Spaceflight Effects and Molecular Responses in the Mouse Eye: Observations After Shuttle Mission STS-133

Susana Beatriz Zanello, Corey Theriot, Claudia Prospero-Ponce, Patricia Chevez-Barrios


Spaceflight exploration presents environmental stressors including microgravity-induced cephalad fluid shift and radiation exposure. Ocular changes leading to visual impairment in astronauts are of occupational health relevance. The effect of this complex environment on ocular morphology and function is poorly understood. Female 10-12 week-old BALB/cJ mice were assigned to a flight (FLT) group flown on shuttle mission STS-133, Animal Enclosure Module (AEM), or vivarium (VIV) ground controls. Eyes were collected at 1, 5 and 7 days after landing and were fixed for histological sectioning. The contralateral eye was used for gene expression profiling by qRT-PCR. Sections were visualized by hematoxylin/eosin stain and processed for 8-hydroxy-2'-deoxyguanosine (8-OHdG), caspase-3, and glial fibrillary acidic protein (GFAP) and β-amyloid double-staining. 8-OHdG and caspase-3 immunoreactivity was increased in the retina in FLT samples at return from flight (R+1) compared to ground controls, and decreased at day 7 (R+7). β-amyloid was seen in the nerve fibers at the post-laminar region of the optic nerve in the flight samples (R+7). Expression of oxidative and cellular stress response genes was upregulated in the retina of FLT samples upon landing, followed by lower levels by R+7. These results suggest that reversible molecular damage occurs in the retina of mice exposed to spaceflight and that protective cellular pathways are induced in the retina and optic nerve in response to these changes.



Abramoff, M.D., Magalhaes, P.J., Ram, S.J. 2004. Image Processing with ImageJ. Biophotonics International 11:36-42.

Awasthi, N., and B.J. Wagner. 2005. Upregulation of heat shock protein expression by proteasome inhibition: an antiapoptotic mechanism in the lens. Invest Ophthalmol Vis Sci. 46:2082-2091.

Byun, J., M.R. Verardo, B. Sumengen, G.P. Lewis, B.S. Manjunath, and S.K. Fisher. 2006. Automated tool for the detection of cell nuclei in digital microscopic images: application to retinal images. Mol Vis. 12:949-960.

Chen, D., M. Pacal, P. Wenzel, P.S. Knoepfler, G. Leone, and R. Bremner. 2009. Division and apoptosis of E2f-deficient retinal progenitors. Nature. 462:925-929.

Cucinotta, F.A., F.K. Manuel, J. Jones, G. Iszard, J. Murrey, B. Djojonegro, and M. Wear. 2001. Space radiation and cataracts in astronauts. Radiat Res. 156:460-466.

D'Amelio, M., V. Cavallucci, and F. Cecconi. 2010. Neuronal caspase-3 signaling: not only cell death. Cell Death Differ. 17:1104-1114.

Friedman, D.I. 2007. Idiopathic intracranial hypertension. Current pain and headache reports. 11:62-68.

Frigeri, A., D.A. Iacobas, S. Iacobas, G.P. Nicchia, J.F. Desaphy, D.C. Camerino, M. Svelto, and D.C. Spray. 2008. Effect of microgravity on gene expression in mouse brain. Exp Brain Res. 191:289-300.

Gerhardinger C, D.Z., Sebastiani P, Park Y, Lorenzi M. 2009. The transforming growth factor-beta pathway is a common target of drugs that prevent experimental diabetic retinopathy. Diabetes. 58:1659-1667.

Gleckman, A.M., R.J. Evans, M.D. Bell, and T.W. Smith. 2000. Optic nerve damage in shaken baby syndrome: detection by beta-amyloid precursor protein immunohistochemistry. Arch Pathol Lab Med. 124:251-256.

Godley, B.F., G.F. Jin, Y.S. Guo, and J.S. Hurst. 2002. Bcl-2 overexpression increases survival in human retinal pigment epithelial cells exposed to H(2)O(2). Exp Eye Res. 74:663-669.

Hargens, A.R., and D.E. Watenpaugh. 1996. Cardiovascular adaptation to spaceflight. Medicine and science in sports and exercise. 28:977-982.

Iwata, A., X.H. Chen, T.K. McIntosh, K.D. Browne, and D.H. Smith. 2002. Long-term accumulation of amyloid-beta in axons following brain trauma without persistent upregulation of amyloid precursor protein genes. J Neuropathol Exp Neurol. 61:1056-1068.

Jaliffa, C., I. Ameqrane, A. Dansault, J. Leemput, V. Vieira, E. Lacassagne, A. Provost, K. Bigot, C. Masson, M. Menasche, and M. Abitbol. 2009. Sirt1 involvement in rd10 mouse retinal degeneration. Invest Ophthalmol Vis Sci. 50:3562-3572.

Justilien, V., J.J. Pang, K. Renganathan, X. Zhan, J.W. Crabb, S.R. Kim, J.R. Sparrow, W.W. Hauswirth, and A.S. Lewin. 2007. SOD2 knockdown mouse model of early AMD. Invest Ophthalmol Vis Sci. 48:4407-4420.

Kipfer-Kauer, A., S.J. McKinnon, B.E. Frueh, and D. Goldblum. 2010. Distribution of amyloid precursor protein and amyloid-beta in ocular hypertensive C57BL/6 mouse eyes. Curr Eye Res. 35:828-834.

Kramer, L.A., A.E. Sargsyan, K.M. Hasan, J.D. Polk, and D.R. Hamilton. 2012. Orbital and Intracranial Effects of Microgravity: Findings at 3-T MR Imaging. Radiology. Jun;263(3):819-27

Lamoke, F., G. Ripandelli, S. Webster, A. Montemari, A. Maraschi, P. Martin, D.M. Marcus, G.I. Liou, and M. Bartoli. 2012. Loss of thioredoxin function in retinas of mice overexpressing amyloid beta. Free Radic Biol Med. 53:577-588.

LaVail, M.M., G.M. Gorrin, and M.A. Repaci. 1987. Strain differences in sensitivity to light-induced photoreceptor degeneration in albino mice. Curr Eye Res. 6:825-834.

Lewis, G.P., and S.K. Fisher. 2003. Up-regulation of glial fibrillary acidic protein in response to retinal injury: its potential role in glial remodeling and a comparison to vimentin expression. Int Rev Cytol. 230:263-290.

Liman, J., L. Faida, C.P. Dohm, J.C. Reed, M. Bahr, and P. Kermer. 2008. Subcellular distribution affects BAG1 function. Brain Res. 1198:21-26.

Lohr, H.R., K. Kuntchithapautham, A.K. Sharma, and B. Rohrer. 2006. Multiple, parallel cellular suicide mechanisms participate in photoreceptor cell death. Exp Eye Res. 83:380-389.

Mader, T.H., C.R. Gibson, A.F. Pass, L.A. Kramer, A.G. Lee, J. Fogarty, W.J. Tarver, J.P. Dervay, D.R. Hamilton, A. Sargsyan, J.L. Phillips, D. Tran, W. Lipsky, J. Choi, C. Stern, R. Kuyumjian, and J.D. Polk. 2011. Optic Disc Edema, Globe Flattening, Choroidal Folds, and Hyperopic Shifts Observed in Astronauts after Long-duration Space Flight. Ophthalmology. 118:2058-2069.

Naidu, S., C.M. Winget, J.W. Jenner, G. Mele, and D.C. Holley. 1995. Effects of housing density on mouse physiology and behavior in the NASA Animal Enclosure Module simulators. J Gravit Physiol. 2:P140.

Nakamura, S., M. Shibuya, H. Nakashima, R. Hisamura, N. Masuda, T. Imagawa, M. Uehara, and K. Tsubota. 2007. Involvement of oxidative stress on corneal epithelial alterations in a blink-suppressed dry eye. Invest Ophthalmol Vis Sci. 48:1552-1558.

NASA. 2010. Longitudinal Study of Astronaut Health database.

Oldham, K.M., S.R. Wise, L. Chen, M. Stacewicz-Sapuntzakis, J. Burns, and P.E. Bowen. 2002. A longitudinal evaluation of oxidative stress in trauma patients. JPEN J Parenter Enteral Nutr. 26:189-197.

Ozawa, Y., S. Kubota, T. Narimatsu, K. Yuki, T. Koto, M. Sasaki, and K. Tsubota. 2010. Retinal aging and sirtuins. Ophthalmic Res. 44:199-203.

Parsons, J.T., F.J. Bova, W.M. Mendenhall, R.R. Million, and C.R. Fitzgerald. 1996. Response of the normal eye to high dose radiotherapy. Oncology (Williston Park). 10:837-847; discussion 847-838, 851-832.

Philpott, D.E., R. Corbett, C. Turnbill, S. Black, D. Dayhoff, J. McGourty, R. Lee, G. Harrison, and L. Savick. 1980.

Retinal changes in rats flown on Cosmos 936: A cosmic ray experiment. Aviat Space Environ Med. 51:556-562.

Philpott, D.E., R. Corbett, C. Turnbill, G. Harrison, D. Leaffer, S. Black, W. Sapp, G. Klein, and L.F. Savik. 1978. Cosmic ray effects on the eyes of rats flown on Cosmos No. 782, experimental K-007. Aviat Space Environ Med. 49:19-28.

Pierce, J.E., J.Q. Trojanowski, D.I. Graham, D.H. Smith, and T.K. McIntosh. 1996. Immunohistochemical characterization of alterations in the distribution of amyloid precursor proteins and beta-amyloid peptide after experimental brain injury in the rat. J Neurosci. 16:1083-1090.

Pietsch, J., J. Bauer, M. Egli, M. Infanger, P. Wise, C. Ulbrich, and D. Grimm. 2011. The effects of weightlessness on the human organism and mammalian cells. Curr Mol Med. 11:350-364.

Pulsinelli, W.A., J.B. Brierley, and F. Plum. 1982. Temporal profile of neuronal damage in a model of transient forebrain ischemia. Ann Neurol. 11:491-498.

Roberts, J.E., B.M. Kukielczak, C.F. Chignell, B.H. Sik, D.N. Hu, and M.A. Principato. 2006. Simulated microgravity induced damage in human retinal pigment epithelial cells. Mol Vis. 12:633-638.

Sannita, W.G., L. Narici, and P. Picozza. 2006. Positive visual phenomena in space: A scientific case and a safety issue in space travel. Vision Res. 46:2159-2165.

Smith, D.H., X.H. Chen, M. Nonaka, J.Q. Trojanowski, V.M. Lee, K.E. Saatman, M.J. Leoni, B.N. Xu, J.A. Wolf, and D.F. Meaney. 1999. Accumulation of amyloid beta and tau and the formation of neurofilament inclusions following diffuse brain injury in the pig. J Neuropathol Exp Neurol. 58:982-992.

Song, D., Y. Song, M. Hadziahmetovic, Y. Zhong, and J.L. Dunaief. 2012. Systemic administration of the iron chelator deferiprone protects against light-induced photoreceptor degeneration in the mouse retina. Free Radic Biol Med. 53:64-71.

Sparrow, J.R., K. Nakanishi, and C.A. Parish. 2000. The lipofuscin fluorophore A2E mediates blue light-induced damage to retinal pigmented epithelial cells. Invest Ophthalmol Vis Sci. 41:1981-1989.

Stein, T.P. 2002. Space flight and oxidative stress. Nutrition. 18:867-871.

Sundaresan, A., and N.R. Pellis. 2009. Cellular and genetic adaptation in low-gravity environments. Ann N Y Acad Sci. 1161:135-146.

Tanito, M., A. Nishiyama, T. Tanaka, H. Masutani, H. Nakamura, J. Yodoi, and A. Ohira. 2002. Change of redox status and modulation by thiol replenishment in retinal photooxidative damage. Invest Ophthalmol Vis Sci. 43:2392-2400.

Tanito, M., T. Takanashi, S. Kaidzu, Y. Yoshida, and A. Ohira. 2003. Cytoprotective effects of rebamipide and carteolol hydrochloride against ultraviolet B-induced corneal damage in mice. Invest Ophthalmol Vis Sci. 44:2980-2985.

Tombran-Tink, J., and C.J. Barnstable. 2006. Space flight environment induces degeneration in the retina of rat neonates. Adv Exp Med Biol. 572:417-424.

Ueta, T., T. Inoue, T. Furukawa, Y. Tamaki, Y. Nakagawa, H. Imai, and Y. Yanagi. 2012. Glutathione peroxidase 4 is required for maturation of photoreceptor cells. J Biol Chem. 287:7675-7682.

van Wijngaarden, P., H.M. Brereton, D.J. Coster, and K.A. Williams. 2007. Stability of housekeeping gene expression in the rat retina during exposure to cyclic hyperoxia. Mol Vis. 13:1508-1515.

Vandesompele, J., K. De Preter, F. Pattyn, B. Poppe, N. Van Roy, A. De Paepe, and F. Speleman. 2002. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 3:RESEARCH0034.

Wang, A.L., T.J. Lukas, M. Yuan, N. Du, M.O. Tso, and A.H. Neufeld. 2009. Autophagy and exosomes in the aged retinal pigment epithelium: possible relevance to drusen formation and age-related macular degeneration. PLoS One. 4:e4160.

Wei, Y., J. Gong, T. Yoshida, C.G. Eberhart, Z. Xu, P. Kombairaju, M.B. Sporn, J.T. Handa, and E.J. Duh. 2011. Nrf2 has a protective role against neuronal and capillary degeneration in retinal ischemia-reperfusion injury. Free Radic Biol Med. 51:216-224.

Wiegand, R.D., N.M. Giusto, L.M. Rapp, and R.E. Anderson. 1983. Evidence for rod outer segment lipid peroxidation following constant illumination of the rat retina. Invest Ophthalmol Vis Sci. 24:1433-1435.

Wilkerson, M.K., P.N. Colleran, and M.D. Delp. 2002. Acute and chronic head-down tail suspension diminishes cerebral perfusion in rats. Am J Physiol Heart Circ Physiol. 282:H328-334.

Wise, K.C., S.K. Manna, K. Yamauchi, V. Ramesh, B.L. Wilson, R.L. Thomas, S. Sarkar, A.D. Kulkarni, N.R. Pellis, and G.T. Ramesh. 2005. Activation of nuclear transcription factor-kappaB in mouse brain induced by a simulated microgravity environment. In Vitro Cell Dev Biol Anim. 41:118-123.

Yang, D., S.G. Elner, X. Chen, M.G. Field, H.R. Petty, and V.M. Elner. 2011. MCP-1-activated monocytes induce apoptosis in human retinal pigment epithelium. Invest Ophthalmol Vis Sci. 52:6026-6034.

Zhu, Y., Y. Zhang, B.A. Ojwang, M.A. Brantley, Jr., and J.M. Gidday. 2007. Long-term tolerance to retinal ischemia by repetitive hypoxic preconditioning: role of HIF-1alpha and heme oxygenase-1. Invest Ophthalmol Vis Sci. 48:1735-1743.

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