozygous p53-deficient mice. Such mice exhibited between 2- to 4-fold higher embryotoxicity and teratogenicity than normal p53-controls. Fetal resorptions reflecting in utero death were genotyped using the polymerase chain reaction and found to be increased 2.6-fold and 3.6-fold respectively with heterozygous and homozygous p53-deficient embryos. These results provide the first direct evidence that p53 may be an important teratological suppressor gene which protects the embryo from DNA-damaging chemicals and developmental oxidative stress.

Mdm2: keeping p53 under control

“…A ubiquitous low level expression pattern was found throughout mouse embryonic development (Montes de Oca Luna et al, 1996) Restricted and reproducible expression patterns of Mdm2 were detected at particular stages of zebra®sh development (B Thisse, C Thisse and JP, unpublished results). These contrasting observations could possibly be reconciled by the recent proposal of an antiteratogenic function for p53 during development (Nicol et al, 1995;MacCallum et al, 1996;Hall and Lane, 1997). A restricted activation of the p53 protein was noticed after gamma irradiation of mouse embryos: indeed, tissues showing important proliferative activities at the time of the teratogenic insult may display the strongest response, including activation of the Mdm2 gene (MacCallum et al, 1996;Gottlieb et al, 1997;Komarova et al, 1997).…”

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

“…The potential carcinogenic relevance of in utero oxidative stress is suggested by the embryopathic importance of oxidative DNA damage and the contravening embryoprotective role for embryonic DNA repair, which are evidenced by the enhanced susceptibility of p53 and ATM knockout mice to ROS-initiating, DNA-damaging teratogens. 11,32,33 The deleterious embryonic and fetal effects of ROS, in the absence of maternal toxicity, likely reflects, in part, the low levels of most embryonic antioxidative enzymes and antioxidants. 6,9 On GD 13, among control embryos exposed in utero to the unsupplemented diet, the increased level of DNA oxidation in p53 null embryos, compared with both their þ/À and þ/þ littermates, suggests that endogenous embryonic oxidative stress in the absence of repair of oxidative DNA damage, one role of p53, may contribute to the more rapid onset of postnatal tumorigenesis in this genotype.…”

“…Our approach was to determine whether postnatal tumorigenesis could be modified by changes in the in utero redox environment produced by maternal dietary supplementation with a low dose of the lipid soluble antioxidant vitamin E (VE). The p53 knockout mouse was selected as the model because it has a high and p53 gene dose-dependent incidence of spontaneous tumorigenesis 10 and exhibits increased susceptibility to the teratogenic effects of ROS-initiating teratogens like benzo[a]pyrene, 11 suggesting that ROS could similarly contribute to the tumorigenic process in this strain. Also, heterozygotes of the p53 knockout model demonstrate a phenotype consistent with the high percentage of spontaneously arising human tumors that exhibit loss of a p53 allele, 12 and this similarity to human cancer syndromes has made the p53 knockout mouse useful as a cancer predisposition model.…”

A p53 dose-response relationship for sensitivity to DNA damage in isogenic teratocarcinoma cells

“…Importantly, high level wild-type p53 expression is required in teratocarcinoma cells for rapid loss of viability following low level DNA damage (Figure 4a). High level wild-type p53 expression appears to be similarly required in non-transformed embryonic cells to sense genotoxic teratogens and prevent fetal malformations (Nicol et al, 1995). The mechanism accounting for latent p53 in teratocarcinoma cells is currently under investigation.…”