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

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.

Chemo brain or tumor brain - that is the question: the presence of extracranial tumors profoundly affects molecular processes in the prefrontal cortex of TumorGraft mice

“…Role of DNA methylation in BMP4 regulation in tumor brain and chemo brain needs to be further substantiated in the large-scale studies. Here, we noted the downregulation of the neurotrophic factors pathway, which was previously reported to be downregulated by chemotherapy agents and radiation [ 14 , 33 ], and may therefore constitute biomarkers of brain toxicity. In the future, to gain a full understanding of pathways and processes affected in tumor brain and chemo brain, it would be important to conduct a detailed analysis of the brain signalome and entire interactome, using novel platforms such as OncoFinder and iPANDA [ 34 , 35 ] that allow an in-depth analysis of entire signalome in context of different diseases and conditions [ 36 – 40 ].…”

“…Western immunoblotting was conducted as previously described [ 14 , 33 , 76 ]. In brief, around 50 mg of PFC tissues were sonicated in ice-cold 1% SDS and immediately boiled.…”

Fractionated low-dose exposure to ionizing radiation leads to DNA damage, epigenetic dysregulation, and behavioral impairment

“…Furthermore, this present study has analyzed radiation effects in male mice. Recent studies have shown that radiation effects are, in fact, more profound in females than in males [ 64 , 65 ]. Therefore, it would be prudent to analyze the effects of fractionated, low-dose radiation as a function of animal sex.…”

Growth of Triple Negative and Progesterone Positive Breast Cancer Causes Oxidative Stress and Down-Regulates Neuroprotective Transcription Factor NPAS4 and NPAS4-Regulated Genes in Hippocampal Tissues of TumorGraft Mice—an Aging Connection

“…Western immunoblotting was carried out as previously described (Silasi et al, 2004 ; Kovalchuk et al, 2016a , b , c ). In brief, hippocampal tissues were sonicated in ice-cold 1% SDS and immediately boiled.…”