Evidence of genotoxic damage in human cataractous lenses

Worgul, Basil V.; David, J.; Odrich, S.; Merriam, George R.; Medvedovsky, C.; Merriam, John C.; Trokel, Stephen L.; Geard, Charles R.

doi:10.1093/mutage/6.6.495

Cited by 34 publications

(23 citation statements)

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“…Most striking was the high incidence of cataracts in Brca2 À/À rats, which may be a consequence of diminished repair of DSBs in the lens epithelium. Unrepaired DNA damage to the epithelial cells of the lens is thought to be related to cataract etiology (Worgul et al, 1991). Similarly, agents causing SSBs and DSBs, such as ionizing radiation received through therapeutic total body irradiation (Zierhut et al, 2000) or space travel (Cucinotta et al, 2001), are associated with increased susceptibility to cataract formation.…”

Section: Discussionmentioning

confidence: 99%

Characterizing a rat Brca2 knockout model

et al. 2006

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Evidence exists that BRCA2 carriers may have an elevated risk of breast, ovarian, colon, prostate, and pancreatic cancer. In general, carriers are defined as individuals with protein truncating mutations within the BRCA2 gene. Many Brca2 knockout lines have been produced and characterized in the mouse. We previously produced a rat Brca2 knockout strain in which there is a nonsense mutation in exon 11 between BRC repeats 2 and 3, and a truncated protein is produced. Interestingly, while such a mutation in homozygous mice would lead to limited survival of approximately 3 months, the Brca2 À/À rats are 100% viable and the vast majority live to over 1 year of age. Brca2 À/À rats show a phenotype of growth inhibition and sterility in both sexes. Aspermatogenesis in the Brca2 À/À rats is due to a failure of homologous chromosome synapsis. Long-term phenotypes include underdeveloped mammary glands, cataract formation and lifespan shortening due to the development of tumors and cancers in multiple organs. The establishment of the rat Brca2 knockout model provides a means to study the role of Brca2 in increasing cancer susceptibility and inducing a novel ocular phenotype not previously associated with this gene.

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Section: Discussionmentioning

confidence: 99%

Characterizing a rat Brca2 knockout model

et al. 2006

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“…-S'agissant du type de cataracte : la cataracte radio-induite est sous capsulaire postérieure ou corticale, pratiquement jamais nucléaire et, logiquement, la plupart du temps, bilatérale. -S'agissant du caractère déterministe des cataractes radio-induites, celui-ci pourrait même être remis en question dans la mesure où : l'existence même d'un seuil n'est plus tout à fait certaine ; l'importance des atteintes génomiques (présence de nombreux micronoyaux) des cellules de l'épithélium antérieur semble prépondérante par rapport aux atteintes cellulaires directes (effet de mort cellulaire) (Worgul et al, 1991).…”

Section: Tableau Récapitulatif Et Discussionunclassified

Cataracte et rayonnements ionisants

Wassilieff

2009

Radioprotection

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RÉSUMÉLa cataracte radio-induite était considérée jusqu'à nos jours comme une pathologie assez peu fréquente, nécessitant de fortes doses de rayonnement (dépassant un seuil élevé, de l'ordre de 2 Grays au cristallin) et se réduisant principalement aux cataractes radiques des patients de radiothérapie. ABSTRACT Cataract and ionizing radiation.The radiation-induced cataract has been up to now considered as a quite rare pathology, needing high-dose radiations (beyond a dose threshold roughly estimated at 2 Grays to the lens) consisting mainly in head tumour radiotherapy complications. Several new studies on different exposed populations such as astronauts, japanese atomic bomb survivors, people undergoing X-ray examinations, Chernobyl accident "liquidators" as well as data from animal experiments, suggest that dose threshold for detectable opacities as well as for clinical posterior subcapsular cataract occurring, might be far lower than those previously assumed. Even the existence of a dose threshold is no longer an absolute certitude insofar as radiation-induced cataract pathogeny might consist not really in a deterministic effect (direct tissue harmful effect, killing or seriously injuring a critical population of cells) as believed until now, but rather in a stochastic effect (genomic damage in target-cells, altered cell division, abnormal lens fiber cell differentiation). More practically, these new data may lead us to reconsider radioprotection of specifically exposed populations: mainly patients and workers. Regarding workers, labour legislation (lens equivalent dose limit of 150 mSv during 12 consecutive months) might be, in the medium term, reassessed downwards.

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“…Analyses of the lenses and aqueous humor from the eye of patients with senile cataracts has demonstrated increased hydrogen peroxide (H 2 O 2 ) levels (9) and decreased reduced form of glutathione (GSH) levels (10) accompanied by extensive damages of protein (3,11), lipid (12) and DNA (1), suggesting the participation of reactive oxygen species (ROS). ROS scavengers such as vitamin C (13,14), vitamin E (15,16), or GSH (17) inhibited the onset of cataracts and protected the crystalline protein of the lens.…”

Section: Introductionmentioning

confidence: 99%

Preventive Effect of Eye Drops of Liposomes Containing Disulfiram and Cefmetazole on Selenite-Induced Cataract in Rat Pups

et al. 2006

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Disulfiram (DSF) and cefmetazole (CMZ), which possess with anti-oxidative activities were tested for anti-cataract effect in rats and were compared with pirenoxine (PRX), which is a marketed product used for the treatment of cataract. These compounds were encapsulated in liposomes and the results were compared with the anti-cataract effect of suspension and solution formulations containing same contents of each other agents. Instillations of DSF-and CMZ-liposomes prevented the development of cataract in seleniteinjected rat pups. On the other hand, no anti-cataract effects were observed in selenite-induced cataract rats instilled with DSF suspensions and CMZ solutions. The reduced form of glutathione (GSH) content of the lenses was decreased by approximately 60% of normal level 96 h after the sodium selenite-injection and the calcium (Ca 2+ ) content was increased. The decreased GSH and increased Ca 2+ levels were prevented by instillation of DSF-and CMZliposomes. Instillation of PRX-liposomes and 0.03% PRX solution had no effect on the development of cataract. The results of this study confirmed that anti-oxidative agents such as DSF and CMZ were useful to prevent cataract development related to oxidative stress.

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Evidence of genotoxic damage in human cataractous lenses

Cited by 34 publications

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Characterizing a rat Brca2 knockout model

Characterizing a rat Brca2 knockout model

Cataracte et rayonnements ionisants

Preventive Effect of Eye Drops of Liposomes Containing Disulfiram and Cefmetazole on Selenite-Induced Cataract in Rat Pups

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