The roles of p53 and p21 in normal development and hyperthermia-induced malformations

BACKGROUND: Hyperthermia (HS) is a well‐studied teratogen that induces serious malformations, including neural tube defects. Our previous studies have shown that HS induces apoptosis by activating the mitochondrial apoptotic pathway. Prior to activation of the mitochondrial apoptotic pathway, HS also activates p53 and its target genes. In the present study, we determine whether p53 and/or p21 play a role as teratogen suppressors or inducers of HS‐induced malformations. METHODS: Pregnant mice carrying all three p53 or p21 genotype embryos were exposed to HS on day 8.5. Subsequently, fetuses were collected on day 15.5, and genotyped. In addition to genotype, we also determined the number of resorptions and dead fetuses as well as the number and types of external malformations. RESULTS: In the absence of HS exposure, fetuses exhibiting exencephaly and spina bifida were observed in approximately 11% of p53 −/− fetuses, whereas no malformations were observed among p21 −/− fetuses. Exposure to HS resulted in an increase in exencephaly and polydactyly in fetuses of all three p53 genotypes. However, the incidence of these malformations was statistically significantly higher in p53 −/− compared to p53 +/− and p53 +/+ fetuses. Exencephaly was the only malformation observed in p21 fetuses exposed to HS, with an approximately 2‐fold increase among p21 +/− and a 3‐fold increase among p21 −/− compared to p21 +/+ fetuses. CONCLUSIONS: Our study confirms that p53 plays a role in normal development and has shown, for the first time that p53 and p21 function to suppress HS‐induced malformations. Birth Defects Res (Part B) 86:40‐47, 2009. © 2009 Wiley‐Liss, Inc.