# Low Dose Ionising Radiation-Induced Hormesis: Therapeutic Implications to Human Health
## 4 The Phenomena of LDIR
### Adaptive Response  
Adaptive response (AR) is the existence of radioprotective mechanisms (stress response) that are upregulated in response to small doses of conditioning ionising radiation exposure (<30 cGy); this could protect against a separate subsequent irradiation larger than the initial dose [92]. [PERSON] et al. (1996) have reported that there is indirect evidence that the low-dose hyper-radiosensitivity (HRS) and induced radioresistance (IRR) in response to single doses is a manifestation of the same underlying mechanism that determine AR in the two-dose case, irrespective of high or low LET as well as a variety of other stress-inducing agents [92]. It has been reported that the underlying AR mechanisms include the transcription of genes, the activation of diverse signalling and stress response pathways that trigger cell defences such as enhanced DNA repair systems, the induction of protein synthesis, enhanced detoxification of free radicals and antioxidant production, cell survival/death pathway (apoptosis), endoplasmic response to stress, cytoprotective processes including autophagy, cell cycle regulation, unfolding of proteins, and enhanced immune/inflammatory response and the suppression of genomic instability in animal and human cells (see references [93; 94; 95; 96]). Generally, the AR is defined as a protective phenomenon induced by an LDIR of \(\leq\)10 cGy, as demonstrated in the use of \({}^{137}\)Cs or \({}^{60}\)Co \(\gamma\) rays delivered at \(\leq\)0.2 cGy/h [94]. Adaptive response is known to be highly variable and is influenced by radiation quality, dose and dose-rate, cell types, tissues, systems, organisms and individuals [97; 98; 99]. However, [PERSON] et al. (2016) demonstrated that both C57 BL/6 and BALB/c mice bone marrow erythrocytes did not show any radio-adaptive response of induction of cytogenetic damage or suppression of erythrocyte proliferation/maturation index in the bone marrow of the mice when exposed to \(\gamma\) irradiation low priming single doses of 20 mGy or 100 mGy or multiples of 20 mGy that were administered at various times prior to 2 Gy radiation [100]. [PERSON] and colleagues (1984) first observed AR in human lymphocyte cultures, where cells were pre-exposed to low-level chronic radiation with [\({}^{3}\)H] thymidine before second exposure to a greater radiation level of 150 cGy of X-rays. As a result, the lymphocyte cells that were previously pre-exposed to low-level chronic radiation yielded less chromatid aberrations in the second challenge doses compared to those exposed separately [101]. With this encouraging finding, a considerable amount of literature over the last three decades has suggested similar phenomena in both in vitro and in vivo studies. A more recent study has highlighted that oxidised cell-free DNA (cfDNA) fragments, released from irradiated mesenchymal stem cells, play a pivotal role as a stress mediator to signal to the other living cells to invoke an adaptive response induced by an LDIR of 10 cGy [102]. These cfDNA fragments were released from apoptotic cells, that penetrated into the cytoplasm of other cells to induce radio-adaptive responses and bystander effect through a cascade of cfDNA-induced signalling events including ROS production, modifications of nuclear DNA, repair of DNA breaks and short-term cell-cycle arrest of the cell. This series of events eventually leads to the activation of DNA repair systems, antioxidant response, and the inhibition of apoptosis as part of the development of the protective response in which cells can rapidly adapt to future challenges. In addition, NO has also been shown to be responsible in the adaptive response post irradiation with a challenging irradiation of 6 Gy subsequent to a priming irradiation of 0.02 Gy through the activation of HDM2 and the depression of p53 accumulations in wild-type (wt) p53 [103; 104].