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Energy Deposition leads to Increase, Neural Remodeling
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Deposition of Energy Leading to Learning and Memory Impairment||non-adjacent||Moderate||Low||Vinita Chauhan (send email)||Open for citation & comment|
Life Stage Applicability
|Not Otherwise Specified||Low|
Key Event Relationship Description
Energy deposition through ionizing radiation can lead to chemical changes including bond breakages and the generation of by-products, such as free radicals from water hydrolysis, which can change cellular homeostasis (Einor et al., 2016; Martinez-López & Hande, 2020; Reisz et al., 2014). This energy can come in many forms (i.e., gamma rays, X-rays, alpha particles, heavy ions, protons), to produce a range in complexity of damage (Drobny, 2013). When deposited onto neurons, oxidative stress can affect neuronal signaling through the induction of alterations to the neuronal architecture and synaptic activity. The energy can further cause necrosis and demyelination, and decrease neurogenesis and synaptic complexity; these together are important to maintain the integrity of the neurons (Cekanaviciute et al., 2018; J. R. Fike et al., 1984; Hladik & Tapio, 2016). Furthermore, there can also be disruptions in neuronal signaling, as well as changes to drebrin cluster and postsynaptic density proteins (PSD), which are known to regulate dendritic spine morphogenesis. Together these can lead to neural remodeling (Takahashi et al., 2003).
Evidence Collection Strategy
The strategy for collating the evidence to support the relationship is described in Kozbenko et al 2022. Briefly, a scoping review methodology was used to prioritize studies based on a population, exposure, outcome, endpoint statement.
Evidence Supporting this KER
Overall Weight of Evidence: Moderate
Multiple reviews provide support of biological plausibility between deposition of energy and neuron remodeling. Numerous studies examine the effects of multiple radiation sources including gamma rays, X-rays, protons, heavy ions, alpha particles, and neutrons, on both in vivo and in vitro model systems. The collected data demonstrate changes in the physical and electrophysiological properties of neurons in response to ionizing radiation exposure (Cekanaviciute et al., 2018; Hladik & Tapio, 2016). Irradiation of the brain induces oxidative stress and inflammation, which is linked to the occurrence of neuronal alterations within the hippocampus, an important structure in the process of learning and memory (Jarrard, 1993; Monje et al., 2003; Rola et al., 2007: Lalkovičová et al., 2022). There is no clear understanding on how deposited energy directly affects neuron integrity; however, immature neurons are found to be more radiosensitive and exhibit significant changes in spine density, dendritic spine length, protein clustering, and decreased cell proliferation, leading to reduced dendritic complexity (Manda et al., 2008a ; Mizumatsu et al., 2003; Okamoto et al., 2009; Rola et al., 2005; Shirai et al., 2013). Many neurodegenerative conditions are related to changes in synaptic plasticity, including changes in neuronal connectivity, action potential, and synaptic protein levels (Vipan Kumar Parihar & Limoli, 2013). These alterations occur primarily within the hippocampus and dentate gyrus, two regions of the mammalian brain where adult neurogenesis can occur (Ming & Song, 2011) following ionizing radiation exposure.
Uncertainties and Inconsistencies
One study shows that at a high dose of 90 Gy (X-rays), hippocampal dendritic spine length is increased compared to the control (Shirai et al., 2013). Kiffer et al. found a decrease in spine length in the CA1 subregion of the hippocampus; however, there was an increase in spine length and dendritic complexity in the dorsal dentate gyrus after exposure to 0.5 Gy 1H and 0.1 Gy 16O (Kiffer et al., 2020). Further research involving different regions of the brain is required to identify the effects of deposition of energy on the dentate gyrus.
The study by Krukowski et al. (2018a), as highlighted in a review by Cekanaviciute et al. (2018), found a lack of cellular changes in hippocampal synapse loss and microgliosis in females subjected to low dose ionizing radiation. Another study highlighted in this review showed greater reduction in new neuronal survival in male than female mice in response to 28Si irradiation (Whoolery et al., 2017). Additional data is required to determine if these differences are sex-related or due to other factors. There is a lack of studies performed on female subjects to identify specific sex-related effects of deposited energy on neuron integrity.
Previous studies have found transient changes in neurogenesis after exposure to 56Fe ions at varying doses ranging from 10 cGy to 1 Gy (DeCarolis et al., 2014; Miry et al., 2021https://pubmed.ncbi.nlm.nih.gov/25170435/https://pubmed.ncbi.nlm.nih.gov/33619310/). These studies found early decreases in neurogenesis, although DeCarolis et al. reported that this reduction returned to normal as early as 7 days post-irradiation. In a separate study, Miry et al. (2021) found that at 12 months post-exposure, neurogenesis levels significantly exceeded controls. Other inconsistent studies include Acharya et al. (2019) and Bellone et al. (2015); the former reported decreases in CA1 pyramidal neuron excitability after exposure to 18 cGy of neutron radiation, whereas the latter study reported increases in post-synaptic excitability within CA1 neurons after 0.5 Gy of proton irradiation.
Known modulating factors
Effects on the KER
SB415286 – a potent and selective cell-permeable, ATP-competitive GSK-3β inhibitor, as GSK-3β induces apoptosis in response to various conditions
Treatment with SB415286 provided significant neuroprotection against radiation necrosis within the brain at 45 Gy.
Jiang et al., 2014
N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) – a melatonin metabolite which has antioxidant properties.
AMFK treatment ameliorated levels of reactive oxygen species, and increased number of immature neurons and proliferating cells post-irradiation in vivo. Without the treatment, exposure to radiation led to a significant decrease in DCX positive cells by 81% and Ki-67 positive cells by 86%. (AMFK) treatment provided protection to immature neurons by 45.38% and proliferating cells by 52.35%.
Manda et al., 2008b
PLX5622-1200 ppm (PLX) diet that contains CSF1-R (colony stimulating factor 1 receptor) inhibitor that induces depletion of microglia within 3 days.
The PLX diet was able to significantly increase the levels of the presynaptic protein, synapsin 1 after exposure to helium irradiation.
Krukowski et al., 2018b
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Most evidence is derived from in vivo studies, predominately using rodent models, whereas evidence from dog models is low. The relationship is applicable in both sexes; however, adult males are used more often in animal studies. Limited studies demonstrate the relationship in preadolescent animals.
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