Named Series: Fatigue, Brain, Behavior, and ImmunityThe biobehavioral and neuroimmune impact of low-dose ionizing radiation☆
Introduction
The impact of ionizing radiation on behavior and neuroimmunity is an emerging field. Currently, the primary focus is on clinically delivered radiation therapy to oncology patients and the consequent adverse biobehavioral impact these critical treatments engender (Bower et al., 2009, Hofman et al., 2007, James, 2006). Therapeutic radiation involves delivery of relatively high doses (30–80 Gy/14–60 days) administered focally and strategically to limit treatment of uninvolved normal tissues (Lawrence et al., 2008). The majority of patients receiving radiotherapy over the past century have been treated with electrons, X-rays (high energy photons) or gamma-rays (high energy photons). The distinction between X- and gamma-rays from a radiotherapy perspective relates to the source of the photons: X-rays originate from outer electrons and gamma rays originate from atomic nuclei. In radiotherapy applications, however, both X- and gamma-rays are photons in the 1–20 MeV energy range. The physical properties of these forms of radiation cause maximal energy deposition (dose) to occur early in the tissue particle track at depths of 0.5–4 cm. Recently, there has been renewed interest in treating patients with heavier charged particles such as protons, which deposit the majority of their dose toward the end of the tissue particle track at depths up to 20–30 cm. This affords more focused delivery of dose to deeply seated neoplasms with less radiation being administered to tissues more distal to the target (Evaluation Subcommittee of ASTRO’s Emerging Technologies Committee, 2009). In addition to the differences in macroscopic dose distribution, photons and protons create disparate microscopic dose distributions due to dissimilar linear energy transfer (LET) coefficients. Importantly, differences in microdosimetric track structure may cause photons and protons to have qualitatively and quantitatively unequal dose-toxicity profiles (Cengel et al., 2010).
In contrast, environmental radiation exposure is ubiquitous, of very low-dose (approximately 6.2 mGy/year) (Schauer and Linton, 2009), whole body and comprised of a mix of particle types that include photons, electrons, protons and heavy ions. This environmental dosage, however, can jump significantly at altitudes that commercial aircraft fly (approximately 6.30–6.79 μGy/h (Mohler, 2003)), in manned space exploration (approximately 50–100 μGy/day during interplanetary travel and 25–50 μGy/day on planetary surfaces (Cucinotta and Durante, 2006)) or during a severe nuclear reactor accident such as occurred at Fukishima Daiichi Nuclear Power Plant in Japan 2011 (ground air as high as 1 Gy) (Makhijani, 2011, Weissmann, 2011). Environmental radiation can be markedly compounded during a solar particle event (SPE) with doses reaching 1.4 Gy/h for skin, 0.8 Gy/h for eyes and 8 cGy for bone marrow in data modeling studies from the August 1972 SPE (Parsons and Townsend, 2000). In addition, SPE irradiation is primarily comprised of relatively superficially penetrating protons with energies less than 50 MeV. The energy spectra of a specific SPE, however, is highly variable and some SPES have had a greater proportion of deeply penetrating, higher energy protons. With the anticipation of expanded near space/space tourism/travel, nuclear power plant construction and threat of nuclear terrorism, the population at risk for total body radiation exposures in the range of 0.5–2 Gy are likely to increase appreciably.
Total body exposure to ionizing radiation can lead to acute radiation syndrome (ARS) that includes the initial prodromal stage defined by nausea, vomiting and diarrhea (N–V–D stage) (Donnelly et al., 2010). An underappreciated component of the prodromal stage is neuroimmune system-mediated sickness symptoms often described as feelings of unease and weakness with an associated lack of motivation and energy (Hofman et al., 2007, Marquette et al., 2003, Young, 1987). Like other maladies associated with weariness and malaise, radiation-induced fatigue is a complex interplay of mental, emotional and physical biobehaviors that are often ignored due to concerns over the manifest illness stage and, ultimately, survival. The first radiation-induced behavioral effects involving the dose and type(s) of radiation present in SPEs were delineated in animals (predominantly primates) during the 1970s and 80s. Memory and cognition testing in monkeys irradiated at dose rates of 0.3, 0.8 and 1.8 Gy/min, (total dose of 10.0 Gy) showed that hampered performance occurred in 81% of animals at 1.8 Gy/min but only in 7% of animals at 0.3 Gy/min. Thus, the effective dose for radiation-induced performance deficits was estimated to occur at doses of 3 Gy or less (Bogo, 1988). In addition, behavioral test complexity appeared impacted by ionizing radiation with tasks requiring greater physical exertion being affected more (Bogo, 1988). As for rodents, conditioned taste aversion could be induced at doses as low as 0.25 Gy (Bogo, 1988). Interestingly, 3 Gy of proton radiation caused a decrease in latency to fall in rotarod testing and loss of acoustic startle habituation (Pecaut et al., 2002). In sum, almost all studies reporting on the behavioral impact of low-dose radiation (⩽10 Gy) examined endpoints of days to weeks post radiation. Therefore, almost nothing is known about the immuno behavioral impact of low-dose ionizing radiation within hours after exposure.
Section snippets
Materials
All reagents and chemicals were purchased from Sigma–Aldrich (St. Louis, MO) except as noted. RNAlater (AM7021) and RiboPure Blood Kits (AM1928) were purchased from Ambion (Austin, TX). QIAGEN RNeasy Lipid Tissue Mini Kits (Cat No. 74804) were purchased from QIAGEN (Valencia, CA). Reverse transcription kits and primers for qPCR were purchased from Applied Biosystems (Foster City, CA). Plastic containment cubes (AMAC530C) were purchased from AMAC Plastic Products (Petaluma, CA).
Animals
Animal use was
Gamma radiation but not proton radiation reduces mouse locomotor activity
Fig. 1A shows that restraint-10 mice exposed to 50 or 200 cGy of gamma radiation (44.5 ± 0.1 cGy/min) had, respectively, a 33.8% and 35.1% reduction in spontaneous distance moved (locomotion) 6 h post irradiation compared to sham irradiated mice. Fig. 1B shows that mean velocity of movement (velocity) was reduced 6 h post irradiation at both 50 and 200 cGy of gamma radiation by 34.7% and 35.7%, respectively. When 50 or 200 cGy of gamma radiation was delivered at approximately 1/100 the dose rate (0.5 ±
Discussion
Near continuous exposure to environmental ionizing radiation of a very low-dose rate is omnipresent. With certain occupations and in certain circumstances, dose rate can increase such that a modest dose of radiation (200 cGy) is received in a relatively short period of time (>8 h). In humans, these exposures are increasing in frequency (nuclear accidents) and becoming better recognized (SPEs). When ionizing radiation doses are significant in duration or energy to cause ARS, prodromal stage
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This research was supported the National Institutes of Health (DK064862, NS058525 and AA019357 to G.G.F.) and by the NSBRI CARR Grant. The NSBRI is funded through NASA NCC 9–58.