ANS National
 Meetings/
 Sessions

November 1995

Sohei Kondo

(Kinki Univ-Japan)

Toshiyuki Norimura

(Univ of OEH-Japan)

Taisei Nomura

(Osaka Univ-Japan)

3. Programmed Cell Death for Defense Against Anomaly and Tumor Formation

"INTRODUCTION

                    "Cell death after exposure to low-level radiation is often considered evidence that radiation is poisonous, however small the dose. Evidence has been accumulating to support the notion that cell death after low-level exposure to radiation results from activation of suicidal genes -‘programmed cell death’ or ‘apoptosis’-for the health of the whole body. This paper gives experimental evidence that embryos of fruit flies and mouse fetuses have potent defense mechanisms against teratogenic or tumorigenic injury caused by radiation and carcinogens, which function through programmed cell death."

"DATA AND DISCUSSION

       "Cell Replacement Repair of Teratogenic Injury in Fruit Flies

                   "When male genital disks of Drosophila melanogaster larvae at the third instar were exposed to 50 Gy, all of them developed into abnormal adult genitalia, whereas when they were transplanted into 2-day younger larvae, all of them developed into normal genitalia.¹ These results fit the model of cell replacement repair, in which cells with teratogenic injury are replaced by healthy ones within the cellular society of a target organ and in which this presumed cell replacement results in complete elimination of injured cells by programmed cell death, since otherwise the residual injured cells would give rise to abnormal portions in the adult organ."

       "Cell Repair of Teratogenic Injury in Mice

                  "Experimental studies with mice have established the empirical rule that irradiation during the pre-implantation period of the embryo (0.5 to 5 days after fertilization) causes a high incidence of prenatal death but virtually no anomalies in the survivors. After the implantation stage, however, fetuses become progressively resistant to prenatal death. The sensitivity to neonatal death or to gross anomalies at term reaches a peak around days 9 and 10. Even at the stage most sensitive to the teratogenic effects of radiation, there is a threshold of ~1 Gy. We irradiated fetuses at 9.5 days with 2 Gy of X rays. Fetuses homozyeous for null mutation of gene p53, (p53^-/-), showed anomaly incidence three times higher than that induced in wild type (p53^+/+) fetuses; fetal p~13 +" cells were sensitive to radiation-induced apoptosis but fetal p53^-/- cells were not sensitive.² These results support the notion that in wild-type mice exposed to below-threshold doses of radiation, cells having induced teratogenic injury commit apoptosis, and dying cells are replaced by healthy ones."

       "Programmed Cell Death Suppresses Tumorigencsis But Not Mutagenesis

                  "Table I (Ref. 3) shows that when fetuses of mice pretreated with urethane or 4-nitroquinoline 1-oxide (4NQO)-an inducer of bulky adducts to purine bases of DNA rcparable by excision repair - were then treated with caffeine for ~1 day at 6-h intervals, the incidence of lung tumors was significantly reduced, whereas the incidence of somatic mutations (detected  by coat color mosaics) was not reduced. These results suggest that urethane and 4NQO act primarily as tumor promoters rather than oncomutagens. Evidence is available to support the notion that caffeine enhances the apoptotic activity of cells damaged by 4NQO in the G2 phase.⁴"

TABLE I (Paper 3)

Effects of Caffeine on Mutations, Malformations, and Tumors Induced in
Mice by Exposure to Urethane or 4NQO (Ref. 3)

^ap< 0.001.
^bp < 0.01.

"CONCLUSION

                 "The fact that the animal body contains cells that are highly sensitive to death by radiation indicate that animals have highly sensitive defenses against risk of low-level radiation rather than that low-level radiation is hazardous to animals, including humans."

1. S. KONDO, Health effects of low-level Radiation, Kinki University Press, Osaka, Japan, and Medical Physics Publishing, Madison, Wisconsin (1993).

2. T. NORIMURA, S. NOMOTO, M. KATSUKI, Y. GONDO, K. NAKANO, S. KONDO, "Mice Deficient for p53 are Susceptible to Radiation-induced Teratogenesis," Proc. 10th Int. Cong. Radial. Res., Abstracts (in press).

3. T. NOMURA, "Diminution of Tumorigenesis Initiated by 6-Nitroquinoline 1-Oxide by Post-Treatment with Caffeine in Mice," Nature, 260, 547 (1976); see also "Comparative inhibiting Effects of Methylxanthines on Urethane-Induced Tumors, Malformations, and Presumed Somatic Mutations in Mice," Cancer Res., 43, 1342 (1983).

4. S. KONDO, "Apoptosis by Antitumor Agents and Other Factors in Relation to Cell Cycle Checkpoints," J. Radiat. Res., 36, 56(1995).