Long-Term Consequences of Radiation-Induced Bystander Effects Depend on Radiation Quality and Dose and Correlate with Oxidative Stress

Abstract

Widespread evidence indicates that exposure of cell populations to ionizing radiation results in significant biological changes in both the irradiated and nonirradiated bystander cells in the population. We investigated the role of radiation quality, or linear energy transfer (LET), and radiation dose in the propagation of stressful effects in the progeny of bystander cells. Confluent normal human cell cultures were exposed to low or high doses of 1GeV/u iron ions (LET ~ 151 keV/μm), 600 MeV/u silicon ions (LET ~ 51 keV/μm), or 1 GeV protons (LET ~ 0.2 keV/μm). Within minutes after irradiation, the cells were trypsinized and co-cultured with nonirradiated cells for 5 h. During this time, irradiated and nonirradiated cells were grown on either side of an insert with 3-μm pores. Nonirradiated cells were then harvested and allowed to grow for 20 generations. Relative to controls, the progeny of bystander cells that were co-cultured with cells irradiated with iron or silicon ions, but not protons, exhibited reduced cloning efficiency and harbored higher levels of chromosomal damage, protein oxidation and lipid peroxidation. This correlated with decreased activity of antioxidant enzymes, inactivation of the redox-sensitive metabolic enzyme aconitase, and altered translation of proteins encoded by mitochondrial DNA. Together, the results demonstrate that the long-term consequences of the induced nontargeted effects greatly depend on the quality and dose of the radiation and involve persistent oxidative stress due to induced perturbations in oxidative metabolism. They are relevant to estimates of health risks from exposures to space radiation and the emergence of second malignancies after radiotherapy.

A correlation of long term effects and radiation quality in the progeny of bystander cells after microbeam radiations: The experimental study of radiotherapy for cancer risk mitigation

“…In this context, during cancer radiotherapy, normal tissues are also irradiated along with the tumor. The transmission of stressful effects from irradiated tumor/normal cells to bystander normal cells, and the persistence of such effects in their progeny would have profound implication for long term health risks of the exposure to radiotherapy such as the emergence of secondary cancer induction in normal cells [6][7][11][12]. Therefore, it is important to elucidate the risk associated with various ionizing radiation type and radiation quality of the current radiotherapies use.…”

“…Bystander effect refers to the phenomenon that the induction of biological effects in non-irradiated bystander cells whose nucleus has not been directly traversed by IR [10]. Genomic instability is found when a cell population surviving after IR, shows an increased rate of chromosome aberrations, gene mutations, the delayed cell death in the progeny of cells surviving irradiation and a hallmark of cancer cells [11,12]. In recent years, heavy ions radiotherapy such as high-LET carbon ion is one of the most effective treatment for cancer patients compared to conventional radiotherapy (such as X rays and  rays).…”

Proteomic overview and perspectives of the radiation-induced bystander effects

“…Most biological effects are largely considered to be directly or indirectly linked with a prominent oxidative stress, inducing genetic instability, related to DNA damages [10,19,[21][22][23]15,24]. An increased frequency of micronuclei formation and sister chromatid exchanges was reported, indicating unrepaired or miss-repaired single and double-strand breaks of DNA.…”

Embryos of the zebrafish Danio rerio in studies of non-targeted effects of ionizing radiation

“…The RIBE was induced by both high and low LET radiation. Nonetheless, there were relatively few studies on the relation between the quality of radiation and the RIBE [15][16][17][18][19][20][21]. For a charged particle with a specific energy, the LET is defined for a medium as the quotient dE L by dl, where dE L is the average energy that is locally imparted to the medium by the charged particle while traversing a distance dl.…”