Table 1. Key findings on the systemic effects induced by ionizing radiation of different types. In this table, we have included the biological system and the affected organs or tissues as well as the main biological molecules and mechanisms involved based on experimental evidence and current status of knowledge.

	Organism/system	Radiation type (targeted organ/tissue)	Surrounding or distant organ/tissue affected: observed effect	Molecules involved – key mechanisms proposed	Ref.
Human			In vivo
	Human	Roentgen-ray therapy prior to chronic granulocytic leukemia treatment (spleen)	Bone marrow:	- Production of “clastogenic factors” in the circulating blood of exposed individuals	244
			- Decrease in bone marrow cellularity
	Human (hepatocellular carcinoma patient)	Radiotherapy prior to thoracic vertebral bone metastasis (thorax)	Liver:	- Host immune response involving cytokines (TNF-α)	74
			- Regression of hepatocellular carcinoma
			- Increased serum levels of TNF-α
			In vitro
	Non-small cell lung carcinoma cells (H1299)	?	Non-irradiated cells treated with radiation-conditioned medium from irradiated cells:	TGF-β1–miR-21–ROS pathway	49
			- ROS level increase
			- DNA damage increase
	Human umbilical vein endothelial cells (HUVECs)	γ-Irradiation (U937 macrophage cells)	HUVECs co-cultured with γ-irradiated U937:	- p38 pathway	56
			- Induction of additional micronuclei and apoptosis	- Irradiated U937 cells release nitric oxide and thereby further triggers apoptotic and inflammatory responses in the bystander HUVECs
			- Overexpression of p38 mitogen-activated protein kinase (MAPK)
			- Increase of the contents of vascular cell adhesion molecule-1 (VCAM-1) and the activities of matrix metalloproteinase-9 (MMP-9) in HUVEC culture medium
	Neonatal human dermal fibroblasts (NHDF-Neo)	UVA, UVB, UVC (NHDF-Neo)	Non-irradiated cells co-incubated with irradiated cells in well dishes allowing diffusion of medium components between them:	- Increased levels of cellular ROS in irradiated cells may cause these bystander effects	66
			- Reduction of survival	- Increased secretion of IL-6 suggests its role as a molecular bystander signal released by irradiated cells, but mutual signaling between irradiated and bystander cells modulates this secretion
			- Increased frequency of apoptosis
			- Increased intracellular oxidation
			- Generation of proinflammatory cytokines
			- Increased levels of cellular ROS
			- Increase of IL-6 concentration in the medium (especially in UVB and UVC experiments)
	Lung adenocarcinoma cells (A549)	6MV X-rays (A549)	- Lower clone forming, apoptosis and survival, and cell circle arrest in phase G2 in both irradiated and irradiated conditioned medium (ICM)-treated cells	- Cytokine production induces changes in the bystander cells	67
Rodents			In vivo
	Rats (Sprague-Dawley)	60Co γ-irradiation (lung base)	Lung apex:	- Clastogenic factor produced in the plasma following irradiation	70
			- Micronuclei induction	- Production of oxygen radicals by the induction of inflammatory cytokines (TNF-α, IL-1)
			- Partial blocking of the DNA damage in the unirradiated lung apex by superoxide dismutase
	Mice	137Cs γ-radiation (whole body)	Spleen, bone marrow:	- Cytokine release	68
			- Macrophage and neutrophil accumulation	- Signaling pathways initiated by extensive macrophage activity
			- Increase phagocytic activity	- Communication between phagocytic cells
	Mice	125I (whole body)	Subcutaneous tumor:	- Various signaling pathways triggered by 125I decay	245
			- Tumor growth arrest/retardation
	Mice	X-rays (whole body/half body)	Cutaneous tissues:	- Internal organ exposure	42
			- DNA double strand breaks	- DNA double strand breaks repair activity proteins
			- Upregulation of Rad51
	Rat	X-rays (whole body/whole body without cranial exposure)	Spleen:	- miR-194 (miRNA)-regulated pathway	50
			- DNA hypomethylation
			- Altered levels of histone methylation and DNA methyltransferases
			- Upregulation of non-coding RNA molecules
	Mice	X-rays (partial body)	Skin:	- Oxidative stress metabolism	53
			- Oxidative clustered DNA lesions induction
	Mice	X-rays (whole body/cranial exposure)	Spleen:	- Cell cycle changes	43
			- DNA damage – apoptosis	- DNA repair
			- Upregulation p53 expression
			- Abnormal cellular proliferation
			- Gender specific abnormal mRNA levels
	Mice	137Cs γ-radiation (whole body)	Haematopoietic clonogenic stem cells:	- Inflammatory mechanisms	54
			- TNF-α secretion	- Oxidative stress
			- Macrophage activation
	Mice	X-rays (whole body/whole body excluding head)	Cerebellum:	- Erroneous DSB repair or complete lack of it, leading to genetic changes	81
			- Double strand breaks	- Clastogenic factors in blood stream
			- Apoptotic cell death
			- Tumor induction
	Mice	X-rays (whole body/cranial exposure)	Spleen, skin:	- miR-194 (miRNA)-regulated pathway	47
			- Epigenetic changes: DNA hypomethylation	- Genomic instability
			- Reduction of MeCP2 (methyl-binding protein) expression	- DNA repair pathways
	Mice	137Cs γ-radiation (whole body)	Bone marrow:	- Genetic susceptibility	69
			- Colony-forming efficiency (CFE) reduction	- Complicated signaling processes
			- Genomic instability	- Activation of cytokines
	Mice	X-rays (cerebellum)	Cerebellum:	- Gap junction intercellular communication via connexin43 (Cx43)	63
			- Upregulation of Cx43	- Oxidative metabolism
			- Adenosine triphosphate release
	Mice (C57BL6)	60Co γ-radiation (whole body)	Bladder:	- Intracellular calcium levels	10
			- Clonogenic death induced by the medium harvest from bladder tissues from acutely irradiated mice	- Genetic background dependent RIBE
	Mice	γ-Radiation (whole body)	Bone marrow:	- Genetic susceptibility	71
			- Fas ligand (FasL) and TNF-α activation	- Cytokine secretion
				- Inflammatory pathway of cyclooxygenase (COX-2)
	Mice	60Co γ-irradiation (whole body)	Hematopoietic stem cells (HSCs):	- Oxidative stress metabolism	55
			- Acute cell death
			- Accelerated proliferation of the bystander HSCs
			- Increase of intracellular ROS
	Mice patched1 heterozygous (Ptch1+/–)	X-rays (partial body exposure)	Skin:	- Gap junction intercellular communication	82
			- Early responses to DNA damage
			- Apoptosis
			- Skin basal cell carcinoma
	Mice (gptdelta transgenic)	X-rays (lower abdominal region)	Lungs:	- COX-2 mediated bystander effects	72
			- Induction of COX-2 in the non-targeted bronchial epithelial cells
			- Increased levels of prostaglandin and 8-hydroxydeoxyguanosine
			- Induction of DNA DSBs
			- Apoptosis in bystander lung tissues
			In vitro
	Normal rat fibroblast cells (208F)	X-rays	Co-culture with (pre-carcinogenic) v-src-transformed rat fibroblast (208Fsrc3):	- In non-irradiated bystander cells: ER stress, cell cycle perturbation, altered interleukin signaling pathways point to fast-released molecules involved in the induction of apoptosis (IIA).	246
			- Extracellular signaling proteins (focus on TGF-β1)
			- Gene expression analysis: perturbed cell cycle related- and interleukin-related pathways
	Normal human fibroblast cells (MRC-5)		Co-culture with (pre-carcinogenic) v-src-transformed rat fibroblast (208Fsrc3):
			- Extracellular signaling proteins (focus on TGF-β1)
	Murine primary haematopoietic stem cells from CBA mice	MRC plutonium-238 α-particle source (murine cells)	Co-culture and media transfer experiments:	- Genomic instability may be significantly induced in bystander cells whether or not cells communicate during irradiation	20
			- Decrease of clonogenic survival, suggesting a major contribution of bystander cell killing
			- Appearance of delayed aberrations (genomic instability induction)
Fish			In vivo
	Rainbow trout	X-rays	Skin, fin, kidney, spleen, and gill of unirradiated trout incubated with an irradiated one in the same container:	- The irradiated fish released factors into the water that can cause bystander responses in unexposed fish	80
			- Reduction of clonogenic survival of HPV-G reporter cells
	Rainbow trout	X-rays	Increased expression of oxidative metabolism and polarity maintenance proteins (hemopexin-like protein, Rho GDP dissociation inhibitor – RhoGDI, pyruvate dehydrogenase – PDH) in gills of nonirradiated trout placed in a container previously occupied by an irradiated one	- Protective proteomic response	76
	Zebrafish	X-rays	Skin and gill of unirradiated zebrafish incubated with an irradiated one in the same container:	- The irradiated fish released factors into the water that can cause bystander responses in unexposed fish	78
			- Reduction in HPV-G reporter cell growth of both irradiated and naive fish
	Zebrafish embryos (Danio rerio)	α-Particles	Unirradiated zebrafish embryos incubated with irradiated embryos in the same agarose plate:	- The irradiated fish released factors into the medium that can cause bystander responses in unexposed zebrafish embryos	247
			- Increase of cell death signals for both irradiated and naive embryos
	Zebrafish embryos (Danio rerio)	α-Particles	Unirradiated zebrafish embryos incubated with the irradiated ones in the same container:	- The irradiated fish released factors into the water that can cause bystander responses in unexposed fish	77
			- Decrease in apoptotic signals in both irradiated and unirradiated bystander embryos
	Partnered zebrafish embryos	High-dose X-rays	Naïve embryos partnered in the same medium with the irradiated ones:	- Bystander effect at the interorganism level.
				Effect mediated by NO signalling pathways.	79
			- 47% increase of apoptotic signals in bystander embryos compared to control
			In vitro
	Embryonic zebrafish fibroblasts (ZF4)	Chronic low dose of 137Cs γ-rays (ZF4)	Non-irradiated cells co-cultured with irradiated cells or with irradiated culture medium:	- A soluble factor contained in the culture medium of irradiated cells is responsible of the DNA DSB appearance in non-irradiated cells, which has a molecular weight higher than 3 kDa and is inactivated by heating	44
			- DNA DSB occurrence	- Neither secretion of specific proteins, nor the oxidation of these secreted proteins may be responsible for bystander effects, although a slight increase of oxidation was noted
			- Increase in global methylation of both irradiated and bystander cells
Plants	Arabidopsis thaliana embryos	Protons (shoot apical meristem)	Whole organism:	- Long distance effect in whole organisms	248
			- Direct damage to the shoot apical meristem
			- Inhibition of root hair differentiation
			- Primary root elongation
			- Lateral root initiation
			- Decrease in the accumulation of the reporter GUS gene transcript
	Arabidopsis thaliana (intact seeds)	Heavy ions (shoot and root apical meristem)	Shoot and root apical meristem:	- Oxidative metabolism disruption and increased generation of ROS	249
			- Inhibition of postembryonic development (germination, root hair differentiation, primary root elongation, lateral root initiation and survival) of both irradiated and non-irradiated shoot apical meristem and root apical meristem cells
	Arabidopsis thaliana (whole plant)	α-Particles (whole plant)	Distal primary roots of young seedlings:	- Oxidative metabolism and ROS production	250
			- Increase in the frequency of homologous recombination (HR) in aerial plants, which occurred in every true leaf during rosette development
			- Short-term up-regulated expression of the HR-related AtRAD54 gene in non-irradiated aerial plants
Other	Daphnia magna	Acute γ-rays	Non-exposed first-generation offspring of irradiated parents:	- Presence of transgenerational effects	251
			- Compromised viability	- Detrimental effects of deleterious mutations induced in the germline of irradiated parents
	C. elegans	Proton microbeam	Apoptotic germ cell death after microbeam-localized irradiation of pharynx tissue	- CEP-1/p53-dependent germ cell death	252
				- Bystander effect mediated via MAPK pathways