Molecular and cellular basis of the dose-rate-dependent adverse effects of radiation exposure in animal models. Part I: Mammary gland and digestive tract

Abstract

While epidemiological data are available for the dose and dose-rate effectiveness factor (DDREF) for human populations, animal models have contributed significantly to providing quantitative data with mechanistic insights. The aim of the current review is to compile both the in vitro experiments with reference to the dose-rate effects of DNA damage and repair, and the animal studies, specific to rodents, with reference to the dose-rate effects of cancer development. In particular, the review focuses especially on the results pertaining to underlying biological mechanisms and discusses their possible involvement in the process of radiation-induced carcinogenesis. Because the concept of adverse outcome pathway (AOP) together with the key events has been considered as a clue to estimate radiation risks at low doses and low dose-rates, the review scrutinized the dose-rate dependency of the key events related to carcinogenesis, which enables us to unify the underlying critical mechanisms to establish a connection between animal experimental studies with human epidemiological studies.

Keywords: animal; cancer; cell; epidemiology; low dose; low dose rate; radiation.

Fig. 1

Parallelogram approach to the integration of epidemiology and animal experiments. The concept of NCRP commentary No. 24 was applied to animal experiments [37].

Fig. 2

53BP1 foci in the mouse small intestine 6 h after 4.0 Gy of X-rays. Multiple foci were induced in the crypt region, while they were rarely detected in villi, indicating that, although DSBs should be induced in every cell, but the DNA damage response, i.e. accumulation of 53BP1, is dependent on differentiation status.

Fig. 3

Architecture of rodent mammary gland.

Fig. 4

Reproductive cell death of different mammary epithelial progenitors in rat mammary gland. Flow-sorted rat mammary epithelial cells were irradiated with γ-rays and colony formation was assessed. Adapted from Kudo et al. [93] (© 2023 Radiation Research Society).

Fig. 5

Architecture of mouse intestine.