UWINEZA, ALICE (2020) Biological mechanisms underlying ionising radiation-induced cataracts. Doctoral thesis, Durham University.
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Author-imposed embargo until 04 June 2022.
Epidemiological data correlate exposure to ionising radiation (IR) with cataract formation. In 2012, the International Commission on Radiological Protection reduced its recommended threshold for IR effects on the eye lens to 0.5 Gy and acknowledged that the biological mechanisms underlying IR-induced cataracts are largely unknown. To determine these processes, the influence of IR on the lens epithelium, cholesterol and membrane proteins was investigated. CD1, C57BL/6J and B6C3F1 mice were exposed to 0.5 - 2 Gy at 0.3 or 0.063 Gy/ min. Lens epithelium cell density was examined at 4 and/ or 12 months post-IR. Differential response to IR in these mice was observed in a strain-, dose-, dose rate-, sex-, Ptch1+/- and Ercc2+/- -dependent manner and the data indicated that low dose IR-induced cataractogenesis requires a relatively long latency period, which is consistent with epidemiological data from longitudinal studies. The plasma membranes of lens fibre cells are among the cholesterol richest membranes in the human body and cholesterol has a vital role in biophysical properties of these membranes. Analysis of IR exposed bovine eye lens membrane extracts (5 and 50 Gy) and eye lenses taken from whole body irradiated mice (0.1 and 2 Gy) showed that IR induced a significant increase in cholesterol oxides i.e. oxysterols. Unlike the isolated lens membranes, the observed enhancement of oxysterol levels in vivo was transient. Furthermore, adding α-tocopherol to isolated lens cortex membranes before exposure to IR prevented the build-up of oxysterols. The increase of oxysterols in mice eye lenses was shown to also be age-related, and was observed in the hippocampus as well. In addition, a dose-dependent increase in protein glycation was noted after IR exposure of lens membrane extracts. Collectively, these data underline that IR contributes to the cataractogenic load through compromising lens membrane integrity and lens epithelium homeostasis.
|Item Type:||Thesis (Doctoral)|
|Award:||Doctor of Philosophy|
|Keywords:||Ionising radiation, cataracts, oxysterols, lipids, anti-oxidants|
|Faculty and Department:||Faculty of Science > Biological and Biomedical Sciences, School of|
|Copyright:||Copyright of this thesis is held by the author|
|Deposited On:||05 Jun 2020 12:01|