Nonlinear ionizing radiation-induced changes in eye lens cell proliferation, cyclin D1 expression and lens shape

Abstract

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.

Progress in low dose health risk research

“…Soon after the discovery of ionising radiation the risk for developing cataracts after exposure to radiation was recognized [180,181]. The lens of the eye is one of the most radiosensitive tissues in the human body.…”

The Impact of Circadian Rhythms on Medical Imaging and Radiotherapy Regimes for the Paediatric Patient

“…In this study the mice were all exposed to IR in the morning, the time when proliferation rate would be expected to be highest. Whereas DNA repair in the central, nonproliferative zone was more efficient even than circulating blood lymphocytes from the same animals, lens epithelial cells in the germinative zone had a delayed DNA repair response (30) . Indeed the link between compromised DNA repair and cataract is clear for the lens.…”

“…Previous studies determined that the lens epithelium, and specifically the region where epithelial cell proliferation is concentrated, i.e. the germinative zone where IR effects are seen (12,30) and by preventing cell proliferation, IR-induced cataract is also prevented (31,32) . Given that the lens epithelium also is subject to circadian rhythm for cell proliferation (11) , why is the germinative zone of the lens especially sensitive to IR?…”

“…Moreover, it is clear that reducing proliferation in the lens epithelium is radio-protective (31,32) . The occurrence and repair of DSBs in DNA differs between the germinative zone and the rest of the eye lens epithelium ( (30) and references therein). In this study the mice were all exposed to IR in the morning, the time when proliferation rate would be expected to be highest.…”

Chernobyl and Fukushima Nuclear Accidents

“…In recent years, in several studies it have been shown that this nonlinearity may be due to the DNA repairing induction only after mammalian cell exposure to a dose exceeding 100 mSv [15][16][17]. A DNA doublestrand breaks (DSBs) is reported which occurs within 30 days after the animals were inoculated once with 137 CsCl intraperitoneally, or with a conditionally high (1.55±0.1 MBq) and low (200±0.3 kBq) doses of 85/90 SrCl 2 intravenously [18].…”