The Role of Gap Junction Communication and Oxidative Stress in the Propagation of Toxic Effects among High-Dose α-Particle-Irradiated Human Cells

Abstract

We investigated the roles of gap junction communication and oxidative stress in modulating potentially lethal damage repair in human fibroblast cultures exposed to doses of α particles or γ rays that targeted all cells in the cultures. As expected, α particles were more effective than γ rays at inducing cell killing; further, holding γ-irradiated cells in the confluent state for several hours after irradiation promoted increased survival and decreased chromosomal damage. However, maintaining α-particle-irradiated cells in the confluent state for various times prior to subculture resulted in increased rather than decreased lethality and was associated with persistent DNA damage and increased protein oxidation and lipid peroxidation. Inhibiting gap junction communication with 18-α-glycyrrhetinic acid or by knockdown of connexin43, a constitutive protein of junctional channels in these cells, protected against the toxic effects in α-particle-irradiated cell cultures during confluent holding. Upregulation of antioxidant defense by ectopic overexpression of glutathione peroxidase protected against cell killing by α particles when cells were analyzed shortly after exposure. However, it did not attenuate the decrease in survival during confluent holding. Together, these findings indicate that the damaging effect of α particles results in oxidative stress, and the toxic effects in the hours after irradiation are amplified by intercellular communication, but the communicated molecule(s) is unlikely to be a substrate of glutathione peroxidase.

Health Risks of Space Exploration: Targeted and Nontargeted Oxidative Injury by High-Charge and High-Energy Particles

“…In this context, our studies have shown that the magnitude of the effects due to connexin channels in enhancing or reducing the propagation of radiation-induced oxidative stress is a function of radiation quality (LET effect). The abundance of reactive species along the track of an HZE particle may be the factor that affects permeability of connexin channels (9)(10)(11). These results are consistent with earlier studies showing that the cellular redox environment together with gap junction communication are the major mediators of the propagation of stressful responses from a particle-irradiated cells to bystander cells in the vicinity (13,17,201,308).…”

Intercellular Communication Amplifies Stressful Effects in High-Charge, High-Energy (HZE) Particle-Irradiated Human Cells

“…7) Here, we extend these studies and investigate the effect of intercellular communication on the modulation of the stress induced in normal human fibroblasts exposed to particulate radiations found in deep space, namely low LET protons and high-LET iron ions. Characterizing the role of the cross-talk among cells exposed to different types of ionizing radiation may contribute to understanding the effects of radiation quality in the enhancement or mitigation of the induced detrimental effects.…”

Exposure to low level environmental agents: The induction of hormesis

“…In contrast, a cell traversed by a single electron track resulting from an exposure to X rays receives a small dose of 0.1 cGy [19]. Hence, as in the case of targeted effects, the nature of propagated non-targeted effects is dose-dependent, with low doses to the targeted cells triggering the propagation of an adaptive response and high doses to the targeted cells of agents such as ionizing radiation or chemotherapeutic drugs inducing the spread of toxic effects [20,21]. …”