Cancer-Prone Mice Expressing the Ki-ras^G12CGene Show Increased Lung Carcinogenesis after CT Screening Exposures

Abstract

A >20-fold increase in X-ray computed tomography (CT) use during the last 30 years has caused considerable concern because of the potential carcinogenic risk from these CT exposures. Estimating the carcinogenic risk from high-energy, single high-dose exposures obtained from atomic bomb survivors and extrapolating these data to multiple low-energy, low-dose CT exposures using the Linear No-Threshold (LNT) model may not give an accurate assessment of actual cancer risk. Recently, the National Lung Cancer Screening Trial (NLST) reported that annual CT scans of current and former heavy smokers reduced lung cancer mortality by 20%, highlighting the need to better define the carcinogenic risk associated with these annual CT screening exposures. In this study, we used the bitransgenic CCSP-rtTA/Ki-ras mouse model that conditionally expresses the human mutant Ki-rasG12C gene in a doxycycline-inducible and lung-specific manner to measure the carcinogenic risk of exposure to multiple whole-body CT doses that approximate the annual NLST screening protocol. Irradiated mice expressing the Ki-rasG12C gene in their lungs had a significant (P = 0.01) 43% increase in the number of tumors/mouse (24.1 ± 1.9) compared to unirradiated mice (16.8 ± 1.3). Irradiated females had significantly (P < 0.005) more excess tumors than irradiated males. No tumor size difference or dose response was observed over the total dose range of 80–160 mGy for either sex. Irradiated bitransgenic mice that did not express the Ki-rasG12C gene had a low tumor incidence (≤0.1/mouse) that was not affected by exposure to CT radiation. These results suggest that (i) estimating the carcinogenic risk of multiple CT exposures from high-dose carcinogenesis data using the LNT model may be inappropriate for current and former smokers and (ii) any increased carcinogenic risk after exposure to fractionated low-dose CT-radiation may be restricted to only those individuals expressing cancer susceptibility genes in their tissues at the time of exposure.

Micro-CT vs. Whole Body Multirow Detector CT for Analysing Bone Regeneration in an Animal Model

“…The radiation dose in an in vivo μCT system (with similar settings to ours) has a range of 272 mGy to 1088 mGy, depending on the resolution and should be kept for in vivo longitudinal measurements below 500 mGy [5, 14]. This dose is assumed to be higher than the dose for MDCT (25 mGy) [15]. However, there is no study evaluating the MDCT dose on small samples such as ours.…”

“…As the scanning time (several minutes) and the radiation exposure of in vivo μCT scans is known to be higher (272–1088 mGy depending on the resolution; [5, 14] and assessments by the authors) compared with MDCT (scanning time: seconds, radiation exposure: 25 mGy) and as several effects of radiation exposure in terms of sequential in vivo μCT analyses like decreased trabecular bone volume are already described [5, 15, 16], the aim of our study was to examine whether the lower resolution of the MDCT is sufficient to qualitatively and quantitatively evaluate bone growth in the rat mandible.…”

Low-dose or low-dose-rate ionizing radiation–induced bioeffects in animal models

“…Recent animal experimental data supports the association of cancer risk with LDIR (Table 2). Using a bitransgenic mouse model to measure the carcinogenic risk of exposure to multiple whole-body CT doses, a significant increase in the number of lung tumors per mouse was observed [27]. Irradiated females had significantly more excess tumors than irradiated males.…”

Densely ionizing radiation affects DNA methylation of selective LINE-1 elements

“…Both sparsely and densely IR are capable of causing pulmonary fibrosis and lung cancer in humans and in experimental models (Maddams et al, 2011; Munley et al, 2011; Yarnold and Brotons, 2010). The role of epigenetic alterations, including aberrant methylation and expression of LINE-1 elements in the development and promotion of radiation-induced fibrosis and lung cancer is becoming increasingly recognized (Ikeda et al, 2013; Saito et al, 2010; Weigel et al, 2015).…”