Cancer Letters

Cancer Letters

Volume 356, Issue 1, 1 January 2015, Pages 17-21
Cancer Letters

Mini-review
Non-targeted effects induced by ionizing radiation: Mechanisms and potential impact on radiation induced health effects

https://doi.org/10.1016/j.canlet.2013.09.009Get rights and content

Highlights

  • Cell-to-cell communication between irradiated cells and non-irradiated cells (NTE's) and its potential impact on human health.

  • Speculation on the factors that might be involved in communicating responses from irradiated cells to non-irradiated cells and eliciting an effect.

  • Relationships between irradiated cells and non-irradiated cells and the implications for delayed health effects.

Abstract

Not-targeted effects represent a paradigm shift from the “DNA centric” view that ionizing radiation only elicits biological effects and subsequent health consequences as a result of an energy deposition event in the cell nucleus. While this is likely true at higher radiation doses (>1 Gy), at low doses (<100 mGy) non-targeted effects associated with radiation exposure might play a significant role. Here definitions of non-targeted effects are presented, the potential mechanisms for the communication of signals and signaling networks from irradiated cells/tissues are proposed, and the various effects of this intra- and intercellular signaling are described. We conclude with speculation on how these observations might lead to and impact long-term human health outcomes.

Section snippets

Definitions

The following definitions of the primary NTE’s are adapted from Kadhim et al. [1] and https://ssl.note-ip.org/index.asp.

What are non-targeted effects and are they interrelated?

NTE’s include RIBE and RIGI, and reflect a number of endpoints including, but not limited to, the induction of mutation and chromosome rearrangements, gene expression changes and cell killing [17]. There appears to be a link between RIBE and RIGI [18], [19]. The overwhelming consensus is that there is a strong link between these manifestations of NTE’s and this has been supported experimentally [20]. Indeed, RIGI might be considered under the rubric of a RIBE. NTE’s appear to be largely a low

Health effects associated with exposure to ionizing radiation

Ionizing radiation is a carcinogen, albeit at low doses a relatively poor one. The role of radiation in non-cancer effects, i.e., cardiovascular effects, hypertension, stroke and opacities in the lens of the eye [25] as well as central nervous system effects [26], is evolving and subject to intense investigation. At higher doses, radiation induced carcinogenesis is less controversial and estimates of cancer risk suggest a 5% increase in risk per Sv of radiation exposure. The risk for

What factors might be involved in communicating non-targeted effects?

As expected from a biological process, there are likely to be multiple pathways to a particular endpoint associated with NTE’s. These presumably reflect the experimental system interrogated, the endpoint analyzed and dose and dose rate effects of the radiation exposure. A number of factors are likely to be involved including connexin mediated cell-to-cell gap junction communication [40]; reactive oxygen/nitrogen species [41]; iNOS [42]; and cytokines/chemokines [43]. There are results that

Potential mechanisms of radiation induced non-targeted effects – a stress response?

NTE’s represents a paradigm shift in our understanding of the mechanism(s) of how radiation might exert its effects. It is likely that multiple pathways are involved in signaling the response from an irradiated cell to a non-irradiated cell, and that different cell types will respond differently to the signaling pathways stimulated. A unifying model has been proposed by Hei et al. [38] that paints in broad strokes the potential signaling pathways that may be involved in communicating NTE’s (see

Bridging the gap between radiation exposure and radiation health effects: a role for NTE’s?

Thus far, most of the available data on NTE’s have been largely phenomenological. While future mechanistic studies are likely to identify signaling pathways and the molecules involved, the relevance of NTE’s to human health remains unclear. A key question in this discussion is whether NTE’s are limited to a specific cell type within an organ, to the whole organ or to the whole organism. The answer to this is not immediately obvious. But the fact that NTE’s occur indicates that the communication

Is there a role for inflammatory responses cancer and non-cancer effects?

Physiological levels of reactive oxygen and nitrogen species play critical roles in numerous cellular functions. In irradiated and NTE cells and tissues the levels of reactive radical species may be increased due to perturbations in oxidative metabolism and chronic inflammatory response [56], both of which impact the carcinogenic processes [57], [58]. For example, a study from Gollapalle et al. [59] showed that several weeks after irradiation non-exposed tissues had high levels of presumably

Relationship of NTE’s to radiation induced health effects

The connections between the manifestations of NTE’s and the hallmarks of carcinogenesis are obvious. Both are complex processes modulated by a number of factors including genetics, epigenetics, environment, and target organ (tissue). Following irradiation, cancer process may be initiated, but a sequelae of factors must come into play to promote this process and override the innate host immune system. NTE’s may well play a role in upsetting tissue homeostasic regulation [54]. The persistence of

Conflict of Interest

The authors declare that there are no conflicts of interest.

Acknowledgments

Supported by Battelle Memorial Institute, Pacific Northwest Division, under Contract No. DE-AC05-76RL0 1830 with the US Department of Energy (DOE), Office of Biological and Environmental Research (OBER) Low Dose Radiation Science Program.

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