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

Abstract

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.

Mechanisms of Radiation Carcinogenesis: What Is Really Induced?

“…Figure 10 represents data from this disease in mice from Tanaka et al . ( 5 , 7 ) . Panel A shows the incidence of malignant lymphoma when mice were serially sacrifice every 100 d ( 7 ) .…”

“…( 5 , 7 ) . Panel A shows the incidence of malignant lymphoma when mice were serially sacrifice every 100 d ( 7 ) . Solid line indicates the control group, and the dotted line indicates the irradiated group (animals were exposed to a low-dose-rate exposure for 400 d to reach a total dose of 8 Gy).…”

Effects of low dose and low dose rate low linear energy transfer radiation on animals – review of recent studies relevant for carcinogenesis

“…In comparison (Tanaka et al 2007), in B6C3F1 strain, both sexes had shorter lifespans for the same total dose and dose rate, and females also showed life shortening with the dose rate of 1 mGy per day for a total dose of 0.4 Gy. In another study, female mice of strain B6C3F1/Jcl daily exposed to 21 mGy of 137 Cs gamma rays beginning with 8 weeks of age (Tanaka et al 2017) were sacrificed at different timepoints throughout irradiation periodat 100, 200, 300, or 400 days, receiving total doses of 2, 4, 6, or 8 Gy. After conclusion of the radiation period at day 400, additional animals were also sacrificed 100, 200, 300, or 400 days later or allowed to live out their entire lifespans.…”

Reflections on Basic Science Studies Involving Low Doses of Ionizing Radiation

“…Many intrinsic and extrinsic factors influence the repair (e.g. (Bladen, Navarre et al 2007, Jeggo and Downs 2014)); experimental in vivo approaches to dissect this concept are difficult yet very informative (Tanaka, Komura et al 2017), but still not used for extensive modelling. Situation is slightly simpler with regard to in vitro modeling in single cells (Ou, Phan et al 2017) where extensive optical and electron microscopy aid in developments of models that describe ultrastructure and three-dimensional organization of chromatin in interphase and mitotic cells.…”