Abstract
Radiosusceptibility is the sensitivity of a biological organism to ionising radiation (IR)-induced carcinogenesis, an outcome of IR exposure relevant following low doses. The tissue response is strongly influenced by the DNA damage response (DDR) activated in stem and progenitor cells. We previously reported that in vivo exposure to 2 Gy X-rays activates apoptosis, proliferation arrest and premature differentiation in neural progenitor cells (transit amplifying cells and neuroblasts) but not in neural stem cells (NSCs) of the largest neurogenic region of the adult brain, the subventricular zone (SVZ). These responses promote adult quiescent NSC (qNSC) activation after 2 Gy. In contrast, neonatal (P5) SVZ neural progenitors continue proliferating and do not activate qNSCs. Significantly, the human and mouse neonatal brain is radiosusceptible.Here, we examine the response of stem and progenitor cells in the SVZ to low IR doses (50–500 mGy). We observe a linear dose-response for apoptosis but, in contrast, proliferation arrest and neuroblast differentiation require a threshold dose of 200 or 500 mGy, respectively. Importantly, qNSCs were not activated at doses below 500 mGy. Thus, full DDR activation in the neural stem cell compartment in vivo necessitates a threshold dose, which can be considered of significance when evaluating IR-induced cancer risk and dose extrapolation.
Highlights
A DNA double strand break (DSB) is the biologically relevant DNA damage induced by ionising radiation (IR)
We previously reported that in vivo exposure to 2 Gy X-rays activates apoptosis, proliferation arrest and premature differentiation in neural progenitor cells but not in neural stem cells (NSCs) of the largest neurogenic region of the adult brain, the subventricular zone (SVZ)
For our assessment of apoptosis, we assessed the total number of cells per lateral ventricle (LV) without distinguishing the response of individual subdomains
Summary
A DNA double strand break (DSB) is the biologically relevant DNA damage induced by ionising radiation (IR). At high IR doses, radiosensitivity arises from the lethal impact of DSBs. human patients, mice and cells deficient in DSB repair show marked radiosensitivity [1,2]. One outcome of low dose exposure is carcinogenesis rather than cell killing, which can potentially arise via DSB mis-repair, such as balanced chromosomal translocation formation. Sensitivity to IR-induced carcinogenesis has recently been defined as radiosusceptibility (compared to radiosensitivity, which represents sensitivity to the killing effects of IR) [6]. Assessing risks to carcinogenesis from low doses is extremely difficult given the lack of a well-defined signature for IR-induced cancers, and that X-ray-treated individuals may have underlying cancer pre-disposing health effects. Previous studies using cultured cells have shown that G2/M checkpoint arrest requires a threshold dose for activation [9,10]
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