Radiation-Induced Teratogenic Effects in Fetal Mice with VaryingTrp53Function: Influence of Prior Heat Stress

Abstract

Teratogenesis induced by radiation in fetal mice has been closely linked to Trp53-dependent apoptosis. This study examined teratogenesis in tails and limb digits of fetal mice with varying Trp53 status after a 4-Gy radiation exposure, with and without a prior 40.5 degrees C, 60-min heat stress. Irradiation earlier in gestation (day 11) produced greater effects than later (day 12) exposure, but in both cases the maximum teratogenic effect of radiation occurred in Trp53 normal fetuses, the minimum in Trp53 null fetuses, and intermediate effects in Trp53 heterozygotes, indicating dominance of Trp53-dependent apoptosis. Heat stress 24 h prior to irradiation on day 11 did not alter the teratogenic effects in Trp53 normal or heterozygous fetuses, but it reduced effects in the Trp53 null fetuses. Conversely, heat stress immediately before irradiation on day 11 amplified teratogenesis in Trp53 null fetuses, still with only a small or no effect on fetuses with full or partial Trp53 function, respectively. These results indicate little effect of mild heat on Trp53-dependent apoptosis after irradiation, but they also suggest heat-induced amplification of Trp53-independent processes that led to apoptosis when heat was delivered near the time of radiation exposure, and heat-induced protection of that process when sufficient expression time was allowed. However, Trp53-dependent apoptosis, when functional, acted as the ultimate determinant of radiation-induced teratogenic effects during early organogenesis. On gestation day 12, radiation effects were diminished, but heat stress 24 h prior to radiation exposure had a large amplifying effect in Trp53 normal or heterozygous fetuses. In the absence of functional Trp53, the sensitizing effect of the heat was diminished. The results may suggest that at later times in organ development, DNA repair is more active, allowing some cells to escape radiation-induced Trp53-dependent apoptosis. However, heat may be able to significantly inhibit this active repair and increase the teratogenic effect of radiation. A diminished effect in the absence of functional Trp53 is consistent with an influence of heat on inhibiting DNA repair, but with a diminished probability of apoptosis.

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

“…In contrast, eye defects in mouse embryos exposed to 2‐chloro‐2′‐deoxyadenosine (2CdA) was mediated by p53‐dependent apoptosis, suggesting that p53 acts as a teratogen inducer (Wubah et al, 1996). Other studies have also shown that the lack of p53‐dependent apoptosis resulted in a reduction in the incidence of limb defects and cleft palate (Boreham et al, 2002; Narai et al, 2006; Wang, 2001). Close examination of this literature suggests that the role of p53 differs by the type of teratogen as well as the type of malformations evaluated.…”

“…Whether p53 plays a role as a teratogen suppressor or inducer has been controversial, although the role of p53 as a teratological suppressor has been more favored based on the protective role of p53 following a variety of environmental stresses (Choi and Donehower, 1999). However, recent studies have shown the role of p53 as a teratological inducer (Boreham et al, 2002; Narai et al, 2006; Wang, 2001), as well as a teratogen suppressor (Baatout et al, 2002; Bekaert et al, 2005; Moallem and Hales, 1998). For example, it has been shown that the loss of p53 alleles increases the incidence of fetal resorption and developmental anomalies in mouse embryos exposed to benzo[a]pyrene (Nicol et al, 1995).…”

“…Close examination of this literature suggests that the role of p53 differs by the type of teratogen as well as the type of malformations evaluated. Studies that have identified p53 as a teratological inducer have investigated specific malformations such as eye defects, limb malformations, and cleft palate (Boreham et al, 2002; Narai et al, 2006; Wang, 2001). Close examination of the literature suggests that whether p53 acts as a suppressor or inducer is determined by the type of teratogen as well as the type of malformations evaluated.…”

Caudal regression in adrenocortical dysplasia (acd) mice is caused by telomere dysfunction with subsequent p53-dependent apoptosis

“…This suggests that the vertebral and limb anomalies in acd mutants are secondary to p53-dependent apoptosis, and our observed rescue of cellular apoptosis in E10.5 acd/acd , p53 −/− mutant embryos confirms this as the most likely mechanism. While apoptosis is known to be integral to normal limb development (Zuzarte-Luis and Hurle, 2005), the role of p53-dependent apoptosis has only been studied in the setting of radiation-induced limb malformations (Boreham et al, 2002; Wang et al, 2000). The surprising finding of polydactyly in acd/acd , p53 −/− embryos suggests the possibility that p53-dependent apoptosis is important during normal limb bud development.…”

Radiation Risk Prediction and Genetics: The Influence of the TP53 Gene in vivo

“…Figure 3 shows the effect of the addition of a mild, short duration heat stress on the teratogenic risk of a high dose radiation exposure in murine fetuses with varying TP53 function (Boreham et al 2002b). Exposure of the fetuses to radiation immediately after a heat stress on gestational day 11 amplified the teratogenic effect of radiation in fetuses lacking TP53 function, but had little or no influence in fetuses with full or partial TP53 function ( Figure 3A).…”