Radiation-induced bystander effects and the DNA paradigm: An “out of field” perspective

doi:10.1016/j.mrfmmm.2005.10.011

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis

Volume 597, Issues 1–2, 11 May 2006, Pages 5-10

https://doi.org/10.1016/j.mrfmmm.2005.10.011 Get rights and content

Abstract

Over the past 20 years there has been increasing evidence that cells and the progeny of cells surviving a very low dose of ionizing radiation [μ-mGy] can exhibit a wide range of non-monotonic effects such as adaptive responses, low dose hypersensitivity and other delayed effects. These effects are inconsistent with the expected dose–response, when based on extrapolation of high dose data and cast doubt on the reliability of extrapolating from high dose data to predict low dose effects. Recently the cause of many of these effects has been tentatively ascribed to so-called “bystander effects”. These are effects that occur in cells not directly hit by an ionizing track but which are influenced by signals from irradiated cells and are thus highly relevant in situations where the dose is very low. Not all bystander effects may be deleterious although most endpoints measured involve cell damage or death. In this commentary, we consider how these effects impact the historical central dogma of radiobiology and radiation protection, which is that DNA double strand breaks are the primary radiation-induced lesion which can be quantifiably related to received dose and which determine the probability that a cancer will result from a radiation exposure. We explore the low dose issues and the evidence and conclude that in the very low dose region, the primary determinant of radiation exposure outcome is the genetic and epigenetic background of the individual and not solely the dose. What this does is to dissociate dose from effect as a quantitative relationship, but it does not necessarily mean that the effect is ultimately unrelated to DNA damage. The fundamental thesis we present is that at low doses fundamentally different mechanisms underlie radiation action and that at these doses, effect is not quantitatively related to dose.

Section snippets

Old historical evidence leading to the DNA paradigm

Classical radiobiology really started in the 1940s with the almost simultaneous publication of two books on mechanisms of action of ionizing radiation on living cells. Lea published “Actions of Radiations on Living Cells” in 1946 [1] and Timofeeff-Ressovsky and Zimmer published “Das Trefferprinzip in der Biologie” in 1947 [2]. At that time the structure of DNA was not known but the stage was set for its adoption as the critical “target” for radiation-induced biological effects by the

The rise of “non-targeted” radiobiology

A fundamental hypothesis shift away from DNA centered radiobiology originated with a growing number of observations that all survivors cannot be regarded as equally normal or healthy and that the progeny of these irradiated survivors exhibit many differences when compared to their unirradiated counterparts. The literature has references to this as early as 1964 [9] but the major lines of evidence came from the late 1980s and early 1990s when demonstrations by many authors using entirely

Is DNA damage required somewhere in the system?

A keenly argued point is whether DNA damage (for example a DSB) is necessary within a cell to trigger non-targeted effects. This has been addressed in several ways using cytoplasmic targeting with microbeams, using medium transfer protocols and using endonucleases instead of radiation to induce breaks, see journal issue [40]. The data are controversial because even with cytoplasmic targeting, the possibility of some nucleic acid being irradiated cannot be excluded, as mitochondria have DNA [43]

What drives the instability phenotype?

Many theories have been advanced to explain how genomic instability effects such as delayed death, chromosomal instability or mutation occur de novo, several generations after exposure. These include induction of mutations in mutator phenotype genes or repair genes, discussed in [53] but mechanisms relying on specific gene mutations induced at the time of exposure cannot explain the persistent, high frequency of the event or its species wide occurrence. They also cannot explain

Is the paradigm intact?

To summarise, this paper presents a discussion from the perspective of biologists working with very low doses, of some of the issues which arise in relation to the integration of very low dose effects into the existing body of knowledge concerning radiobiological mechanisms. The historical data leading to the conclusion that DNA damage, and more particularly, DSB's are the critical site of energy deposition which causes radiobiological effects such as cell death and chromosome aberrations are

Acknowledgements

We wish to acknowledge our funding agencies in Ireland (Science Foundation Ireland and Irish Cancer Research), and in Canada (the Canada Chair programme and the National Science and Engineering Research Council).

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Radiation-induced bystander effects and the DNA paradigm: An “out of field” perspective

Abstract

Section snippets

Old historical evidence leading to the DNA paradigm

The rise of “non-targeted” radiobiology

Is DNA damage required somewhere in the system?

What drives the instability phenotype?

Is the paradigm intact?

Acknowledgements

Mutat. Res.

Mutat. Res.

DNA Repair (Amst.)

Biochimie

Mutat. Res.

J. Exp. Haematol.

FEMS Yeast Res.

Mutat. Res.

Mutat. Res.

Action of Radiations on Living Cells

Das Trefferprinzip in der Biologie

The interaction of radiation energy with nucleic acids

Curr. Top. Radiat. Res. Quart.

Radiation-induced DNA damage and its repair

Int. J. Radiat. Biol.

DNA damage detection and repair, and the involvement of epigenetic states

Hum. Mutat.

The Radiobiology of Cultured Mammalian Cells

Action of X-rays on mammalian cells

J. Exp. Med.

X-ray-induced heritable damage (small-colony formation) in cultured mammalian cells

Radiat. Res.

Heritable cell cycle disturbances and late recovery in X-irradiated murine lymphoma L5178Y-S cell populations in vitro

Adv. Exp. Med. Biol.

Hereditary radiation-induced lesions in somatic mammalian cells

Postepy Biochem.

Discrimination of slow growth from non-survival among small colonies of diploid Syrian hamster cells after chromosome damage induced by a range of X-ray doses

Int. J. Radiat. Biol. Relat. Stud. Phys. Chem. Med.

Heavy-ion irradiation of human and Chinese hamster cells in vitro

Radiat. Res.

Cellular Radiobiology

DNA replication in the face of (in)surmountable odds

Cell Cycle

UV-induced DNA damage and repair: a review

Photochem. Photobiol. Sci.

The theory of dual radiation action

Curr. Top. Radiat. Res.

A molecular theory of cell survival

Phys. Med. Biol.

RBE-LET relationships for different types of lethal radiation damage in mammalian cells: comparison with DNA dsb and an interpretation of differences in radiosensitivity

Int. J. Radiat. Biol.

The mutagenic potential of DNA double-strand break repair

Toxicol. Lett.

The role of membrane damage in radiation-induced cell death

Adv. Exp. Med. Biol.

Utility of biological membranes as indicators for radiation exposure: alterations in membrane structure and function over time

Stem Cells

A metabolic theory of cell survival curves

Phys. Med. Biol.