[Mechanisms of radioresistance in terminally differentiated cells of mature retina].
Retinopathy of animals is induced by many agents damaging DNA. This fact shows that DNA lesions may initiate retinal degeneration. The aim of our work was to study the effects of gamma and proton irradiation, and methylnitrosourea (MNU) on mice retina. We evaluated morphological changes, DNA damage and repair in retina, and expression of 5 proteins participating in apoptosis: p53, ATM, FasR, PARP and caspase 3 active. Dose of 14 Gy is equitoxic in terms of induction of DNA single strand breaks by both gamma and proton irradiation. But protons were 2 fold more effective than gamma-rays in induction of DNA double strand breaks. All breaks were repaired within < or =10 h. Irradiation resulted in increased expression of p53 and ATM. But no sings of cell death and retinal degeneration were observed during 7 days after irradiation. Proton irradiation in dose of 25 Gy resulted in increasing over time destructive changes localized mainly in photoreceptor layer of retina. These changes were followed by increased expression of proapoptotic proteins. A single systemic administration of MNU (70 mg/kg) increased intracellular levels of p53, PARP, FasR, caspase 3 active, which was followed by destructive changes in retina with sings of apoptosis of photoreceptors. As in the case of irradiation, the 2-fold dose reduction of MNU abrogated cytotoxic effect of MNU on retina. High level of spontaneous DNA damage such as apurine and apyrimidine sites were observed in mouse retina. The results of our study demonstrate the occurrence of genotoxic threshold in the initiation of retinal cell death in vivo. Topoisomerase 2 of retina is suggested to translate primary DNA damage to cytotoxic effect.
V A
VA
Tronov
Iu V
IuV
Vinogradova
M Iu
MIu
Loginova
V A
VA
Poplinskaia
M A
MA
Ostrovskiĭ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D053904:DNA Breaks, Single-Stranded / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D005720:Gamma Rays / Q000009:adverse effects*; D015870:Gene Expression; D008770:Methylnitrosourea / Q000633:toxicity; D051379:Mice; D011522:Protons / Q000009:adverse effects*; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D012160:Retina / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D011522:Protons; D025521:Tumor Suppressor Proteins; D008770:Methylnitrosourea; D004250:DNA Topoisomerases, Type II