Effects of Continuous Gamma-Ray Exposure In Utero in B6C3F1 Mice on Gestation Day 18 and at 10 Weeks of Age.

Pregnant C57BL/6JJcl mice were exposed to γ rays at low dose rate (20 mGy/day, LDR) or medium dose rate (200 and 400 mGy/day, MDR) from gestation day (GD) 0-18 to total accumulated doses of 360, 3,600 and 7,200 mGy, respectively. An additional group of pregnant mice were acutely exposed to 2 Gy at high dose rate (HDR) of 0.77 Gy/min on GD 11. In experiment 1, fetuses collected via cesarean section on GD 18 were examined for external and skeletal abnormalities. While the results of LDR exposure (20 mGy/day) did not significantly differ from the nonirradiated controls in all parameters examined, MDR (200 and 400 mGy/day) and acute HDR (2 Gy) exposure caused growth retardation and significantly increased incidence of unossified bones. Increased incidence of external abnormalities was observed only in the acute HDR group. In experiment 2, the dams were allowed to give birth and the pups were clinically monitored and weighed periodically until 10 weeks of age when they were sacrificed and subjected to pathological examination. Pups exposed at MDRs of 200 and 400 mGy/dayand at acute HDR of 0.77 Gy/min had lower bodyweights from weaning (3 weeks) to 10 weeks of age except for females exposed to 400 mGy/day MDR. None of the pups exposed to an acute 2 Gy dose on GD 11 survived to 10 weeks of age. Histopathological changes were not significantly different between the nonirradiated control and the 20 mGy/day LDR groups. However, at both MDR exposures of 200 and 400 mGy/day. gonadal (testes and ovary) hypoplasia/atrophy was observed in all the 10-week-old pups. Our results show that in utero LDR exposure to 20 mGy/day for the entire gestation period did not cause any significant effect in pups when compared to the nonirradiated controls up to 10 weeks of age. However, pups exposed in utero to MDRs showed dose-related growth retardation with delayed ossifications (400 mGy/day) and gonadal hypoplasia/atrophy. These findings suggest that increased post-implantation loss in dams exposed at MDR is due to early embryonic deaths resulting in early resorption.

Pathology of Serially Sacrificed Female B6C3F1 Mice Continuously Exposed to Very Low-Dose-Rate Gamma Rays.

We have previously reported on life span shortening as well as increased incidence rates in several neoplasms in B6C3F1 mice that were continuously exposed to 21 mGy/day of gamma rays for 400 days. To clarify whether the life shortening was due to early appearance of neoplasms (shortened latency) or increased promotion/progression, 8-week-old female specific-pathogen-free B6C3F1 mice were gamma-ray irradiated at a low dose rate of 20 mGy/day for 400 days. At 100 days postirradiation, 60-90 mice were sacrificed, and thereafter every 100 days alongside the age-matched nonirradiated controls, for 700 days. Additional groups were allowed to live out their natural life span. Pathological examination was performed on all mice to identify lesions, non-neoplastic and neoplastic, as well as to determine the cause of death. Body weights were significantly increased in irradiated mice from sacrifice days 200-500. Incidence rates for spontaneously occurring non-neoplastic lesions, such as adrenal subcapsular cell hyperplasia, fatty degeneration of the liver, atrophy and tubulostromal hyperplasia of the ovaries, were significantly increased in irradiated mice. Significantly increased incidence rates with no shortening of latency periods were observed in irradiated mice for malignant lymphomas, hepatocellular adenomas/carcinomas, bronchioloalveolar adenomas, harderian gland adenoma/adenocarcinoma. Shortened latencies with significantly increased incidence rates were observed for adrenal subcapsular cell adenomas and ovarian neoplasms (tubulostromal adenoma, granulosa cell tumors) in irradiated mice. Life span shortening in mice exposed to 20 mGy/day was mostly due to malignant lymphomas. Multiple primary neoplasms were significantly increased in mice exposed to 20 mGy/day from sacrifice days 400-700 and in the life span group. Our results confirm that continuous low-dose-rate gamma-ray irradiation of female B6C3F1 mice causes both cancer induction (shortened latency) and promotion/progression (early death), depending on the neoplasm's organ/tissue of origin.

Adiposity in female B6C3F1 mice continuously irradiated with low-dose-rate gamma rays.

Abstract We previously reported significant increases in body weight in B6C3F1 mice continuously exposed to low-dose-rate (21 mGy/day) gamma rays compared to that of nonirradiated control mice (Tanaka et al., Radiat. Res. 167, 417-437, 2007). To further study the underlying cause of the increase in body weight, feed consumption, adipose tissue weight, liver and serum lipid contents, and selected factors related to glucose and lipid metabolism such as serum levels of insulin and adipocytokines were examined in female B6C3F1 mice irradiated continuously with gamma rays at 20 mGy/day in group-housed or individually housed rearing conditions. Increased body weight, adipose tissue weight, serum levels of leptin, and lipid contents of the liver and serum were observed in both group-housed (accumulated dose = 6 Gy, 43 weeks from start of irradiation) and individually housed (accumulated dose = 4.4 Gy, 31 weeks from start of irradiation) irradiated mice compared to nonirradiated controls. Feed consumption measurements, however, revealed no significant difference between irradiated mice and nonirradiated controls when mice were housed individually. Our results show for the first time that the increase in the body weight of mice continuously irradiated with low-dose-rate gamma rays is due to adiposity with no corresponding increase in feed consumption.

Cause of death and neoplasia in mice continuously exposed to very low dose rates of gamma rays.

Four thousand 8-week-old SPF B6C3F1 mice (2000 of each sex) were divided into four groups, one nonirradiated (control) and three irradiated. The irradiated groups were exposed to (137)Cs gamma rays at dose rates of 21, 1.1 and 0.05 mGy day(-1) for approximately 400 days with total doses equivalent to 8000, 400 and 20 mGy, respectively. All mice were kept until natural death, and pathological examination was performed to determine the cause of death. Neoplasms accounted for >86.7% of all deaths. Compared to the nonirradiated controls, the frequency of myeloid leukemia in males, soft tissue neoplasms and malignant granulosa cell tumors in females, and hemangiosarcoma in both sexes exposed to 21 mGy day(-1) were significantly increased. The number of multiple primary neoplasms per mouse was significantly increased in mice irradiated at 21 mGy day(-1). Significant increases in body weights were observed from 32 to 60 weeks of age in males and females exposed to 1.1 mGy day(-1) and 21 mGy day(-1), respectively. Our results suggest that life shortening (Tanaka et al., Radiat. Res. 160, 376-379, 2003) in mice continuously exposed to low-dose-rate gamma rays is due to early death from a variety of neoplasms and not from increased incidence of specific neoplasms.

No lengthening of life span in mice continuously exposed to gamma rays at very low dose rates.

Late effects of continuous exposure to ionizing radiation are potential hazards to workers in radiation facilities as well as to the general public. Recently, low-dose-rate and low-dose effects have become a serious concern. Using a total of 4000 mice, we studied the late biological effects of chronic exposure to low-dose-rate radiation as assayed by life span. Two thousand male and 2000 female 8-week-old specific-pathogen-free (SPF) B6C3F1 mice were randomly divided into four groups (one nonirradiated control and three irradiated). Irradiation was carried out for approximately 400 days using (137)Cs gamma rays at dose rates of 21 mGy day(-1), 1.1 mGy day(-1) and 0.05 mGy day(-1) with total doses equivalent to 8000 mGy, 400 mGy and 20 mGy, respectively. All mice were kept under SPF conditions until they died spontaneously. Statistical analyses showed that the life spans of mice of both sexes irradiated with 21 mGy day(-1) (P < 0.0001) and of females irradiated with 1.1 mGy day(-1) (P < 0.05) were significantly shorter than those of the control group. Our results show no evidence of lengthened life span in mice continuously exposed to very low dose rates of gamma rays.