Profound and Sexually Dimorphic Effects of Clinically-Relevant Low Dose Scatter Irradiation on the Brain and Behavior.

Anna Kovalchuk,Arif Muhammad,Abhijit Ghose,Shakhawat Hossain,Bryan Kolb,Olga Kovalchuk,Charles Kirkby,Yaroslav Ilnytskyy,Esmaeel Ghasroddashti,Richelle Mychasiuk

doi:10.3389/fnbeh.2016.00084

Abstract

Irradiated cells can signal damage and distress to both close and distant neighbors that have not been directly exposed to the radiation (naïve bystanders). While studies have shown that such bystander effects occur in the shielded brain of animals upon body irradiation, their mechanism remains unexplored. Observed effects may be caused by some blood-borne factors; however they may also be explained, at least in part, by very small direct doses received by the brain that result from scatter or leakage. In order to establish the roles of low doses of scatter irradiation in the brain response, we developed a new model for scatter irradiation analysis whereby one rat was irradiated directly at the liver and the second rat was placed adjacent to the first and received a scatter dose to its body and brain. This work focuses specifically on the response of the latter rat brain to the low scatter irradiation dose. Here, we provide the first experimental evidence that very low, clinically relevant doses of scatter irradiation alter gene expression, induce changes in dendritic morphology, and lead to behavioral deficits in exposed animals. The results showed that exposure to radiation doses as low as 0.115 cGy caused changes in gene expression and reduced spine density, dendritic complexity, and dendritic length in the prefrontal cortex tissues of females, but not males. In the hippocampus, radiation altered neuroanatomical organization in males, but not in females. Moreover, low dose radiation caused behavioral deficits in the exposed animals. This is the first study to show that low dose scatter irradiation influences the brain and behavior in a sex-specific way.

Highlights

Ionizing radiation is a well-established DNA damaging agent that can exert a wide array of effects in exposed cells (Morgan and Sowa, 2005)
In order to establish whether or not such low doses exert any influence on the brain, and to understand the role of scattered radiation in contributing to observed effects that otherwise may be assumed to be due to secondary signals received by the cells in the brain, we developed a new model for the investigation of scatter irradiation
We did not detect any H2AX phosphorylation in either the hippocampus or the prefrontal cortex (PFC) tissues of the exposed animals in two independent technical iterations of the experiment. This may indicate that no DNA damage was induced by the low dose scatter irradiation or that any damage was effectively repaired within 2 weeks of the exposure, which was when the analysis was conducted

Summary

Introduction

Ionizing radiation is a well-established DNA damaging agent that can exert a wide array of effects in exposed cells (Morgan and Sowa, 2005). It is clear that radiation effects occur beyond the exposed tissues and cells can signal distress to both close and distant unexposed naïve neighbors inducing indirect consequences. When applied to a recipient cell culture, these factors induce chromosome damage (Hollowell and Littlefield, 1968; Pant and Kamada, 1977; Marozik et al, 2007; reviewed in Mothersill et al, 2004; Morgan and Sowa, 2007; Kovalchuk and Baulch, 2008). We showed that directly irradiating a rat liver while shielding the rest of the animal caused distal systemic effects—molecular and neuroanatomical changes in brain and affected animal behavior (Kovalchuk et al, 2016)

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