Persistent Impact of In utero Irradiation on Mouse Brain Structure and Function Characterized by MR Imaging and Behavioral Analysis

Abstract

Prenatal irradiation is known to perturb brain development. Epidemiological studies revealed that radiation exposure during weeks 8–15 of pregnancy was associated with an increased occurrence of mental disability and microcephaly. Such neurological deficits were reproduced in animal models, in which rodent behavioral testing is an often used tool to evaluate radiation-induced defective brain functionality. However, up to now, animal studies suggested a threshold dose of around 0.30 Gray (Gy) below which no behavioral alterations can be observed, while human studies hinted at late defects after exposure to doses as low as 0.10 Gy. Here, we acutely irradiated pregnant mice at embryonic day 11 with doses ranging from 0.10 to 1.00 Gy. A thorough investigation of the dose-response relationship of altered brain function and architecture following in utero irradiation was achieved using a behavioral test battery and volumetric 3D T2-weighted magnetic resonance imaging (MRI). We found dose-dependent changes in cage activity, social behavior, anxiety-related exploration, and spatio-cognitive performance. Although behavioral alterations in low-dose exposed animals were mild, we did unveil that both emotionality and higher cognitive abilities were affected in mice exposed to ≥0.10 Gy. Microcephaly was apparent from 0.33 Gy onwards and accompanied by deviations in regional brain volumes as compared to controls. Of note, total brain volume and the relative volume of the ventricles, frontal and posterior cerebral cortex, cerebellum, and striatum were most strongly correlated to altered behavioral parameters. Taken together, we present conclusive evidence for persistent low-dose effects after prenatal irradiation in mice and provide a better understanding of the correlation between their brain size and performance in behavioral tests.

A detailed characterization of congenital defects and mortality following moderate X‐ray doses during neurulation

“…Information on adult weight after irradiation during neurulation is very sparse. Although we did not observe any significant weight loss after X‐irradiation at E7.5, a recent study illustrated that irradiation at E11 with 0.66 Gy and 1.0 Gy, immediately after neurulation (i.e., at the time of neurogenesis), significantly reduced brain and body weights respectively at W50 (Verreet, Rangarajan, et al, ). Irradiation during even later stages of development (E14 and E17) using a 60 Co gamma source also showed decreased brain weight at 6 and 12 months of age, using doses starting at 0.5 Gy (Hossain, Chetana, & Devi, ).…”

“…In terms of physical factors, several studies already identified the risks of exposure to ionizing radiation during pregnancy and stipulated a causal link with several congenital malformations (reviewed in [De Santis et al, ; Jacquet, ; Verreet, Rangarajan et al, ; Verreet, Verslegers et al, ]). For example, in prenatally irradiated survivors of the Chernobyl disaster, the prevalence of both NTDs (e.g., exencephaly; exposed brain tissue) and EDs (e.g., microphthalmos; reduced eye size) was found to be increased (Burrow et al, ; Wertelecki, ; Wertelecki et al, ).…”

“…To this end we decided that it was necessary to expand on the aforementioned studies and use shorter and better defined time intervals for radiation sensitivity characterization, whilst also using radiation doses at levels more relevant to potential exposures of pregnant women in situations of medicine (e.g., CT) and accidents. Furthermore, due to the focus of most recent studies on radiation‐induced defects at later developmental stages, that is, during neurogenesis (E11–E17) (Quintens et al, ; Verreet et al, ; Verreet, Rangarajan et al, ; Verreet, Verslegers et al, ), there is a general lack of information on the impact of irradiation during neurulation, which starts at E7.5.…”

p53 drives premature neuronal differentiation in response to radiation-induced DNA damage during early neurogenesis

“…In agreement with previous observations 26 , irradiation of C57BL/6 mouse fetuses at embryonic day 11 (E11) resulted in a mild general growth deficit (male 6.8%, female 8.9%; Fig. 1a) as seen in 10-day old (P10) mice, and a strongly reduced brain weight (male 27%, female 27%; Fig.…”

“…Microarray data from adriamycin-treated ESCs are from GSE26360 (Gene Expression Omnibus). ( j-l ) Gene expression changes of IR_unique, Magoh_unique and Overlap genes in case studies of Mdm4 knockout neural stem cells ( Mdm4 -KO NSCs) 42 , Tlx -deficient NSCs ( Tlx f/Z;CreER NSC + TM) 43 , and neural crest cells constitutively expressing moderate levels of p53 ( Trp53 25,26/+ NCCs) 45 . Data represent mean ± S.D.…”