@misc{oai:repo.qst.go.jp:00070432,
 author = {Sawa, Yurika and Shang, Yi and Kakinuma, Shizuko and Nogawa, Hiroyuki and Shimada, Yoshiya and 澤 百合香 and 尚 奕 and 柿沼 志津子 and 島田 義也},
 month = {Mar},
 note = {Background: 
With a rapid increase in the frequency of medical radiation exposure, radiation effects on the children have become a great concern in recent years.  Therefore, firm evidences are required for radiation protection for medical exposure.  It has been reported that neonatal B6C3F1 mice had high sensitivity of radiation-induction of liver tumors and life shortening compared with adult mice. However, little is known about the underlying mechanism of its high susceptibility.  We hypothesize here that the unique characteristic response of neonatal hepatocytes to radiation may contribute to high susceptibility to radiation hepatocarcinogenesis.  In this study, we aimed to investigate the normal development, focusing on proliferative activity of fetal, neonatal and adult livers histologically, and then to analyze the hepatocyte response to radiation in terms of cell cycle arrest and apoptosis. 
\nMaterials and Methods: 
For investigation of normal development of liver in B6C3F1 mice, the livers of mice at various ages, from 13-days post-conception (fetus) up to 10-week of age (adult), were analyzed histologically. For investigation of the age dependence of hepatocyte response to radiation, 17 days post-conception, 1-week-old (neonatal), and 7-week-old mice were whole-body irradiated with 4 Gy at a dose rate of gamma-rays from 137Cs. Subsequently, mice were killed at 0 (unirradiated), 1, 3, 6, 12, 24 and 48 hours. Then immunohistochemical analyses, using antibody against p53, Ki67, active caspase3, PCNA, and gamma-H2AX, were performed. BrdU and TUNEL analyses were also performed at 3 to 48h after irradiation.
\nResults and Discussion: 
The liver proliferative status was dramatically changed during development from fetus to adult stage. There were many active proliferaive hepatic cells as well as hematopoietic cells in the fetal livers.  Immature bile ducts and hepatic cords were formed at 1 week of age. At 7 weeks of age, matured hepatic cells were morphologically fully developed. 
We here found that radiation responses, in terms of cell cycle arrest and induction of apoptosis, were different among fetus, neonatal and adult hepatocytes. In fetal hepatocytes, p53 was accumulated soon after irradiation, which was followed by cell cycle arrest and apoptosis.  In adult hepatocytes, which are rarely proliferating, there showed few apoptotosis after irradiation.  In great contrast, the neonatal hepatocytes showed, surprisingly, the few apoptotosis after irradiation and continued proliferation. The resistance to apoptosis and continued proliferation may contribute to the accumulation of damaged cells, which may lead to high susceptibility to radiation tumorigenesis., The 3rd JCA-AACR Special Joint Conference},
 title = {Age dependency of hepatic response to gamma-rays in B6C3F1 mice.},
 year = {2011}
}