Targeted and Nontargeted Effects of Low-Dose Ionizing Radiation on Delayed Genomic Instability in Human Cells

Abstract

All humans receive some radiation exposure and the risk for radiation-induced cancer at low doses is based on the assumption that there is a linear non-threshold relationship between dose and subsequent effect. Consequently, risk is extrapolated linearly from high radiation doses to very low doses. However, adaptive responses, bystander effects, and death-inducing effect may influence health effects associated with low-dose radiation exposure. Adaptive response is the phenomenon by which cells irradiated with a sublethal radiation dose can become less susceptible to subsequent high-dose radiation exposure. Bystander effects are nontargeted effects observed in cells that were not irradiated but were either in contact with or received soluble signals from irradiated cells. These non-hit bystander cells can exhibit damage typically associated with direct radiation exposure. Death-inducing effect is a phenomenon whereby medium from human-hamster hybrid cells displaying radiation-induced chromosomal instability is toxic to unirradiated parental cells. In this study, we show that human RKO cells do not exhibit adaptive response, bystander effect, or death-inducing effect, as measured by cell killing, or delayed genomic instability in a stably transfected plasmidbased green fluorescent protein assay measuring homologous recombination and delayed mutation/deletion events. However, growth medium conditioned by some chromosomally unstable RKO derivatives induced genomic instability, indicating that these cells can secrete factor(s) that elicit responses in nonirradiated cells. Furthermore, low radiation doses suppressed the induction of delayed genomic instability by a subsequent high dose, indicative of an adaptive response for radiation-induced genomic instability. These results highlight the inherent variability in cellular responses to low-dose radiation exposure and add to the uncertainties associated with evaluating potential hazards at these low doses. [Cancer Res 2007;67(3):1099-104]

Intercellular Communication in Response to Radiation Induced Stress: Bystander Effects in Vitro and in Vivo and Their Possible Clinical Implications

“…Some of them are clastogenic and can induce chromosomal damage in nonirradiated cells, analogous to that in directly-hit cells. Huang et al (2007) observed that growth medium conditioned by some chromosomally unstable RKO derivatives induced genomic instability, indicating that these cells can secrete factor(s) that elicit responses in non-irradiated cells. Furthermore, low radiation doses suppressing the induction of delayed genomic instability by a subsequent high dose, are indicative of an adaptive response for radiation-induced genomic instability.…”

A Review: Development of a Microdose Model for Analysis of Adaptive Response and Bystander Dose Response Behavior

“…Morgan (2006) has recently suggested that the issue of the validity of the Linear-No Threshold hypothesis hinges on the significance of the adaptive response protection versus the deleterious bystander damage with little significance placed on apoptosis and genomic instability. Even more recent work (Huang et al 2007) finds that genomic instability experiences an adaptive response suppression from low-dose radiation exposure.…”

Direct and delayed X‐ray‐induced DNA damage in male mouse germ cells

“…These biological effects are attributed to unrepaired or misrepaired DNA damage in cells directly hit by radiation. However, the effects of ionizing radiation also extend to cells that were not themselves irradiated, but were neighbors or the progeny of irradiated cells [Huang et al, 2007;Sowa, 2007, 2009;Kovalchuk and Baulch, 2008;Rzeszowska-Wolny et al, 2009;Wright, 2010]. The molecular mechanisms of these non-targeted effects are a matter of intensive investigation and are not fully understood.…”