Deposition of Energy Leading to Learning and Memory Impairment

Ahmad Sleiman¹, Kathleen Miller², Danicia Flores³, Jaqueline Kuan³, Kaitlyn Altwasser³, Benjamin Smith³, Hailey Adams⁴ Tatiana Kozbenko³, Robyn Hocking³, Carole Yauk⁵, Ruth Wilkins³, Vinita Chauhan³  

(1) Institut de Radioprotection et de Sûreté Nucléaire, St. Paul Lez Durance, Provence, France 

(2) National Institute of Aerospace, Hampton, Virginia, USA 

(3) Consumer and Clinical Radiation Protection Bureau, Environmental and Radiation Health Sciences Directorate, Health Canada, Ottawa, Ontario, Canada 

(4) Radiation Protection Bureau, Environmental and Radiation Health Sciences Directorate, Health Canada, Ottawa, Ontario, Canada

(5) Department of Biology, University of Ottawa, Ottawa, Ontario, Canada

Consultants 

Scott Wood¹, Janice Huff², Christelle-Adam Guillermin³, Nobuyuki Hamada⁴

(1) NASA Johnson Space Center, Houston, Texas, USA 

(2) NASA Langley Research Center, Hampton, Virginia, USA 

(3) Institut de Radioprotection et de Sûreté Nucléaire, St. Paul Lez Durance, Provence, France 

(4) Biology and Environmental Chemistry Division, Sustainable System Research Laboratory, Central Research Institute of Electric Power Industry (CRIEPI), Tokyo, Japan

An adverse outcome pathway (AOP) is described from the molecular initiating event (MIE) of deposition of energy to the adverse outcome (AO) of learning and memory impairment. This AOP uses well-understood mechanistic events that encompass oxidative stress, DNA damage, tissue resident cell activation, altered signaling pathways, neuroinflammation, and their interactions, leading to eventual neural remodeling. The empirical evidence to support this AOP is primarily derived from studies that utilize ionizing radiation stressors relevant to space travel and radiotherapy treatments. Following deposition of energy (MIE, KE#1686), the adjacent key events are oxidative stress (KE#1392), tissue resident cell activation (KE#1492) and increased DNA strand breaks (KE#1635). Uncontrolled radical production within the cell has an adjacent connection with increased DNA strand breaks (KE#1635), altered signaling pathways (KE#2066) and tissue resident cell activation (KE#1492). Tissue resident cell activation has an adjacent connection to increased proinflammatory mediators (KE#1493). Prolonged neuroinflammation and altered signaling pathways have adjacent connections with neural remodeling (KE#2098) and subsequently learning and memory impairment (AO, KE#341). The AOP also includes multiple non-adjacent connections between key events. The overall evidence for this AOP is moderate. Despite multiple knowledge gaps that are present, the evidence demonstrates a high-level of biological plausibility. The quantitative understanding is low as there is high uncertainty in the quantitative predictions between the KEs. This AOP has wide applicability and is particularly relevant to exposures from long-duration space flight and medical exposures using radiation therapy. 

Understanding the impact of ionizing radiation on non cancer outcomes of the central nervous system (CNS) is essential as there are many possibilities for exposure including from medical procedures and occupational settings (e.g. astronuats). Various studies have reported cognitive deficits after high-doses of radiation from radiotherapy treatments, though there is a reported individual variability in human cohorts (Greene-Schloesser et al., 2012; Katsura et al., 2021; Turnquist et al., 2020). In preclinical animal models, studies suggest that even low-to-moderate doses of ionizing radiation from heavy ions can cause structural and functional impairments to the CNS including reductions in neurogenesis, changes in dendritic properties, activation of glial cells, and neuronal remodeling (Cekanaviciute et al., 2018; Kiffer et al., 2019b). However, how key changes in structural and functional properties of the CNS from ionizing radiation exposure are related to changes in cognitive function have yet to be delineated. Furthermore, preclinical studies also suggest that ionizing radiation may impact two major cognitive processes: learning and memory. Learning is the ability to create new associative or non-associative relationships and memory is the ability to recall sensory, short-term or long-term information (Desai et al., 2022, Kiffer et al., 2019b). Both learning and memory involve multiple brain areas including the hippocampal region, as well as the amygdala, the prefrontal cortex and the basal ganglia (Cucinotta et al., 2014; Desai et al., 2022; NCRP Commentary, 2016). Thus far, direct pathways linking  radiation to key cellular and molecular events leading to an AO of impaired learning and memory have not been established.   This AOP can serve as a starting pathway for expansion to other cognitive disorders and CNS diseases from an MIE of deposition of energy. 

The development strategy for this AOP has been described by Kozbenko et al., 2022. In brief, a structured literature search was conducted that included screening and prioritization of the references. Initial searches involved study inclusion through key words relevant to the MIE and AO, followed by focused searches for each of the KEs and KERs. Studies at all levels of biological organization, regardless of the species, life stage, or sex, were considered. References were excluded using a Population, Exposure, Outcome, Endpont (PEOE) statement. Studies were included if they met definitions of a population (human, mouse, rat, etc.), exposure (i.e., radiation), and/or mention of one of the key events (KEs) or outcome (AO) of interest. Studies were excluded if they lacked full text, and/or were not a peer-reviewed manuscript (i.e., thesis/dissertations, presentations, posters or conference abstracts). Non-English studies were included provided the data could be identified within the abstract. Relevant studies were identified in the context of the modified Bradford Hill criteria, which contain biological plausibility, temporal-, dose-, incidence-concordance, and essentiality. 

Pre-screening was completed using SWIFT Review (http://www.sciome.com/swift-review/version 1.43). In SWIFT, software generated tags were created based on study abstracts that helped group references and create lists to aid in prioritizing relevant studies. Reviewers could include or exclude references based on the tags and abstracts.  DistillerSR (Evidence Partners. www.evidencepartners.com/products/distillersr-systematic-reviewsoftware released 12.06.2020 version 2.34.0R) was then used in a three-level screening exercise: Title and Abstract (Level 1), Full-Text (Level 2), and Data Extraction (Level 3). Human screeners used the PEOE statement to assess relevance for inclusion or exclusion. At the data extraction level, studies needed to support elements of  the Bradford Hill criteria, including taxonomic (human, animal) and life-stage (adult, children) applicability. A final screening of all studies was conducted manually to ensure data was relevant to the KERs in the pathway in the context of the Bradford Hill criteria. No risk-of-bias evaluation was undertaken.  

Summary of evidence (KE & KER relationships and evidence) 

This AOP was derived from data that investigates the CNS of humans, animals and cellular models following exposure to ionizing radiation. Stressors in the present pathway include a range of doses (low (<0.1 Gy) to high (>1 Gy) doses), dose rates and radiation qualities (low-LET and high-LET) with an emphasis on low-to-moderate (0.1-1 Gy) dose heavy-ion studies relevant to space travel. The goal of this AOP is to model the connectivity of the MIE of deposition of energy through the cellular and biological KEs that lead to the AO of impaired learning and memory. The KEs chosen for this AOP had strong biological plaucibility with available empirical evidence, however, other KEs may be added later to incorporate new mechanisms and AOs into its broader network. The pathway is applicable to  multiple stressors of deposition of energy including radiation exposure from space travel and radiotherapy.  

Biological Plausibility 

The overall biological plausibility in this AOP is high. The KERs in the AOP have either moderate or high evidence for mechanistic relationships between the upstream and downstream KEs. The KEs are well-studied, and an understanding of the structural and functional linkages are well-established.  

This AOP is initiated with deposition of energy. Deposition of energy can damage DNA via direct mechanisms, by which the electrons ionize DNA molecules themselves, or via indirect mechanisms, by which the ionization of water produces hydroxyl radicals that can damage DNA bases causing DNA strand breaks (Nikjoo et al., 2016; Wilkinson et al., 2023) or directly upregulating enzymes involved in reactive oxygen and nitrogen species (RONS) production (i.e., catalase)  (de Jager, Cockrell and Du Plessis, 2017). Both reactive oxygen species (ROS) as well as reactive nitrogen species (RNS) (Ahmadi et al., 2022; Karimi et al., 2017; Slezak et al., 2015; Tahimic & Globus, 2017; Wang et al., 2019a) may be produced after deposition of energy. If RONS cannot be eliminated quickly and efficiently by the cell’s defense system, oxidative stress ensues (Balasubramanian, 2000; Ganea & Harding, 2006; Karimi et al., 2017). Within the brain, oxidative stress can lead to the activation of microglial cells (Fishman et al., 2009; Schnegg et al., 2012; Zhang et al., 2017) and astrocytes (Daverey & Agrawal, 2016; Wang et al., 2017). These cells then release pro-inflammatory mediators and initiate antioxidant defenses (Lee, Cha & Lee, 2021; Simpson & Oliver, 2020). However, if the antioxidant capacity is overwhelmed, chronic inflammation may result. 

Oxidative stress can also lead to altered signaling pathways. Directly, ROS causes oxidation of amino acid residues resulting in conformational changes, protein expansion, and protein degradation. This can cause changes in the activity and level of signaling proteins (Ping et al., 2020; Li et al., 2013). Oxidation of key functional amino acids can also alter the activity of signaling proteins, resulting in downstream alterations in signaling pathways (Ping et al., 2020; Schmidt-Ullrich et al., 2000; Valerie et al., 2007; Lehtinen & Bonni, 2006; Ramalingam & Kim, 2012). DNA strand breaks from oxidative damage can activate DNA damage response signaling and modify the expression of other signaling proteins (Ping et al., 2020; Nagane et al., 2021; Schmidt-Ullrich et al., 2000; Valerie et al., 2007). 

Both increased pro-inflammatory mediators and altered signaling pathways can lead to neural remodeling. Various pro-inflammatory cytokines can affect neural remodeling, the most common being IL-1β, TNF-α, IL-6 and IFN-γ. During an inflammatory response, these cytokines act on different receptors to initiate several signaling pathways to induce neuronal degeneration, apoptosis or to propagate further pro-inflammatory responses (Mousa & Bakhiet, 2013; Prieto & Cotman, 2018). These signaling pathways include, but are not limited to PI3K/Akt pathways, MAPK pathways, senescence signaling, and apoptosis pathways. The PI3K/Akt and MAPK pathways are involved in many processes in neurons, including cell survival, morphology, proliferation, differentiation, and synaptic activity (Davis and Laroche, 2006; Falcicchia et al., 2020; Long et al., 2021; Mazzucchelli and Brambilla, 2000; Mielke and Herdegen, 2000; Nebreda and Porras, 2000; Rai et al., 2019; Rodgers and Theibert, 2002; Sherrin, Blank, and Todorovic, 2011). The apoptosis pathway influences cell number, while senescence signaling can influence the regenerative potential of the cell and therefore, neurogenesis (Betlazar et al., 2016; McHugh and Gil, 2018; Mielke and Herdegen, 2000). Disruptions to components of these pathways will lead to neuronal remodeling, which includes alterations in both morphological properties and functional properties of the neurons (Betlazar et al., 2016; Davis and Laroche, 2006; Mazzucchelli and Brambilla, 2000; Nebreda and Porras, 2000). However, the biological changes that follow perturbation of these pathways is not understood in every context and cell type, making the biological plausibility for this relationship moderate (Nebreda and Porras, 2000). Decreased morphological properties of neurons, including reductions in dendritic complexities and spine densities, as well as altered functional properties of neurons including altered synaptic signaling and neurogenesis, has been associated with learning and memory impairment (Bálentová & Adamkov, 2020; Hladik & Tapio, 2016; Monje & Palmer, 2003; Romanella et al., 2020; Tomé et al., 2015). 

Empirical Support (Temporal, Dose, and Incidence Concordance) 

This AOP demonstrates moderate empirical evidence to support the modified Bradford Hill criteria. Overall, many studies demonstrated that upstream KEs occurred at lower or the same doses and at earlier or the same times as downstream KEs. There were some inconsistencies where the KEs were only measured at one dose or time. The evidence collected was gathered from various studies using in vitro and in vivo rat, mice, rabbit, squirrel, bovine and human models. Various stressors were applied, including UV, UVB, UVA, gamma ray, X-ray, protons, alpha particle, neutron, and heavy ion irradiation. 

Regarding time concordance, deposition of energy occurs immediately following irradiation, and downstream events will always occur at a later time-point. DNA damage occurs within nanoseconds of deposition of energy with DNA strand breaks measured from seconds to minutes later and altered signaling measured minutes to days later (Acharya et al., 2010; Antonelli et al., 2015; Mosconi et al., 2011; Rogakou et al., 1999; Rothkamm and Lo, 2003; Sabirzhanov et al., 2020; Zhang et al., 2017). Rapid increases in ROS (Limoli et al., 2004; Giedzinski et al., 2005; Suman et al., 2013) and activation of microglia and astrocytes have been observed within hours of irradiation and can persist for 12 months (Kyrkanides et al., 1999; Hwang et al., 2006; Suman et al., 2013). For tissue resident cell activation and increase in pro-inflammatory mediators, studies generally show that these events occur at a similar time frame (Parihar et al., 2018; Liu et al., 2010; Dong et al., 2015; Lee et al., 2010; Zhou et al., 2017). The alteration of signaling pathways is a molecular-level KE like oxidative stress, and both can occur concurrently (Xu et al., 2019), although increased ROS levels can be initiated significantly before altered signaling pathways (Suman et al., 2013). Neural remodeling has been observed at various time points from hours to months after exposure to a stressor, and its upstream KEs (altered signaling and increased pro-inflammatory mediators) generally appear earlier (Kanzawa et al., 2006; Limoli et al., 2004; Pius-Sadowska et al., 2016) or at similar times, respectively (Zonis et al., 2015; Wong et al., 2004, Green et al., 2012; Ryan et al., 2013; Vallieres et al., 2002). In response to irradiation, impaired learning and memory is typically observed at similar time-points of neural remodeling due to the timing of measurements (Raber et al., 2004; Parihar et al., 2016; Madsen et al., 2003; Winocur et al., 2006; Rola et al., 2004).  

Regarding dose concordance, multiple studies also demonstrate that the upstream KEs occur at lower or the same doses as downstream KEs as energy is deposited immediately at any dose of radiation. Some studies report a linear-dose-dependent increases in DNA strand breaks for a large range of doses (Antonelli et al., 2015; Hamada et al, 2006; Rübe et al., 2008). In addition, neural precursor cells irradiated with protons at 1, 2, 5 and 10 Gy showed a dose-dependent increase in ROS levels (Giedzinski et al., 2005). In another study, activation of microglia and astrocytes were seen at doses as low as 5 cGy that persisted to 30 cGy (Parihar et al., 2018). However, dose concordance is not consistently observed across studies, which can be attributed to differences in experimental design. Some studies also only measured the key events at one dose, which presented further inconsistencies.  

Few studies showed incidence concordance where the upstream KE demonstrated a greater change than the downstream KE following a stressor. Not all KERs displayed an incident-concordant relationship, but for those that did, only a small proportion of the empirical evidence supported this relationship. For example, mice exposed to 2 Gy of gamma irradiation showed increases of pro-apoptotic markers p53 and BAX by 8.4- and 2.3-fold, respectively. A 0.6-fold decrease in Bcl-2 (anti-apoptotic marker) was also observed, and gamma rays cause a decrease in cortical thickness by 0.9-fold (Suman et al., 2013).

Uncertainties, Inconsistencies, and Data Gaps 

There are a few inconsistencies in this AOP. Some studies show sex-specific changes in the KEs. For example, two studies reported that tissue resident cell activation was not affected in female mice after 0.3 and 0.5 Gy of radiation (Krukowski et al., 2018a; Parihar et al., 2020) while a separate study showed that only female mice had activated cells after 2 Gy (Raber et al., 2019). Another study reported a greater radiation-induced reduction in neurogenesis in male mice compared with female mice (Kalm et al., 2013). More research is necessary to identify if these results are sex-specific or due to other modulating factors.  

There have been some inconsistencies reported in the KER Deposition of Energy (KE#1686) to Increase DNA Strand Breaks (KE#1635). For example, dose-rates and radiation quality may influence dose-response relationships (Brooks et al., 2016, Sutherland et al., 2000; Nikjoo et al., 2001; Jorge et al., 2012). More research is necessary to understand the impact low-doses of ionizing radiation exposure on DNA damage as some studies report low-dose exposures may invoke protection against spontaneous genomic damage (as reviewed by ICRP (2007) and UNSCEAR (2008)).  

Anatomical location of change in the KEs may impact its response. For example, in response to ionizing radiation, changes occurred in hippocampal dendritic spines CA1 subregion of hippocampus but not in the dorsal dentate gyrus (Kiffer et al., 2019a).  

Changes in KEs and the AO may be dose and stressor specific when assessed using animal models. For example, cue feared conditioning, a measure of learning and memory had different responses in mice at 0.2 Gy vs. 1 Gy of 28Si exposure (Whoolery et al., 2017). Also in mice, object memory was impaired after 0.1 or 0.25 Gy 16O exposure and social novelty learning was impaired after 0.25 Gy 16O exposure, but neither dose impaired short-term spatial memory (Kiffer et al., 2019a). 

Changes in signaling pathways may provide inconsistent outcomes in neural remodeling.  For example, the p38 pathway is involved in many, often opposing, biological processes (Nebreda and Porras, 2000). Furthermore, the MAPK pathways can exhibit varied responses after exposure to oxidative stress (Azimzadeh et al., 2015).  

Many studies do not report direct measures of oxidative stress. As free radicals are quickly scavenged, the quantitative understanding of this relationship can be inconsistent, due to varied response of antioxidant enzymes across experimental conditions and time measurements. This has led to some inconsistencies within the KERs. For example, in contrast to other studies demonstrating an increase in oxidative stress following deposition of energy, neutron radiation decreased malondialdehyde, a product of oxidative stress (Chen et al., 2021).  

Finally, many of the KERs do not include studies in humans. More research could be done to observe these relationships in human models. 

There were multiple challenges present in the development of this AOP which identified gaps in the data. The majority of the evidence for this AOP is extracted from preclinical animal and cellular models. Therefore, the low availability of human studies presents a challenge as translation of the animal and cellular models to humans is difficult due to differences in physiology, methods and measurements. In addition, although both age and sex are listed as modulating factors, there is more research necessary to elucidate the interaction between age and sex on the KEs, particularly how these factors may modulate the causal connectivity of the relationships and the AO. Direct comparisons between studies were also difficult due to differences in model, radiation quality, dose, dose rate and endpoint which led to some inconsistencies. Many studies reported limited dose ranges or time-points and often measured a single KE, limiting evidence for direct KERs.  The current AOP has low quantitative evidence supporting the KERs, however, this AOP can be expanded with experiments that further exemplify the level of dose- and time- concordance across multiple endpoints.  This will improve the quantitative understanding of the relationships which can then support the development of risk models and tools for mitigating risk. 

This AOP was developed to bring together mechanistic knowledge in the area of impairments in learning and memory from exposure to  radiation. It includes studies from multiple species at multiple life stages and radiation exposures that contain different doses, dose-rates, and radiation qualities. Relevant studies have been  selected, consolidated, and reported using the framework.  

There are multiple considerations for potential applications of the AOP. Since exposure to radiation can occur in humans from multiple events, including occupational settings, accidental exposures, nuclear events, radiotherapy treatment and space travel, understanding its impact on CNS structure and function is essential. This AOP outlines a biological framework for the connection between the MIE and AO. It can be expanded to other pathophysiologies of the CNS. The qualitaive information presented within each KER can be used to inform on risk-model strategies,  countermeasure development, and identification of gaps in the evidence base where more research is necessary. Importantly, this AOP is a dynamic document so it can be modified as new evidence emerges.

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