Radiation‐Induced Apoptosis and Developmental Disturbance of the Brain*

Abstract

The developing mammalian brain is highly susceptible to ionizing radiation.A significant increase in small head size and mental retardation has been noted in prenatally exposed survivors of the atomic bombing, with the highest risk in those exposed during 8-15 weeks after fertilization. This stage corresponds to day 13 of pregnancy for mice and day 15 for rats in terms of brain development. The initial damage produced by radiation at this stage is cell death in the ventricular zone (VZ) of the brain mantle, the radiosensitive germinal cell population. During histogenesis of the cerebellum, on the other hand, the external granular layer (EGL) is also radiosensitive. Although extensive cell death results in microcephaly and histological abnormality, both VZ and EGL have an ability to recover from a considerable cell loss and form the normal structure of the central nervous system. The number of cell deaths to induce tissue abnormalities in adult brain rises in the range of 15-25% of the germinal cell population; and the threshold doses are about 0.3 Gy for cerebral defects and 1 Gy for cerebellar anomalies in both mice and rats. A similar threshold level is suggested in human cases in induction of mental retardation.Radiation-induced cell death in the VZ and EGL has been revealed as apoptosis, by the nuclear and cytoplasmic condensation, transglutaminase activation, required macromolecular synthesis, and internucleosomal DNA cleavage. Apoptosis of the germinal cell is assumed to eliminate acquired genetic damage. Once an abnormality in DNA has been induced and fixed in a germinal cell, it would be greatly amplified during future proliferation, bringing with it the risk of producing malformations and tumors. These cells would commit suicide when injured for replacement by healthy cells, rather than undertake DNA repair which is rarely complete. In fact they show very slow repair of cellular damage.Thus the high sensitivity of undifferentiated neural cells to the lethal effect of radiation may constitute a biological defense mechanism.

Defective stratum corneum and early neonatal death in mice lacking the gene for transglutaminase 1 (keratinocyte transglutaminase)

“…As TGase 1 Ϫ/Ϫ mice were smaller than control mice, we examined the skeleton of neonatal TGase 1 Ϫ/Ϫ mice by using Alcian blue and alizarin red S staining (45). No anomaly of cartilage or bones in the skeleton was observed, except that skeletal growth was slightly retarded in these mice.…”

Abnormal skeletal patterning in embryos lacking a single Cbp allele: A partial similarity with Rubinstein–Taybi syndrome

“…Bone and cartilage stained specimens were prepared essentially as described by Inouye (38). Fetuses on 18.5 dpc were recovered, and the tails were used for genotyping.…”

Disruption of brain development in male rats exposed prenatally to 5‐bromo‐2‘‐deoxyuridine

“…In experimental animals, exposure to a number of compounds or treatments induces micrencephaly. Gestational administration with alcohol, a combination of aspirin and alcohol, procarbazine, hydroxyurea, hyperthermia, or irradiation resulted in micrencephalic offspring, usually with little or no loss of viability (Bonthius et al, 1989;Fukui et al, 1990;Hoshino, 1983;Hutcinson et al, 1984;Inoue, 1995;Johnston ef al., 1985;Miller et al, 1991;Tamaki et al, 1989). In some cases, developmental delays or cognitive deficits were evident in micrencephalic offspring.…”