Therapeutic and space radiation exposure of mouse brain causes impaired DNA repair response and premature senescence by chronic oxidant production

Abstract

Despite recent epidemiological evidences linking radiation exposure and a number of human ailments including cancer, mechanistic understanding of how radiation inflicts long-term changes in cerebral cortex, which regulates important neuronal functions, remains obscure. The current study dissects molecular events relevant to pathology in cerebral cortex of 6 to 8 weeks old female C57BL/6J mice two and twelve months after exposure to a γ radiation dose (2 Gy) commonly employed in fractionated radiotherapy. For a comparative study, effects of 1.6 Gy heavy ion56Fe radiation on cerebral cortex were also investigated, which has implications for space exploration. Radiation exposure was associated with increased chronic oxidative stress, oxidative DNA damage, lipid peroxidation, and apoptosis. These results when considered with decreased cortical thickness, activation of cell-cycle arrest pathway, and inhibition of DNA double strand break repair factors led us to conclude to our knowledge for the first time that radiation caused aging-like pathology in cerebral cortical cells and changes after heavy ion radiation were more pronounced than γ radiation.

A Radiation-Induced Hippocampal Vascular Injury Surrogate Marker Predicts Late Neurocognitive Dysfunction

“…Most importantly, the early BBB opening in the female hippocampus was correlated with the delayed and late-delayed memory function declines. The greater sensitivity to radiation-induced neurocognitive declines in the elderly females is supported by the biological findings of radiation-caused aging-like pathology 26 .…”

“…Although the exact mechanism of the age-dependent radiosensitivity remained unknown, previous studies 24, 25 have shown that RT has more adverse effects on older patients. Moreover, the radiation-induced aging-like pathology in cerebrocortical cells has been suggested 26 , including shrinkage of cortical thickness, activation of cell-cycle arrest pathway and inhibition of DNA double strand break repair. Also, it has been shown that exposing cerebral cortex to radiation increases chronic oxidative stress, oxidant DNA damage, lipid peroxidation, and apoptosis 26 .…”

“…Moreover, the radiation-induced aging-like pathology in cerebrocortical cells has been suggested 26 , including shrinkage of cortical thickness, activation of cell-cycle arrest pathway and inhibition of DNA double strand break repair. Also, it has been shown that exposing cerebral cortex to radiation increases chronic oxidative stress, oxidant DNA damage, lipid peroxidation, and apoptosis 26 . In terms of sex-dependent radiation sensitivity, higher mortality and morbidity rates from radiation-induced injury in females have been reported 27 ; also, it has been shown that girls could be more sensitive than boys in learning and memory decline following conformal radiotherapy 28 .…”

Dose- and ApoE Isoform-Dependent Cognitive Injury after Cranial56Fe Irradiation in Female Mice

“…Baluchamy et al (2012Baluchamy et al ( , 2010 and Suman et al (2013) demonstrated induction of lipid peroxidation and ROS in mouse brains accompanied by reduced levels of glutathione and superoxide dismutase activity following γ-ray, 1 H, and 56 Fe ion exposures. In mice, persistent oxidative changes are induced by <1 Gy of charged particles.…”

Nestin expression as an independent indicator of poor prognosis for patients with anaplastic thyroid cancer

“…In light of these data, nestin may have a role in acquiring resistance to radiation therapy. Nestin has also been reported to be expressed increasingly after radiation injury to the brain (26), although the precise mechanism of this finding was not identified. This observation may indicate an important role of nestin in the response to cellular injury by irradiation therapy.…”