Aside from the skin, the eye is the organ most susceptible to sunlight and artificial lighting induced damage. Solar radiation exposes the eye to UV-B (280–315 nm), UV-A (315–400 nm) and visible light (400–700 nm) (1). Light is transmitted through the eye and then signals the brain directing both sight and circadian rhythm. Therefore, light absorbed by the eye must be benign. However, under certain circumstances, the eye may be damaged by solar and artificial radiation.
Factors which determine light damage to the eye
The primary factors, which determine whether ambient radiation will injure the human eye are the intensity of the light, the wavelength emitted and received by ocular tissues, and the age of the recipient (2).
UV and visible light intensity The greater the intensity of light, the more likely it is to damage the eye. Light that may not ordinarily be harmful can do acute damage if it is sufficiently intense. For example, it is well known that the eye can be damaged (temporarily or permanently) by exposure to reflective sunlight from snow (snow blindness), or from staring at the sun during an eclipse (3,4). There is an increase in UV radiation with a thinning of the protective ozone layer (5). Similarly, the eye can sustain damage from artificial light sources that emit UV-A or UV-B (6). Cumulative light damage results from less-intense exposure over a longer period of time and is often a result of an underlying age-related loss of antioxidant protection (7,8).
Ambient radiation wavelength Ambient radiation, from the sun or from artificial light sources, contains varying amounts of UV-C (100–280 nm), UV-B, UV-A and visible light (1). The shorter the wavelength, the greater the energy and therefore the greater the potential for the radiation to do biological damage. However, although the longer wavelengths are less energetic, they more deeply penetrate ocular tissues (9).
For a photochemical reaction to occur, the emitted wavelengths of light from the source must be absorbed in a particular ocular tissue. The primate/human eye has unique filtering characteristics that determine in which area of the eye each wavelength of light will be absorbed (Fig. 1). All radiation below 295 nm is filtered by the human cornea (all UV-C and some UV-B) before they reach the human lens (10). The transmission characteristics of the human lens changes with age.
In adults, the lens absorb UV-B above 295 nm and all of UV-A. However, the very young human lens transmit a small window of UV-B light (320 nm) to the retina, whereas the elderly lens filters out much of the short blue visible light (400–500 nm) (11). Transmission characteristics through ocular tissues also differs with species; the lenses of mammals other than primates transmit ultraviolet light longer than 295 nm to the retina (12).
Antioxidant system efficacy Most damage by ambient light to the young and adult eye is avoided because the eye is protected by a very efficient antioxidant system. In addition, there are protective pigments located in the young and adult retina and lens, which absorb ambient radiation and dissipate its energy without causing damage (13).
Ordinarily lutein and zeaxanthan in the macular (center) of the retina (14), vitamin E (15,16), glutathione (7) and other antioxidants (17) throughout the eye protects the retina against both inflammatory and photooxidative damage.
Unfortunately with age, these protective agents become depleted. After middle age (40-year old) there is a decrease in the production of ocular antioxidant enzymes and low-molecular weight antioxidants and the retina loses its protection against reactive oxygen species (ROS) toxicity (7,18,19). In addition, the content and function of cardiolipin which facilitates retention of cytochrome c in mitochondria, preventing the cells from apoptosis diminishes progressively in humans with age to the level constituting ca 60% of the value detected in children (20).
The RPE and choroid contains melanin, which absorbs UV and short-wavelength visible light and protects the retina against photic damage. However, with age ocular melanin is photobleached and this decreases its protective effectiveness against UV damage (21).
At the same time, the protective pigments are chemically modified and now these ocular pigments damage the lens and retina on exposure to ambient radiation (21–23).
Mechanism of light damage to the eye
The role of chromophores Chronic exposure to less-intense radiation does damage to the eye through a phototoxidation reaction. In such type of oxidation reactions, a chromophore in the eye absorbs UV or visible light, produces ROS such as singlet oxygen and superoxide and these damage ocular tissues. The chromophore may be endogenous (natural) or exogenous (drug, herbal medication or nanoparticle) that has accumulated in the eye (24).
Absorption of light excites the chromophore to a transient singlet state (Fig. 2). The excess of energy of the chromophore singlet state can be dissipated (13), emitted as fluorescence or used for intersystem crossing to the triplet state. The chromophore can return to its ground energy level by dissipation of the excess of energy or phosphorescence. The chromophore lifetime at triplet state is long enough to let its molecules transfer electrons via a Type I and form free radical or the excess of energy via a Type II to different molecules, for example oxygen and produce its singlet form (singlet oxygen). The reactive species generated during these processes can cause the eventual damage. Photooxidation can occur in the eye either by Type-I or -II mechanism or both concurrently.
Human retina The retina in the mammalian eye is composed of the photoreceptor cells (rods and cones) that receive light and the neural portion (ganglion, amacrine, horizontal and bipolar cells) that transduces light signals through the retina to the optic nerve. Behind the photoreceptor cells are the retinal pigment epithelial (RPE) cells, which are separated from choroid with Bruchs’ membrane.
RPE cells The RPE cells form a single-cell layer that is the most distal layer of the retina. The cells transport ions, water and metabolic end products from the subretinal space to the blood (25), and deliver nutrients, such as glucose, retinol and fatty acids in the opposite direction—from the blood to the photoreceptors. Moreover, the RPE cells phagocyte light-damaged photoreceptor outer segments (POS) (26) in a circadian regulated process, and then shed, digest, recycle and transport the essential elements of their contents back to the photoreceptors (25,27). However, a part of undigested material accumulates with age and is stored in lysosomes as an age pigment called lipofuscin (28) (Fig. 3).
The RPE cells are permanently exposed to factors that potentially induce oxidative stress. Those conditions assure that RPE cells contain high amounts of antioxidant enzymes, such as superoxide dismutase and catalase (25). In addition, the presence of aldehyde dehydrogenase was affirmed in the RPE cells (29). This cytosolic enzyme participates in the oxidation of various aldehydes, including all-trans-retinal. It was shown by Ishibashi et al. (30) that the expression of aldehyde dehydrogenase 6 was reduced in the retinal pigment epithelial cells isolated from older human eyes.
UV damage and “blue light hazard” The young retina is at particular risk for damage from UV exposure because the young lens has not as yet synthesized the yellow chromophore (3-hydroxykynurenine and its o-β-glucoside) that prevents UV transmission to the retina (31). UV damage to the eye is cumulative and may increase the possibility of developing eye disorders (ocular melanoma and macular degeneration) later in life.
In addition to UV damage to the young retina, short blue visible light (430 nm) damages the retina in persons over 50 years of age through photooxidation reactions (2,32–34). The human retinal pigment epithelium (RPE) and the anterior layers of the retina in adults constantly receive intense visible light (>400 nm) (35,36) (Fig. 1). Studies performed on animals including primates have shown that short-term light exposures (<12 h) at relatively high intensity can induce damage in photoreceptors and the RPE cells (33,37,38). The most phototoxic effect was produced by light at wavelengths around 430 nm, then referred as the “blue light hazard” (39,40). Agarwal et al. (41) observed that thickness of the retinal outer nuclear layer, photoreceptor segment length and RPE thickness were 60–70% reduced when rat retinas were evaluated 4 weeks after blue light exposure. Light damage observed in rats resulted in a retinal degeneration exhibiting features of atrophic age-related macular degeneration (AMD), including photoreceptor and RPE degeneration and choriocapillaris atrophy (38). The most recent experiments demonstrated that 6–h blue light (450 nm) exposure of rats caused significant shortening of the photoreceptor inner and outer segment lengths, when retinas were evaluated immediately after irradiation (33). In addition, 40–50% of the photoreceptor nuclei were pyknotic with condensation of chromatin and dark staining nuclei.
The photodamage observed in the RPE cells is oxygen-dependent (42,43) and is diminished by antioxidants (15,31,44,45), which suggests that the blue light effect is associated with oxidative stress. The dramatic changes observed in the photoreceptors and the RPE after light exposure made investigators to find potential chromophores that would be able to absorb light in the blue region and convert excessive energy to production of reactive intermediates. Photoreceptor damage may be mediated through rhodopsin, as blue light (403 ± 10 nm) causes its photoreversal bleaching and increased generation of toxic rhodopsin intermediates (46,47). There are several endogenous RPE chromophores, including melanin, the mitochondrial enzyme cytochrome c oxidase and riboflavin that can act as potential photosensitizers and may be responsible for visible light short-wavelength damage to the RPE (48,49). The reduced form of cytochrome c oxidase absorbs mainly blue light with a maximum at 440 nm (50). Blue light (425 ± 20 nm) can induce generation of ROS by mitochondrial cytochromes (51), inhibit cytochrome c oxidase leading to ATP depletion (52,53), and lead to calcium accumulation (54) and apoptosis (55).
Nevertheless, photoreactivity of melanin, cytochrome c oxidase or riboflavin present in the RPE seems to be negligible compared with a visual cycle retinoid—all-trans-retinal (56–58) or chromophores present in the age pigment—lipofuscin accumulated in age in the RPE cells (59–62).
Macular degeneration The relatively high concentration of oxygen in the retina, exposure to light, age-related changes in the level of antioxidants and the presence of chromophores formed during lifetime in situ or xenobiotics create favorable conditions for oxidative stress (36), which can be a major factor of retinal diseases including macular degeneration.
AMD is the major cause of visual impairment and blindness (63,64) among the elderly in the United States and in European and Australian (Oceanic, Pacific) nations (65–70). It is estimated that more than 1.5% of caucasians at age more than 70 years old suffer advanced form of AMD and another 10% have symptoms of early macular degeneration (64,70). AMD is the disease involving photoreceptors, RPE and the choroid in the elderly eyes. It is initially characterized by thickening of Bruch’s membrane and accumulation of lipid material (drusen) on the inner collagenous layer of the membrane (70) (Fig. 3B). The early stages of AMD can evolve into “wet” form, where blood vessel proliferation is observed or to geographic atrophy (GA) associated with the RPE cell death.
Little is known about AMD etiology. However, several risk factors, namely: aging, tobacco smoking, female gender, hypertension, high-body mass index, a high fat diet and some genetic predispositions are considered as those that can contribute to development of the disease (70–73). Sunlight is an environmental factor that has been identified (39,74), but epidemiologic studies assessing the link between light exposure and AMD have provided inconsistent results. Three cohort based studies (34,75–78) showed an association; case control studies (79,80) failed to confirm this relationship, but the age-related eye disease study (AREDS) (81) did suggest a connection between increased light exposure and AMD. An improved study (AREDS2) is presently being conducted (82). In epidemiological studies performed on 4000+ participants, Fletcher et al. (83) found associations between blue light exposure and development of early stages of AMD as well as its neovascular form in persons who had low levels of antioxidants (vitamin C and E, zeaxanthin) in their blood and low uptake of dietary zinc. Indeed, the role of antioxidants seems to be considerable in AMD. Epidemiological studies have shown that, although there is no evidence that supplementation of antioxidants important in the retina metabolism (lutein, zeaxanthin, vitamin C and E and zinc) (14) prevents early AMD development, but it slows down progression to advanced AMD (81,84). Therefore, oxidative stress seems to be the major mechanism involved in development of the disease (85,86).