Radiation Cataractogenesis Research Paper
Radiation cataractogenesis (RCG) is deterministic. It does not occur below a minimum threshold dose. RCG is generally believed as dose-related. Sliney (1986) believed that its severity is also dose-related. The severity increased and the latency decreased as radiation dose increased above that threshold. The lens of the eye is nonvascular and is known to experience no cell loss over its lifetime, indicating that any damage to its cells will not result to the removal of these cells for lack of existing mechanism. Three induction mechanisms were explored (direct, indirect, and oxidative, which separately creates oxidative stress inside the lens and stimulates cascades of events in radiation cataractogenesis through either the genetic or the biochemical path or both simultaneously. Both paths lead to the calcium oxalate-rich crystallin aggregates called retrodots, which later transform into darker spheroliths that populate advance cataracts. Current understanding of these mechanisms and developmental paths expands their application to other fields such as radiotherapy and nutrition.
1.0 Background information
Radiation cataractogenesis (RCG) is deterministic. It does not occur below a minimum threshold dose. RCG is generally believed as dose-related. Sliney (1986) believed that its severity is also dose-related. The severity increased and the latency decreased as radiation dose increased above that threshold (Shore, Neriishi & Nakashima, 2010). However, the exact minimum threshold has been subject to many ongoing studies and controversy as to which threshold estimate will be acceptable as valid or useful as reference standard. The International Commission on Radiological Protection (ICRP) defined the threshold for absorbed radiation dose upon brief exposures of at 0.5 – 2 Gy to cause detectable lens opacities (ICRP, 2011). However, cataract surgery dose threshold among A-bomb survivors ranged between zero to only 0.8 Gy (Shore, Neriishi & Nakashima, 2010).
Another controversial issue involves the causative mechanisms of radiation damage. It has been accepted that cataractogenic radiation damage occurs either by direct or oxidative mechanism (Shore, Neriishi & Nakashima, 2010). However, Sliney (1986) noted that direct damage (e.g. by direct ultraviolet radiation [UVR]) has very limited value due to the fact that most 300-nm UVR exposure upon the crystalline lens is indirect and scattered even at the peak irradiance period between 9:00 a.m. and 3:00 p.m. Moreover, the UVR exposure upon the eye came from the ground reflections and from the sky near the horizon. This means that, apart from the controversial probability of direct radiation damage, an indirect mechanism had been involved in RCG. Nonetheless, this essay aims to understand the RCG mechanism.
2.0 Mechanism of radiation cataractogenesis
The lens of the eye is nonvascular and is known to experience no cell loss over its lifetime, indicating that any damage to its cells will not result to the removal of these cells for lack of existing mechanism (Shore, Neriishi & Nakashima, 2010). This damage can result in opacities referred to as ‘cataracts.’
The RCG literature in many mammalian species, their clinic-histopathological changes similar (Kleinman, et al., 2007), indicates several types of radiation that are involved: heavy charged particles, neutrons, gamma radiation, X-ray, ultraviolet, microwaves, and white light (Wolf, et al., 2008). Radiation damage occurs through two mechanisms: direct and oxidative (Shore, Neriishi & Nakashima, 2010). In both mechanisms, similar events occur: DNA breakage, aberrant cell migration, and complex biological changes that cause the abnormal crystalline protein to fold, and unregulated lens cell morphology.
2.1 Initial inductive mechanisms
Direct and indirect mechanisms: In these mechanisms, the above-threshold radiation level immediately causes direct changes in the internal lens proteins (Wolf, et al., 2008; Ozgen, et al., 2012). Oftentimes this involves direct energy transfer to the anterior surface of the lens. The human cornea, generally, absorbs almost all wavelengths higher than 3000nm (infrared radiation C [IR-C]) and most radiation above 1400nm wavelength (infrared radiation A [IR-A]) (Voke, 1999). Some radiation between 900nm and IR-A are also absorbed. The same is true with the ultraviolet radiations. The only difference between the two radiation-wave ranges is the level of energy they bring to the lens. Infrared photons have much lower energy than that of the ultraviolet photons.
The greatest concern rests in the heating effect that these radiations had to the lens (and the retina) (Voke, 1999). Lens has different reactions to these radiations. It absorbs only a small portion of infrared while much of ultraviolet. For infrared to cause damage to the lens, the overall exposure must be very high or continuous. Through a buildup of temperature, radiation heat damages the anterior surface where dividing cells form a clear crystalline protein fiber that migrates toward the posterior pole of the lens, particularly the subcapsular (PSC) region.
Oxidative mechanism: Oxidative stress is considered the major initiating event in the cataractogenesis induced by other agents, not only radiation (Kleinman, et al., 2007). In age-related cortical cataracts, for instance, the accumulation of DNA, nuclear, and mitochondrial debris appeared among ROS at damaged sites. In this mechanism, however, irradiation from the environment, not mediated by any direct assault on the lens, triggers the formation reactive oxygen species (ROS), without direct energy transfer (Wolf, et al., 2008). Changes in cellular potential, membrane function, mitochondrial viability and DNA damage immediately followed (Kleinman, et al., 2007).
Although these three inductive mechanisms differ in important aspects, it is largely evident that separately each creates oxidative stress inside the lens, which becomes the primary stimulus in the subsequent cascades of events in radiation cataractogenesis.
Furthermore, although oxidative changes in the lens may result to varied levels of pathologic changes, this essay will focus only on two most common paths: genetic and biochemical processes.
2.2 Major paths in radiation cataractogenesis
2.2.1 Genetic path
Current theory goes that a crisis occur when O2 enters the lens at surface sites stripped of LEC, altered the normal anaerobe status of the lens (Kleinman, et al., 2007). Then, increased production and accumulation ROS followed towards a level beyond enzymatic control. In fact, the presence of massive ROS had been observed in developing cataracts. The cataractogenesis is marked by rapid metabolic and cellular changes.
The accumulated ROS damages the ATM and HRAD9 genes, which play critical roles in the multiple cellular response to DNA damage, and makes the lens epithelial cells (LEC) more sensitive to radiation-induced transformation (Kleinman, et al., 2007; Wolf, et al., 2008). Lens protein coagulation had been reported too.
The ATM and HRAD9 genes are important in maintaining genomic integrity of the LEC at least partly by regulating cell cycle checkpoints that radiation induced, in DNA repair, and in apoptosis (Kleinman, et al., 2007). ATM gene encodes the serine/threonine protein kinase called ataxia telangiectasia mutated (ATM). The enzyme gets activated in the presence of DNA double-strand breaks (Shiloh & Ziv, 2013). HRAD9 is a cell cycle checkpoint control gene that encodes 414 amino acids (Hopkins, et al., 2003). Upon exposure to radiation, for instance, it gets damaged, and becomes vulnerable to ATM kinase phosphorylating activity.
It is not yet fully known how many other genes are damaged by the ROS accumulation. However, as oxidative stress and the subsequent ROS production increased, it is believed that the haploin-sufficiency for RAD9 reduce the ability of the lens cells to repair the accompanying DNA damage, leading to increased cataract frequency. These unrepaired DNA damages interfere with LEC differentiation, resulting to an incomplete development (Wolf, et al., 2008). The damaged LEC then behaves abnormally, migrating from the lens surface at inappropriate sites with accompanying localized ROS. The abnormal migration behavior, in theory, may have been a result of the interaction between integrin beta-1 (ITGB1), TGF-ß2, and focal adhesion kinase. ITGB1 is a fibronectin (glycoprotein) membrane-receptor involved in cell adhesion and recognition in a variety of processes including tissue repair (Srichi & Zent, 2010). The transforming growth factor-ß2 (TGF-ß2) is a cytokine (an extracellular glycosylated protein) that stunts local tumor immune response (Park, et al., 2012).
Although, the progenitor LEC survived the irradiation, they contain retained DNA damages (strand breaks and abnormal chromosome content), needing repair, exhibit an abnormal functional behavior wherein the damaged DNA continue to replicate (Wolf, et al., 2008). The gene phosphorylation in this pathway may have failed due to the initial radiation damage and propagated in the descendant LEC. The cataract development speed is half-dependent on the rate of damaged LEC replication, the aberrant differentiation, and the migration to the posterior pole, and on the radiation exposure dose above the threshold (Kleinman, et al., 2007).
Slit-lamp biomicroscopy studies showed clinic-histopathological changes in RCG that conform to distinguishable stages (Kleinman, et al., 2007). Initial presentation of RCG usually involves a posterior superficial opacification of the lens, referred to as ‘posterior subscapular cataract.’ These interior changes are theorized as a result to concentration of such ions as calcium flux and other molecular changes in the lens crystallins (Wolf, et al., 2008).
2.2.2 Biochemical path
Foundation of the biochemical path in radiation cataractogenesis resides in the extensive biochemico-histopathological studies of Bron, Brown, and colleagues (Bron & Brown, 1987, 1983; Bron & Matsuda, 1981; Bron & Habgood, 1976; Brown, 1971). In this theory, vulnerability of the lens occur when the antioxidative protective system, the most significant of which is the glutathione system, weakens through a drop in its most significant biochemical components, such as glutathione peroxidase, superoxide dismutase, and ascorbic acid (Bron & Brown, 1987).
Ascorbic acid, for instance, is abundant in human adult lens (more than the aqueous levels) at a normal level of 24.1 mg/100 g wet weight, about 20 – 40 times the plasma levels (Bron & Brown, 1987). It is believed that the ciliary epithelium actively secretes ascorbic acid. Ascorbic acid is a powerful oxidative inhibitor in the photo-oxidation of amino acids such as tryptophan. Comparatively, immature cataractous lens only contain 6.7 mg/100 g; while mature cataracts, 5.8 mg/100 g. Conversely, glutathione is found in normal lens at 354.3 mg/100 g. Immature and mature cataracts contain only 29.6 mg/100 g and 3.2 mg/100 g, respectively.
Bron and Brown (1987) believed that continued irradiation assaults at the lens results to the oxidation of these protective substances, making the lens increasingly vulnerable upon continued and persistent assaults. The earliest change to occur upon exposure to ionizing radiation is the fall in glutathione levels even when ascorbic acid remains unchanged. Some studies, however, noted a combined fall of glutathione and ascorbic acid.
The loss of reduced glutathione results to the formation of protein-protein disulphides and protein-glutathione disulphides (Bron & Brown, 1987). These events further lead to the formation of crystallin aggregates, which are insoluble and of high molecular weight.
In addition, oxidation of ascorbic acid through the assaults of radiation results to the formation of hydrogen peroxide, which increases POS challenge in the lens and further oxidize both glutathione and ascorbic acid. At biological pH, ascorbic acid, particularly the L-isomer, is readily, but reversibly, oxidized to L-dehydroascorbate, which can be further degraded through 2,3 diketo-L-gulonic acid involvement to L-theonic acid and oxalic acid by oxidation (or to L-lyxonic acid by carboxylation).
The cataractogenic process proceeds once oxalic acid, usually in the form of calcium oxalate, continues to accumulate as a metabolic end product, 89-99 percent of which is normally excreted in the urine if those found in the lens find their way to the bloodstream (Bron & Brown, 1987). Increased levels of calcium oxalate in the lens eventually aggregate to form retrodots, opacities that are also high in calcium, low in sulphur, and lacking in phosphate. These crystalline structures reside mainly in the deep lens cortex (but also found in the nucleus). They are the early precursors of the dark-looking spheroliths, which are most commonly found in advanced cataract.
Although, the precise inducing mechanisms of radiation cataractogenesis remains unknown, or at least not fully known, scientists generally accept that genomic damage leads to altered cell division, abnormal lens fiber cell differentiation and/or transcription (Kleinman, et al., 2007). The probable roles of the ATM and HRAD9 genes open the possibility to explain the variations in human reaction to radiation incidents, and the possibility that certain subsets of human population may be genetically predisposed to radiation effects, not just with cataractogenesis, and other subsets not as sensitive to the same levels of irradiation.
It is likely that these genetic changes resulting from irradiation may have occurred as a result of or in parallel with the biochemical changes that also occurred in the lens due to continued or substantial radiation assaults and the consequent formation of POS. The biochemical path provides a perspective that may indicate that threshold levels in irradiation dose may not only be the only critical factor in the formation of POS that eventually cascaded into genetic and biochemical deterioration in the lens. Apparently, continued exposure to below threshold levels may still initiate the radiation cataractogenesis in humans.
Current understanding of the mechanisms of irradiation impacts on the lens and the genetic and biochemical paths of cataractogenesis expand the application of these scientific developments to other fields such as radiotherapy. Nutrition also appeared critical in protecting the human lens from the unavoidable radiation assaults from the environment or the workplace, either through mechanisms direct, indirect or oxidative.
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