Light damage in Abca4 and Rpe65rd12 mice.
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Journal: 2014/May - Investigative Ophthalmology and Visual Science
ISSN: 1552-5783
Abstract:
OBJECTIVE
Bisretinoids form in photoreceptor cells and accumulate in retinal pigment epithelium (RPE) as lipofuscin. To examine the role of these fluorophores as mediators of retinal light damage, we studied the propensity for light damage in mutant mice having elevated lipofuscin due to deficiency in the ATP-binding cassette (ABC) transporter Abca4 (Abca4(-/-) mice) and in mice devoid of lipofuscin owing to absence of Rpe65 (Rpe65(rd12)).
METHODS
Abca4(-/-), Rpe65(rd12), and wild-type mice were exposed to 430-nm light to produce a localized lesion in the superior hemisphere of retina. Bisretinoids of RPE lipofuscin were measured by HPLC. In histologic sections, outer nuclear layer (ONL) thickness was measured as an indicator of photoreceptor cell degeneration, and RPE nuclei were counted.
RESULTS
As shown previously, A2E levels were increased in Abca4(-/-) mice. These mice also sustained light damage-associated ONL thinning that was more pronounced than in age-matched wild-type mice; the ONL thinning was also greater in 5-month versus 2-month-old mice. Numbers of RPE nuclei were reduced in light-stressed mice, with the reduction being greater in the Abca4(-/-) than wild-type mice. In Rpe65(rd12) mice bisretinoid compounds of RPE lipofuscin were not detected chromatographically and light damage-associated ONL thinning was not observed.
CONCLUSIONS
Abca4(-/-) mice that accumulate RPE lipofuscin at increased levels were more susceptible to retinal light damage than wild-type mice. This finding, together with results showing that Rpe65(rd12) mice did not accumulate lipofuscin and did not sustain retinal light damage, indicates that the bisretinoids of retinal lipofuscin are contributors to retinal light damage.
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Invest Ophthalmol Vis Sci 55(3): 1910-1918
PMID: 24576873

Light Damage in <em>Abca4</em> and <em>Rpe65<sup>rd12</sup></em> Mice

Department of Ophthalmology, Columbia University, New York, New York
Pathology and Cell Biology, Columbia University, New York, New York
Correspondence: Janet R. Sparrow, Columbia University, Department of Ophthalmology, 630 W 168th Street, New York, NY 10032; ude.aibmuloc@88srj.
Received 2014 Jan 1; Accepted 2014 Feb 17.
Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

Abstract

Purpose.

Bisretinoids form in photoreceptor cells and accumulate in retinal pigment epithelium (RPE) as lipofuscin. To examine the role of these fluorophores as mediators of retinal light damage, we studied the propensity for light damage in mutant mice having elevated lipofuscin due to deficiency in the ATP-binding cassette (ABC) transporter Abca4 (Abca4−/− mice) and in mice devoid of lipofuscin owing to absence of Rpe65 (Rpe65rd12).

Methods.

Abca4−/−, Rpe65rd12, and wild-type mice were exposed to 430-nm light to produce a localized lesion in the superior hemisphere of retina. Bisretinoids of RPE lipofuscin were measured by HPLC. In histologic sections, outer nuclear layer (ONL) thickness was measured as an indicator of photoreceptor cell degeneration, and RPE nuclei were counted.

Results.

As shown previously, A2E levels were increased in Abca4−/− mice. These mice also sustained light damage–associated ONL thinning that was more pronounced than in age-matched wild-type mice; the ONL thinning was also greater in 5-month versus 2-month-old mice. Numbers of RPE nuclei were reduced in light-stressed mice, with the reduction being greater in the Abca4−/− than wild-type mice. In Rpe65rd12 mice bisretinoid compounds of RPE lipofuscin were not detected chromatographically and light damage–associated ONL thinning was not observed.

Conclusions.

Abca4−/− mice that accumulate RPE lipofuscin at increased levels were more susceptible to retinal light damage than wild-type mice. This finding, together with results showing that Rpe65rd12 mice did not accumulate lipofuscin and did not sustain retinal light damage, indicates that the bisretinoids of retinal lipofuscin are contributors to retinal light damage.

Keywords: Abca4, bisretinoid, light, lipofuscin, retina, retinal degeneration, retinal pigment epithelium
Abstract

Acknowledgments

Supported by National Institutes of Health Grants RO1 EY12951, RO1 {"type":"entrez-nucleotide","attrs":{"text":"EY004367","term_id":"159069364","term_text":"EY004367"}}EY004367, and P30EY019007 and by a grant from Research to Prevent Blindness to the Department of Ophthalmology, Columbia University.

Disclosure: L. Wu, None; K. Ueda, None; T. Nagasaki, None; J.R. Sparrow, None

Acknowledgments

References

  • 1. Hunter JJ, Morgan JI, Merigan WH, Sliney DH, Sparrow JR, Williams DR. The susceptibility of the retina to photochemical damage from visible light. Prog Retin Eye Res. 2012; 31: 28–42
  • 2. Organisciak DT, Vaughan DK. Retinal light damage: mechanisms and protection. Prog Retin Eye Res. 2010; 29: 113–134
  • 3. Organisciak DT, Darrow RA, Barsalou L, Kutty RK, Wiggert B. Circadian-dependent retinal light damage in rats. Invest Ophthalmol Vis Sci. 2000; 41: 3694–3701 [[PubMed]
  • 4. Beatrice J, Wenzel A, Reme CE, Grimm C. Increased light damage susceptibility at night does not correlate with RPE65 levels and rhodopsin regeneration in rats. Exp Eye Res. 2003; 76: 695–700 [[PubMed]
  • 5. Hafezi F, Marti A, Munz K, Reme CE. Light-induced apoptosis: differential timing in the retina and pigment epithelium. Exp Eye Res. 1997; 64: 963–970 [[PubMed]
  • 6. Wenzel A, Grimm C, Samardzija M, Reme CE. Molecular mechanisms of light-induced photoreceptor apoptosis and neuroprotection for retinal degeneration. Prog Retin Eye Res. 2005; 24: 275–306 [[PubMed]
  • 7. Noell WK, Walker VS, Kang BS, Berman S. Retinal damage by light in rats. Invest Ophthalmol. 1966; 5: 450–473 [[PubMed]
  • 8. Williams TP, Howell WL. Action spectrum of retinal light damage in albino rats. Invest Ophthalmol Vis Sci. 1983; 24: 285–287 [[PubMed]
  • 9. Ham WT, Mueller HA. Retinal sensitivity to damage from short wavelength light. Nature. 1976; 260: 153–154 [[PubMed]
  • 10. van Norren D, Gorgels TGMF. The action spectrum of photochemical damage to the retina: a review of monochromatic threshold data. Photochem Photobiol. 2011; 87: 747–753 [[PubMed]
  • 11. Grimm C, Wenzel A, Hafezi F, Yu S, Redmond TM, Reme CE. Protection of Rpe65-deficient mice identifies rhodopsin as a mediator of light-induced retinal degeneration. Nat Genet. 2000; 25: 63–66 [[PubMed]
  • 12. Maeda A, Maeda T, Golczak M, et al Involvement of all-trans-retinal in acute light-induced retinopathy of mice. J Biol Chem. 2009; 284: 15173–15183
  • 13. Danciger M, Matthes MT, Yasamura D, et al A QTL on distal chromosome 3 that influences the severity of light-induced damage to mouse photoreceptors. Mamm Genome. 2000; 11: 422–427 [[PubMed]
  • 14. Wenzel A, Reme CE, Williams TP, Hafezi F, Grimm C. The Rpe65 Leu450Met variation increases retinal resistance against light-induced degeneration by slowing rhodopsin regeneration. J Neurosci. 2001; 21: 53–58
  • 15. Sieving PA, Chaudhry P, Kondo M, et al Inhibition of the visual cycle in vivo by 13-cis retinoic acid protects from light damage and provides a mechanism for night blindness in isotretinoin therapy. Proc Natl Acad Sci U S A. 2001; 98: 1835–1840
  • 16. Keller GA, Grimm C, Wenzel A, Hafezi F, Reme CE. Protective effects of halothane anesthesia on retinal light damage: inhibition of metabolic rhodopsin regeneration. Invest Ophthalmol Vis Sci. 2001; 42: 476–480 [[PubMed]
  • 17. Rapp LM, Tolman BL, Koutz CA, Thum LA. Predisposing factors to lightinduced photoreceptor cell damage: retinal changes in maturing rats. Exp Eye Res. 1990; 51: 177–184 [[PubMed]
  • 18. Vaughan DK, Nemke JL, Fliesler SJ. Evidence for a circadian rhythm of susceptibility to retinal light damage. Photochem Photobiol. 2002; 75: 547–553 [[PubMed]
  • 19. Hao W, Wenzel A, Obin MS, et al Evidence for two apoptotic pathways in light-induced retinal degeneration. Nat Genet. 2002; 32: 254–260 [[PubMed]
  • 20. Weng J, Mata NL, Azarian SM, Tzekov RT, Birch DG, Travis GH. Insights into the function of Rim protein in photoreceptors and etiology of Stargardt's disease from the phenotype in abcr knockout mice. Cell. 1999; 98: 13–23 [[PubMed]
  • 21. Lamb TD, Pugh EN. Dark adaptation and the retinoid cycle of vision. Prog Retin Eye Res. 2004; 23: 307–380 [[PubMed]
  • 22. Becker RS, Inuzuka K, Balke DE. Comprehensive investigation of the spectroscopy and photochemistry of retinals, I: theoretical and experimental considerations of absorption spectra. J Am Chem Soc. 1971; 93: 38–42 [[PubMed]
  • 23. Mellerio J. Light effects on the retina. In: DM Albert, Jakobiec FA., editors. eds Principles and Practice of Ophthalmology: Basic Science. Philadelphia, PA: WB Saunders Co; 1994; 1326–1345 [PubMed]
  • 24. Boyer NP, Higbee D, Currin MB, et al Lipofuscin and N-retinylidene-N-retinylethanolamine (A2E) accumulate in the retinal pigment epithelium in the absence of light exposure: their origin is 11-cis retinal. J Biol Chem. 2012; 287: 22276–22286
  • 25. Sparrow JR, Boulton M. RPE lipofuscin and its role in retinal photobiology. Exp Eye Res. 2005; 80: 595–606 [[PubMed]
  • 26. Yamamoto K, Yoon KD, Ueda K, Hashimoto M, Sparrow JR. A novel bisretinoid of retina is an adduct on glycerophosphoethanolamine. Invest Ophthalmol Vis Sci. 2011; 52: 9084–9090
  • 27. Parish CA, Hashimoto M, Nakanishi K, Dillon J, Sparrow JR. Isolation and one-step preparation of A2E and iso-A2E, fluorophores from human retinal pigment epithelium. Proc Natl Acad Sci U S A. 1998; 95: 14609–14613
  • 28. Kim SR, Jang YP, Jockusch S, Fishkin NE, Turro NJ, Sparrow JR. The all-trans-retinal dimer series of lipofuscin pigments in retinal pigment epithelial cells in a recessive Stargardt disease model. Proc Natl Acad Sci U S A. 2007; 104: 19273–19278
  • 29. Wu Y, Fishkin NE, Pande A, Pande J, Sparrow JR. Novel lipofuscin bisretinoids prominent in human retina and in a model of recessive Stargardt disease. J Biol Chem. 2009; 284: 20155–20166
  • 30. Gaillard ER, Atherton SJ, Eldred G, Dillon J. Photophysical studies on human retinal lipofuscin. Photochem Photobiol. 1995; 61: 448–453 [[PubMed]
  • 31. Rozanowska M, Jarvis-Evans J, Korytowski W, Boulton ME, Burke JM, Sarna T. Blue light-induced reactivity of retinal age pigment: in vitro generation of oxygen-reactive species. J Biol Chem. 1995; 270: 18825–18830 [[PubMed]
  • 32. Boulton M, Dontsov A, Jarvis-Evans J, Ostrovsky M, Svistunenko D. Lipofuscin is a photoinducible free radical generator. J Photochem Photobiol B. 1993; 19: 201–204 [[PubMed]
  • 33. Wassell J, Davies S, Bardsley W, Boulton M. The photoreactivity of the retinal age pigment lipofuscin. J Biol Chem. 1999; 274: 23828–23832 [[PubMed]
  • 34. Godley BF, Shamsi FA, Liang FQ, Jarrett SG, Davies S, Boulton M. Blue light induces mitochondrial DNA damage and free radical production in epithelial cells. J Biol Chem. 2005; 280: 21061–21066 [[PubMed]
  • 35. Schutt F, Davies S, Kopitz J, Holz FG, Boulton ME. Photodamage to human RPE cells by A2-E, a retinoid component of lipofuscin. Invest Ophthalmol Vis Sci. 2000; 41: 2303–2308 [[PubMed]
  • 36. Sparrow JR, Cai B. Blue light-induced apoptosis of A2E-containing RPE: involvement of caspase-3 and protection by Bcl-2. Invest Ophthalmol Vis Sci. 2001; 42: 1356–1362 [[PubMed]
  • 37. Sparrow JR, Nakanishi K, Parish CA. The lipofuscin fluorophore A2E mediates blue light-induced damage to retinal pigmented epithelial cells. Invest Ophthalmol Vis Sci. 2000; 41: 1981–1989 [[PubMed]
  • 38. Sparrow JR, Vollmer-Snarr HR, Zhou J, et al A2E-epoxides damage DNA in retinal pigment epithelial cells. Vitamin E and other antioxidants inhibit A2E-epoxide formation. J Biol Chem. 2003; 278: 18207–18213 [[PubMed]
  • 39. Kim SR, Fishkin N, Kong J, Nakanishi K, Allikmets R, Sparrow JR. The Rpe65 Leu450Met variant is associated with reduced levels of the RPE lipofuscin fluorophores A2E and iso-A2E. Proc Natl Acad Sci U S A. 2004; 101: 11668–11672
  • 40. Wu L, Nagasaki T, Sparrow JR. Photoreceptor cell degeneration in Abcr−/− mice. Adv Exp Med Biol. 2010; 664: 533–539
  • 41. Kim SR, Nakanishi K, Itagaki Y, Sparrow JR. Photooxidation of A2-PE, a photoreceptor outer segment fluorophore, and protection by lutein and zeaxanthin. Exp Eye Res. 2006; 82: 828–839 [[PubMed]
  • 42. Fishkin N, Sparrow JR, Allikmets R, Nakanishi K. Isolation and characterization of a retinal pigment epithelial cell fluorophore: an all-trans-retinal dimer conjugate. Proc Natl Acad Sci U S A. 2005; 102: 7091–7096
  • 43. Grimm C, Wenzel A, Williams TP, Rol PO, Hafezi F, Reme CE. Rhodopsin-mediated blue-light damage to the rat retina: effect of photoreversal of bleaching. Invest Ophthalmol Vis Sci. 2001; 42: 497–505 [[PubMed]
  • 44. Mittag TW, Bayer AU, LaVail MM. Light-induced retinal damage in mice carrying a mutated SOD I gene. Exp Eye Res. 1999; 69: 677–683 [[PubMed]
  • 45. Tanito M, Elliot MH, Kotake Y, Anderson RE. Protein modifications by 4-hydroxynonenal and 4-hydroxyhexenal in light-exposed rat retina. Invest Ophthalmol Vis Sci. 2005; 46: 3859–3868 [[PubMed]
  • 46. Maeda A, Maeda T, Golczak M, Palczewski K. Retinopathy in mice induced by disrupted all-trans-retinal clearance. J Biol Chem. 2008; 283: 26684–26693
  • 47. Sparrow JR, Blonska A, Flynn E, et al Quantitative fundus autofluorescence in mice: correlation with HPLC quantitation of RPE lipofuscin and measurement of retina outer nuclear layer thickness. Invest Ophthalmol Vis Sci. 2013; 54: 2812–2820
  • 48. Radu RA, Yuan Q, Hu J, et al Accelerated accumulation of lipofuscin pigments in the RPE of a mouse model for ABCA4-mediated retinal dystrophies following Vitamin A supplementation. Invest Ophthalmol Vis Sci. 2008; 49: 3821–3829
  • 49. Pang JJ, Chang B, Hawes NL, et al Retinal degeneration 12 (rd12): a new, spontaneously arising mouse model for human Leber congenital amaurosis (LCA). Mol Vis. 2005; 11: 152–162 [[PubMed]
  • 50. Katz ML, Redmond TM. Effect of Rpe65 knockout on accumulation of lipofuscin fluorophores in the retinal pigment epithelium. Invest Ophthalmol Vis Sci. 2001; 42: 3023–3030 [[PubMed]
  • 51. Maeda T, Maeda A, Casadesus G, Palczewski K, Margaron P. Evaluation of 9-cis-retinyl acetate therapy in Rpe65-/- mice. Invest Ophthalmol Vis Sci. 2009; 50: 4368–4378
  • 52. Grey AC, Crouch RK, Koutalos Y, Schey KL, Ablonczy Z. Spatial localization of A2E in the retinal pigment epithelium. Invest Ophthalmol Vis Sci. 2011; 52: 3926–3933
  • 53. Fan J, Rohrer B, Frederick JM, Baehr W, Crouch RK. Rpe65-/- and Lrat-/- mice: comparable models of Leber congenital amaurosis. Invest Ophthalmol Vis Sci. 2008; 49: 2384–2389
  • 54. Noell WK. Possible mechanisms of photoreceptor damage by light in mammalian eyes. Vis Res. 1980; 20: 1163–1171 [[PubMed]
  • 55. Reme CE, Hafezi F, Marti A, Munz K, Reinboth JJ. Light Damage to Retina and Retinal Pigment Epithelium. New York, NY: Oxford University Press; 1998; 68–85 [PubMed]
  • 56. Organisciak DT, Winkler BS. Retinal light damage:practical and theoretical considerations. Prog Retin Eye Res. 1994; 13: 1–29 [PubMed]
  • 57. Boulton M. Melanin and the Retinal Pigment Epithelium. New York, NY: Oxford University Press; 1998. [PubMed]
  • 58. Pautler EL, Morita M, Beezley D. Hemoprotein(s) mediate blue light damage in the retinal pigment epithelium. Photochem Photobiol. 1990; 51: 599–605 [[PubMed]
  • 59. Hoppeler T, Hendrickson P, Dietrich C, Reme CE. Morphology and time-course of defined photochemical lesions in the rabbit retina. Curr Eye Res. 1988; 7: 849–860 [[PubMed]
  • 60. Maeda A, Golczak M, Maeda T, Palczewski K. Limited roles of Rdh8, Rdh12, and Abca4 in all-trans-retinal clearance in mouse retina. Invest Ophthalmol Vis Sci. 2009; 50: 5435–5443
  • 61. Ham WT, Mueller HA, Ruffolo JJ, et al Basic mechanisms underlying the production of photochemical lesions in the mammalian retina. Curr Eye Res. 1984; 3: 165–174 [[PubMed]
  • 62. Ham WTJ, Allen RG, Feeney-Burns L, et al The involvement of the retinal pigment epithelium. In: Waxler M, Hitchins VM, editors. eds CRC Optical Radiation and Visual Health. Boca Raton, FL: CRC Press, Inc; 1986; 43–67 [PubMed]
  • 63. Friedman E, Kuwabara T. The retinal pigment epithelium, IV: the damaging effects of radiant energy. Arch Ophthalmol. 1968; 80: 265–279 [[PubMed]
  • 64. Busch EM, Gorgels TGMF, Roberts JE, van Norren D. The effects of two stereoisomers of N-acetylcysteine on photochemical damage by UVA and blue light in rat retina. Photochem Photobiol. 1999; 70: 353–358 [[PubMed]
  • 65. Ham WT, Ruffolo JJ, Mueller HA, Clarke AM, Moon ME. Histologic analysis of photochemical lesions produced in rhesus retina by short-wavelength light. Invest Ophthalmol Vis Sci. 1978; 17: 1029–1035 [[PubMed]
  • 66. Bush RA, Remé CE, Malnoë A. Light damage in the rat retina: the effect of dietary deprivation of N-3 fatty acids on acute structural alterations. Exp Eye Res. 1991; 53: 741–752 [[PubMed]
  • 67. Tanito M, Kaidzu S, Anderson RE. Protective effects of soft acrylic yellow filter against blue light-induced retinal damage in rats. Exp Eye Res. 2006; 83: 1493–1504 [[PubMed]
  • 68. Organisciak DT, Darrow RM, Jiang YI, Marak GE, Blanks JC. Protection by dimethylthiourea against retinal light damage in rats. Invest Ophthalmol Vis Sci. 1992; 33: 1599–1609 [[PubMed]
  • 69. Tomita H, Kotake Y, Anderson RE. Mechanism of protection from light-induced retinal degeneration by the synthetic antioxidant phenyl-N-tert-butylnitrone. Invest Ophthalmol Vis Sci. 2005; 46: 427–434 [[PubMed]
  • 70. Haruta M, Bush RA, Kjellstrom S, et al Depleting Rac1 in mouse rod photoreceptors protects them from photo-oxidative stress without affecting their structure or function. Proc Natl Acad Sci U S A. 2009; 2009: 9397–9402
  • 71. Sparrow JR, Gregory-Roberts E, Yamamoto K, et al The bisretinoids of retinal pigment epithelium. Prog Retin Eye Res. 2012; 31: 121–135
  • 72. Zhou J, Jang YP, Chang S, Sparrow JR. OT-674 suppresses photooxidative processes initiated by an RPE lipofuscin fluorophore. Photochem Photobiol. 2008; 84: 75–80 [[PubMed]
  • 73. Tanito M, Li F, Elliot MH, Dittmar M, Anderson RE. Protective effect of TEMPOL derivatives against light-induced retinal damage in rats. Invest Ophthalmol Vis Sci. 2007; 48: 1900–1905 [[PubMed]
  • 74. Tanito M, Li F, Anderson RE. Protection of retinal pigment epithelium by OT-551 and its metabolite TEMPOL-H against light-induced damage in rats. Exp Eye Res. 2010; 91: 111–114
  • 75. Zhou J, Cai B, Jang YP, Pachydaki S, Schmidt AM, Sparrow JR. Mechanisms for the induction of HNE- MDA- and AGE-adducts, RAGE and VEGF in retinal pigment epithelial cells. Exp Eye Res. 2005; 80: 567–580 [[PubMed]
  • 76. Yamamoto K, Zhou J, Hunter JJ, Williams DR, Sparrow JR. Toward an understanding of bisretinoid autofluorescence bleaching and recovery. Invest Ophthalmol Vis Sci. 2012; 53: 3536–3544
  • 77. Morgan JI, Dubra A, Wolfe R, Merigan WH, Williams DR. In vivo autofluorescence imaging of the human and macaque retinal pigment epithelial cell mosaic. Invest Ophthalmol Vis Sci. 2009; 50: 1350–1359
  • 78. Morgan JI, Hunter JJ, Masella B, et al Light-induced retinal changes observed with high-resolution autofluorescence imaging of the retinal pigment epithelium. Invest Ophthalmol Vis Sci. 2008; 49: 3715–3729
  • 79. Cideciyan AV, Swider M, Aleman TS, Roman MI, Sumaroka A, Schwartz SB. Reduced-illuminance autofluorescence imaging in ABCA4-associated retinal degenerations. J Opt Soc Am A Opt Image Sci Vis. 2007; 24: 1457–1467
  • 80. Cideciyan AV, Hood DC, Huang YZ, et al Disease sequence from mutant rhodopsin allele to rod and cone photoreceptor degeneration in man. Proc Natl Acad Sci U S A. 1998; 95: 7103–7108
  • 81. Naash ML, Peachey NS, Li Z-Y, et al Light-induced acceleration of photoreceptor degeneration in transgenic mice expressing mutant rhodopsin. Invest Ophthalmol Vis Sci. 1996; 37: 775–782 [[PubMed]
  • 82. Wang M, Lam TT, Tso MO, Naash MI. Expression of a mutant opsin gene increases the susceptibility of the retina to light damage. Vis Neurosci. 1997; 14: 55–62 [[PubMed]
  • 83. Cideciyan AV, Jacobson SG, Aleman TS, et al In vivo dynamics of retinal injury and repair in the rhodopsin mutant dog model of human retinitis pigmentosa. Proc Natl Acad Sci U S A. 2005; 102: 5233–5238
  • 84. Organisciak DT, Darrow RM, Barsalou L, Kutty RK, Wiggert B. Susceptibility to retinal light damage in transgenic rats with rhodopsin mutations. Invest Ophthalmol Vis Sci. 2003; 44: 486–492 [[PubMed]
  • 85. Tomany SC, Cruickshanks KJ, Klein R, Klein BEK, Knudtson MD. Sunlight and the 10-year incidence of age-related maculopathy: The Beaver Dam Eye Study. Arch Ophthalmol. 2004; 122: 750–757 [[PubMed]
  • 86. McCarty CA, Mukesh BN, Fu CL, Mitchell P, Wang JJ, Taylor HR. Risk factors for age-related maculopathy: the Visual Impairment Project. Arch Ophthalmol. 2001; 119: 1455–1462 [[PubMed]
  • 87. Hyman LG, Lilienfeld AM, Ferris FL, Fine SL. Senile macular degeneration: a case-control study. Am J Epidemiol. 1983; 118: 213–227 [[PubMed]
  • 88. Delcourt C, Carriere I. Ponton-Sanchez A, Sourrey S, Lacroux A, Papoz L. Light exposure and the risk of age-related macular degeneration. Arch Ophthalmol. 2001; 119: 1463–1468 [[PubMed]
  • 89. Fletcher AE, Bentham GC, Agnew M, et al Sunlight exposure, antioxidants, and age-related macular degeneration. Arch Ophthalmol. 2008; 126: 1396–1403 [[PubMed]
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