Nonlinear ionizing radiation-induced changes in eye lens cell proliferation, cyclin D1 expression and lens shape.
Elevated cataract risk after radiation exposure was established soon after the discovery of X-rays in 1895. Today, increased cataract incidence among medical imaging practitioners and after nuclear incidents has highlighted how little is still understood about the biological responses of the lens to low-dose ionizing radiation (IR). Here, we show for the first time that in mice, lens epithelial cells (LECs) in the peripheral region repair DNA double strand breaks (DSB) after exposure to 20 and 100 mGy more slowly compared with circulating blood lymphocytes, as demonstrated by counts of γH2AX foci in cell nuclei. LECs in the central region repaired DSBs faster than either LECs in the lens periphery or lymphocytes. Although DSB markers (γH2AX, 53BP1 and RAD51) in both lens regions showed linear dose responses at the 1 h timepoint, nonlinear responses were observed in lenses for EdU (5-ethynyl-2'-deoxy-uridine) incorporation, cyclin D1 staining and cell density after 24 h at 100 and 250 mGy. After 10 months, the lens aspect ratio was also altered, an indicator of the consequences of the altered cell proliferation and cell density changes. A best-fit model demonstrated a dose-response peak at 500 mGy. These data identify specific nonlinear biological responses to low (less than 1000 mGy) dose IR-induced DNA damage in the lens epithelium.
School of Biological and Biomedical Sciences, University of Durham, Durham DH1 3LE, UK.
Ewa
E
Markiewicz
Public Health England, Centre for Radiation, Chemical & Environmental Hazards, Chilton, Didcot, Oxon OX11 0RQ, UK.
Stephen
S
Barnard
Public Health England, Centre for Radiation, Chemical & Environmental Hazards, Chilton, Didcot, Oxon OX11 0RQ, UK.
Jackie
J
Haines
Public Health England, Centre for Radiation, Chemical & Environmental Hazards, Chilton, Didcot, Oxon OX11 0RQ, UK.
Margaret
M
Coster
School of Biological and Biomedical Sciences, University of Durham, Durham DH1 3LE, UK Faculty of Science, KU Leuven, Kasteelpark Arenberg 11, Leuven 3001, Belgium.
Orry
O
van Geel
School of Biological and Biomedical Sciences, University of Durham, Durham DH1 3LE, UK Biophysical Sciences Institute, University of Durham, Durham DH1 3LE, UK.
Weiju
W
Wu
School of Biological and Biomedical Sciences, University of Durham, Durham DH1 3LE, UK.
Shane
S
Richards
Public Health England, Centre for Radiation, Chemical & Environmental Hazards, Chilton, Didcot, Oxon OX11 0RQ, UK.
Elizabeth
E
Ainsbury
Public Health England, Centre for Radiation, Chemical & Environmental Hazards, Chilton, Didcot, Oxon OX11 0RQ, UK.
Kai
K
Rothkamm
Public Health England, Centre for Radiation, Chemical & Environmental Hazards, Chilton, Didcot, Oxon OX11 0RQ, UK.
Simon
S
Bouffler
School of Biological and Biomedical Sciences, University of Durham, Durham DH1 3LE, UK Biophysical Sciences Institute, University of Durham, Durham DH1 3LE, UK r.a.quinlan@dur.ac.uk.
Roy A
http://orcid.org/0000-0003-0644-4123
RA
Quinlan
D000465:Algorithms; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000528:radiation effects*; D048430:Cell Shape / Q000528:radiation effects*; D019938:Cyclin D1 / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004260:DNA Repair; D004307:Dose-Response Relationship, Radiation; D004847:Epithelial Cells / Q000378:metabolism / Q000528:radiation effects; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007908:Lens, Crystalline / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects*; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D014965:X-Rays
D006657:Histones; C475961:gamma-H2AX protein, mouse; D019938:Cyclin D1
DNA DSB; cyclin D1; eye lens; ionizing radiation; non-linear effect; γH2AX