22nd Annual NASA Space Radiation Investigators' Workshop (2011)
7118.pdf
Mechanisms of Ocular Cataracts
N.J. Kleiman , L.B. Smilenov , H.B. Lieberman1,2, C.D. Elliston2, D.J. Brenner1,2 and E.J. Hall2
1
Dept. Environmental Health Sciences, Mailman School of Public Health and 2Center for
Radiological Research; Columbia University, New York, NY
1
2
Our research utilizes a radiation cataract model to determine the genetic, epigenetic and
individual basis for human health risks from exposure to space radiation, with particular
emphasis on radiation induced DNA damage, repair and cell cycle control in a complex, highly
differentiated tissue. These studies are designed to help elucidate the mechanistic nature of
radiation induced biological damage and determine the relative contribution of genetic defects to
radiosensitivity. The unique morphology of the lens and the ease of non-invasive observation of
its radiation response facilitate these investigations. We further hypothesize that the cellular and
molecular pathways of the biological response to space radiation exposure in the lens has
fundamental relevance and parallels to radiation carcinogenesis in other tissues and that radiation
cataract arises from damaged or misrepaired DNA and subsequent errors in cell cycle control,
division and differentiation. This view is supported by a 2011 report from the ICRP which states
“The precise mechanism of radiation cataractogenesis is not known, but genomic damage
resulting in altered cell division, transcription and/or abnormal lens fibre cell differentiation is
considered to be the salient injury, … heterozygosity for genes involved in cell cycle checkpoint
control, DNA damage recognition, or DNA repair might also contribute to this phenomenon”.
To date, our NASA funded research has been examining the influence of genetic
heterogeneity on radiation cataract development after ocular exposure to low doses of either Xirradiation or HZE particles. Our previous findings demonstrated earlier radiation cataract onset
and increased severity in mice haplo- insufficient for Atm or Rad9 with even greater effect in
AtmRad9 double heterozygotes. More recently, we have examined the effect of genetic
heterogeneity on radiation cataract in singly or doubly haploinsufficient Atm and Brca1 mice
after exposure to either low dose X-ray or 56Fe. Current research indicates single or double
haploinsufficiency for Atm, Brca1, Rad9, PTEN and p21, which have important roles in
recognizing and repairing radiation induced DNA damage, inducing cell cycle arrest and
initiating apoptosis, is also directly related to onset, latency and progression of radiation cataract
after low-LET or HZE exposures. Most recently, as an adjunct to conventional slit lamp exam,
we have adapted a new independent, contrast sensitivity based methodology, Virtual Optometry,
to quantitate actual visual disability in the mouse eye. Lastly, we have begun study of potential
epigenetic changes in the methylation status of upstream CpG islands in the promoter regions of
Atm, pten, Rad9, Brca1, and p53, in irradiated lens tissue.
These animal studies provide an opportunity to study the influence and effects of genetic
heterogeneity in highly organized lens tissue in a genetically defined mouse model that has broad
implications for human radiation exposure and risk assessment These findings are likely to shed
light on the genetic control and cellular mechanisms of both heavy ion and low-LET induced
DNA damage, repair and cell cycle control. In particular, our findings suggest that individual
human genetic differences in radiosensitivity might help explain the wide variation in reported
time of cataract onset, degree of opacification and subsequent progression to visual disability
among exposed populations. Of greater import, these findings have significant implications for
occupational exposure in radiosensitive subsets of the human population, such as the astronaut
core and aid in determining future national space radiation risk policies.
Supported by NASA grant NNJ05HI38G (E.J. Hall, p.i.) and DOE grant DE-FG0207ER64334 (NJ Kleiman, p.i.)