23rd Annual NASA Space Radiation Investigators' Workshop (2012)
8013.pdf
Iron Ion Irradiation Produces Changes in DNA Ploidy of Human Normal Fibroblast
Cells Without Affecting Proliferation or Cell Death.
Elizabeth A. Kosmacek1, Michael A. Mackey2,1, and Fiorenza Ianzini1,2*
Departments of 1Pathology and 2Biomedical Engineering, University of Iowa, Iowa City,
IA. *Presenting Author
Through the use of live cell imaging combined with molecular techniques we
demonstrate that moderate doses of 1 GeV/n iron ion irradiation initially depresses cell
proliferation but minimally affects cell survival in MRC-5 cells. DNA content
measurements demonstrate that iron ion irradiation leads to the formation of large
polyploid multinucleated cells displaying a variety of DNA complements. Such DNA
content heterogeneity is a typical feature of solid cancers. The polyploid cells maintain
proliferative capability, as evidenced by the high expression of the proliferation marker
Ki67 and a low senescence rate. High proliferation rates in multinucleated polyploid
cells is a hallmark of cancer cells. Thus, one of the effects of iron ion irradiation in
normal cells is the induction of a cancer phenotype. Further analyses reveal that the
irradiated cells display persistent γ-H2AX foci and express the meiosis-specific
synaptonemal complex protein 3 (SYCP3), a protein that is involved in pairing of
homologous chromosomes in the late zygotene and pachytene stages of meiosis I, and
specifically mediates chromosome pairing, synapsis, and crossover. These data support
the hypothesis that continuous activation of DNA repair enzymes and uncharacteristic
pathways of cell division may favor successful divisions of the irradiated polyploid cells,
in that H2AX, by restoring chromatin nucleosomal organization, and SYCP3, by
facilitating chromosome interchanges, may aid these cells to become more suited to
long-lasting proliferation. Such successful proliferation may add significantly to the
overall long-term risk from iron ion radiation exposure, as it is likely that these cells have
accumulated genetic damage. Further genetic analysis and transformation properties
after charged particle radiation are underway to define the overall and long-term
carcinogenic risk from space radiation exposures in normal cells.
Support: NIH/NCI 2P30CA086862; NASA NRA NNJ06HH68G; NASA NNX10AJ31G