Table 1.

List of relevant publications related to the effect of dose rate on gene expression, protein modification, and cell cycle effects

Type of animal, strain/age, or in vitro cell type	Irradiation details	Outcomes recorded, time post-exposure	Definitive findings	Reference
ML-1 human myeloid leukaemia cell line	γ-Irradiation Doses: 50, 100, 250, 500 mGy Dose rates: 1.68  × 102, 1.44 .× 103 1.6,8 × 104 and 1.68 × 105 mGy/h	Cell cycle, apoptosis, gene expression (2 h after exposure)	Decrease in the slope of the dose response curve with decreasing dose rate for some genes and no effect on some others	Amundson et al. (2003)
Shewanella oneidensis	Underground vs above ground environment (WIPP, US) Inside DUL: ~ 10–6 mGy/h	RNASeq-based transcriptome analysis carried out on early and late-exponential S. oneidensis cultures (after 5–8-13 17 and 24 h underground)	Stress response when deprived of background levels of ionising radiation. Down-regulation of ribosomal proteins and tRNA genes; up-regulation of membrane transporters among others	Castillo et al. (2015)
AG1522 normal human skin fibroblast (synchronised in G0/G1; grown in 3D on carbon scaffold)	γ-Irradiation Dose: 100 mGy Dose rates: 3 mGy/h and 30 mGy/h Dose: 4000 mGy Dose rate: 1.2 × 103 mGy/h	miRNA expression pattern (evaluated at 3 h or 8 h after exposure)	Evidence of dose, dose rate, and time dependent variations in miRNA expression pattern	Chaudhry et al. (2012)
Chinese hamster V79 cells	Underground vs above ground environment (CJPL, China) Inside DUL: ~ 10–5 mGy/h	Whole transcriptome analysis (after two days of culture underground)	No significant difference in miRNA. Altered RNA profiles in lncRNAs, mRNAs and circRNAs. Differentially expressed RNAs involved in many pathways including ECM-RI, PI3K-Akt signalling, RNA transport and the cell cycle Cell growth inside DUL could induce transcriptional repression, thus reducing metabolic process and reprogramming the overall gene expression profile in V79 cells	Duan et al. (2021)
A11 mouse hybridoma cells	Underground vs above ground environment (LNGS, Italy) Inside DUL: ~ 10–6—~ 10–5 mGy/h (inside a shielded or an unshielded incubator)	Cell proliferation, caspase-3 activation and PARP1 cleavage (western blot) (4 weeks of continuous culture in different environments plus 2 weeks above ground)	No differences in cell proliferation; switch of the over-growth-induced cell apoptosis to autophagy underground, Caspase-3 activation and PARP1 cleavage in cells entering in over-growth status above ground only; p53 activation underground; scarce influence of further gamma ray shielding underground	Fischietti et al. (2020)
Chinese hamster V79 cells	Underground vs above ground environment (LNGS, Italy) Inside DUL: ~ 10–6 mGy/h	Gene expression (RT-qPCR) and activities of antioxidant enzymes (GPX, SOD, CAT) (10 months of continuous culture in different environments plus 6 months above ground)	Higher degree of defence against endogenous damage in reference conditions: GPX activity significantly decreased underground and remaining at the same level even after further 6 months above ground	Fratini et al. (2015)
Zebrafish AB strain	γ-irradiation Doses: 5.2, 31 Gy Dose rates: 8.7 and 53 mGy/h	Mating, gene expression, health parameters. (month or years later), health of F1	Few genes in F1 from different doses overlapping, more overlapping between higher dose 1-month F1 and lower dose 1-year F1	Hurem et al. (2018)
Mouse C57Bl/6	γ-irradiation Doses: 3 × 102, 6 × 103 mGy Dose rates: 0.042 and 0.83 mGy/h	Gene expression analysis (after 300 days of exposure)	Differentially expressed gene lists according to dose rate	Kempf et al. (2016)
Chinese hamster V79 cells FD-LSC-1 Laryngeal Squamous Carcinoma Cells	Underground vs above ground environment (CJPL, China) Inside DUL: ~ 10–5 mGy/h	Proteome profile, cell proliferation (up to 1 week), morphology (TEM) (one passage and 2 days or 4 days of growth for V79 or FD-LSC-1 cells respectively)	Reduced growth rate and changes in the protein profile: up-regulation of ribosomal proteins, spliceosome, RNA transport, and energy metabolism among others	Liu et al. (2020a), Liu et al. (2020b)
Chinese hamster CH0-K1 cells	X-irradiation Doses: up to 15 Gy Dose rates: 1.86 × 102, 1 × 103 mGy/h, 3 × 103 and 6 × 103 mGy/h (fractionated and continuous exposure)	Cell survival and cell cycle	Increase survival with decreasing dose rate; accumulation of the cells in G2 during exposure with LDR; delay of DNA synthesis and accumulation of the cells in S/G2 during the exposure with intermediate dose rates (e.g., 3 × 103 mGy/h), Blocks of cell cycle progressing in whole checkpoints (G1/S and G2/M checkpoints) and delay of DNA synthesis during the exposure with higher dose rate (e.g., 6 × 103 Gy/h)	Matsuya et al. (2017) Matsuya et al. (2018)
Paramecium tetraurelia	Underground vs above ground environment (CNRS Moulis, Pyrenees Mountains, France) Inside DUL: in the absence 1,9 × 10–4 mGy/h or in the presence of Pb shielding (1,1 × 10–5 mGy/h) or after chronic irradiation with a 60Co-source (4,6 × 10–4 mGy/h). In orbit on Salyut 6 4.6 × 10–3 mGy/h) or in balloon flight (in the presence of microgravity) 4 × 10–3 mGy/h	Protozoan growth rate (10 days of culture underground, 2 days in balloon and 4 days on Salyut 6)	Background radiation or chronic γ-irradiation at very low dose rate can stimulate cell proliferation Stimulation was also observed at high altitude and in space	Planel et al. (1987)
Primary human Lung fibroblasts Bronchial epithelial cells	Underground vs above ground environment (WIPP, USA) Inside DUL: ~ 10–6 mGy/h	Western Blot (after 10 passages underground)	Upregulation of HSP 90B and HSP 70); expression further upregulated after acute exposure to 10 cGy X-rays	Smith et al. (2011)
Caenorhabditis elegans	Underground vs above ground environment (WIPP, USA) Inside DUL: ~ 10–5 mGy/h	Gene expression, rate of larvae growth; egg layering (after 1 week or 8 months underground)	More than 100 genes differentially regulated, compared to normal background radiation levels, faster rates of larval growth, and early egg laying	Van Voorhies et al. (2020)
Bacillus subtilis and Escherichia coli	Underground environment (Boulby, UK) Inside DUL: ~ 10–7 -10–5 mGy/h (in the absence or in the presence of a gamma source)	Bacterial growth and susceptibility to stress (UVC exposure)	No significant effect on bacterial growth from exposure to radiation doses ranging from 0.01 times the levels of background radiation to 100 times that background No preconditioned susceptibility to stress was observed in the bacterial strains grown in sustained low radiation	Wadsworth et al. (2020)
Drosophila melanogaster	Underground vs above ground environment (DULB-4900, BNO, Russia) Inside DUL: ~ 10–5 mGy/h	Transcriptome analysis after one development cycle (14 days)	Gene expression changes in several genes (77) in response to underground environment	Zarubin et al. (2021)
Human umbilical vein endothelial cells (HUVECs)	γ-irradiation Dose: ~ 2 × 103 mGy and ~ 4 × 103 mGy, depending on the dose rate Dose rates: 1.4, 2.4 and 4.1 mGy/h Chronic exposure for up to 10 weeks	Transcriptome and proteome analysis, cell proliferation and senescence	Dose-rate-dependent signatures of proteomic changes involved mainly in the PI3K/Akt/mTOR pathway and oxidative stress; gene expression profiling demonstrating an early stress response characterised by the expression of inflammation-related genes possibly activating radiation-induced premature senescence via the IGFBP5 signalling pathway	(Rombouts et al. 2014; Yentrapalli et al. 2013a, 2013b)