Application of radiation omics in the development of adverse outcome pathway networks: an example of radiation-induced cardiovascular disease

Figures & data

Table 1. List of the transcriptomic studies on radiation-induced CVD.

Experimental model	Radiation Dose	Radiation quality	Time after irradiation	Analytical platform	Main observations	Reference
Neonatal rat cardiac myocytes and cardiac fibroblasts	8.5 Gy	X-rays	1 d	Microarray analysis	Gene expression responses are cell type-specific Genes involved in oxidative stress, p53 signaling, MAPK, cholesterol biosynthesis, fibrosis, and cytoskeleton	Boerma et al. (2005)
Human arterial biopsies	60.4 Gy (range 50–68 Gy)	Radiotherapy (γ-rays)	30 weeks (range 4–500 weeks)	Microarray analysis Gene enrichment analysis	Overexpression of 13 inflammatory genes related to NF-kB Activation	Halle et al. (2010a)
C57BL/6 mice, 8–12 weeks old, male	Local, to the heart 16 Gy	X-rays, 0.94 Gy/min	4, 20, and 40 weeks	Illumina Bead Array	Increased fibrosis-related genes, TGF-b1, ALK 5, and PDGF (40 weeks) Increased gene expression related to inflammatory and immunological related disease	Seemann et al. (2013)
Zebrafish embryo (26 hpf)	TBI 1, 2, 5, 10 Gy	Cobalt-60	94 h	Microarray analysis	Gene enrichment associated with cardiovascular development, function, and disease	Freeman et al. (2014)
Human umbilical vein endothelial cells (HUVECs)	4 Gy	^137Cs 1.4 and 4.1 mGy/h	1, 3, and 6 weeks	Microarray analysis Gene set enrichment analysis	Early stress response Inflammation-related expression profile IGFBP5 related signaling	Rombouts et al. (2014)
C57BL/6 mice, 10-week-old, male	Local, to the heart 8, 16 Gy	X-rays	16 weeks	Targeted transcriptomics	Alterations in PI3K signaling-related genes Altered gene expression involved in endothelial senescence	Azimzadeh et al. (2015)
C57Bl/6NT mice, 8–9 month old, male	TBI 0.15 and 0.9 Gy	Iron ions Protons	1, 3, 7, 14, and 28 d	Microarray analysis	Cell cycle, oxidative responses Transcriptional regulation functional groups involving ERK1/2, p38 MAPK, NFATc4, GATA4, STAT3, and NF-kB	Coleman et al. (2015)
HUVECs	2.5 Gy	X-rays, 5 Gy/min	6, 12, and 24 h	Microarray analysis	Downregulation of the cell cycle regulation genes Increased in inflammatory response genes, Type 1 interferon response Identification of interferon response factor 7 gene network	Furusawa et al. (2016)
C57BL/6J mice, 8-week old, male	16 Gy	X-rays	40 weeks	Illumina Expression Bead Chips Mouse Whole Genome	Overexpression of genes involved in TGF beta and MAPK signaling, down regulation of genes of PPAR alpha signaling	Subramanian et al. (2017)
Human telomerase-immortalized coronary artery endothelial cells	0.05, 0.1, 0.5, and 2 Gy	X-rays, 0.5 Gy/min	24 h 7 and 14 d	Microarray analysis Functional enrichment Analysis Transcription factor binding site Enrichment analysis	Dose- and time-dependent changes in gene expression linked to cell cycle progression and inflammation	Baselet, Belmans, et al. (2017)
Human telomerase-immortalized coronary artery endothelial cells	2 Gy	X-rays, Fe ions 1.5 Gy/min	24 h, 7 d	Transcriptomics and proteomics	Induction of endothelial inflammation and adhesiveness	Baselet, Azimzadeh, et al. (2017)
Human telomerase-immortalized coronary artery endothelial cells	10 Gy	X-rays	14 d	Targeted transcriptomics	Activation of Type I-interferon- mediated signaling	Philipp et al. (2017)
Transgenic hiPSC-derived cardiomyocytes	5 Gy	X-rays, 1 Gy/min	2 d	RNA sequencing Large-scale gene function analysis	Gene expression linked to cell cycle processes, Genes implicated in cardiac calcium homeostasis, oxidative stress response, and etiology of cardiomyopathy	Becker BV et al. (2018)
Primary endothelial cells derived from adult human bone marrow (hBMECs)	6 Gy	^60Co	24 h	Microarray analysis Gene ontology and enrichment analysis Protein–protein interaction (PPI)	Increased in adhesion pathways (leukocyte adhesion and migration) Alterations in adhesion pathways (cell-substrate adhesion and cell spreading) when combined with amifostine	Gupta and Gangenahalli (2019)
Rat brain microvascular endothelial cell (BMEC)	20 Gy	X-rays, 2.5 Gy/min	24 h	Next-generation sequencing functional pathway enrichment	Cell cycle Apoptosis Vascular permeability Extracellular junctions Ca^2+ signaling, PI3K/Akt signaling Methionine degradation	Wu K et al. (2019)
CB6F1/Hsd mice, 3–4-month old, female	TBI 3–26, 4–32, and 40–160 cGy	^137Cs ^14Si ^22Ti	16 months	Microarray analysis with self-organizing map machine and Gene enrichment analyses	Expressed gene clusters identified for three radiation types	Garikipati et al. (2021)

Table 2. List of the miRNA analyses of radiation-induced CVD.

Experimental model	Radiation Dose	Radiation quality	Time after irradiation	Analytical platform	Main observations	Reference
HDMEC	2 Gy	Photon	6 h	Locked nucleic acid (LNA)-based miRNA microarrays	Upregulation of miRNA let-7g, −16, −20a, −21, and −29c, and downregulation of miR-18a, −125a, −127, −148 b, −189, and −503	Wagner-Ecker et al. (2010)
EA.hy926 cells and HUVECs	2.5 Gy	X-rays, 0.94 Gy/min	4 and 24 h	TaqMan^® Low-Density Array A v.2	Alterations in several miRNAs in different time points	Kraemer et al. (2011)
6–8-week old female C57BL/6 J mice	1, 2, 4, 8, 12 Gy.	X-rays, 1.05 Gy/min	48 h	Agilent Mouse miRNA arrays	Upregulation of miR-149-3p, −6538, −8101, −7118-5p, −211-3p, and −3960 after 12 Gy	Aryankalayil et al. (2021).
HCAEC	0.2 Gy	^60Co	4 and 24 h	TaqMan^® miRNA assay	Downregulation of miRNA-21 at 4 h and upregulation of miRNA-146b after 24 h	Barjaktarovic, Anastasov, et al. (2013)
EA.hy926	2.5 Gy	X-rays, 0.94 Gy/min	4, 12, and 24 h	In silico interactions between miRNA and proteins	Overlap between radiation-responsive miRNAs or proteins at different time points	Sriharshan (2014)
Human heart autopsies	<0.1, 0.1–0.5, >0.5 Gy	TBI	Chronic	TaqMan^® miRNA assay	Upregulation of miRNA-21 and miNA-146a in group exposed to doses >0.5 Gy	Azimzadeh, Azizova, et al. (2017)
HUVEC	2 Gy	X-rays	2 and 24 h	TaqMan^® miRNA assay	Time dependent-alterations in miRNA-146a, −155, −221, and −222 in	Esplugas, Bellés, et al. (2019)

Table 3. List of the proteomics studies on radiation-induced CVD.

Experimental model	Radiation dose	Radiation quality	Time after irradiation	Analytical platform	Main observations	Reference
human endothelial cell line EA.hy926	0.2 Gy	^60Co 0.02-0.19 Gy/min	4 and 24 h	MALDI-TOF/TOF tandem mass spectrometry	Alterations in Ran and RhoA pathways, fatty acid metabolism, and stress response	Pluder et al. (2011)
C57BL/6 mice	3 Gy TBI	γ-rays	5 and 24 h	Isotope-coded protein labeling (ICPL) and 2-dimensional difference-in-gel-electrophoresis (2-D DIGE)	Alterations in mitochondrial proteins, inflammation, antioxidative defense, and structural reorganization	Azimzadeh et al. (2011)
C57BL/6N mice mitochondrial	0.2, 2 Gy Local heart	X-rays, 1.5 Gy/min Fe ions, 1.5 Gy/min	4 weeks	ICPL and DIGE	Alterations in oxidative phosphorylation, the pyruvate metabolism, and the cytoskeletal structure	Barjaktarovic et al. (2011)
Human endothelial cell line EA.hy926	2.5 Gy	γ-rays	4 and 24 h	Stable isotope labeling with amino acids in cell culture (SILAC) and 2 D-DIGE	Alterations in glycolysis/gluconeogenesis and synthesis/degradation of ketone bodies, oxidative phosphorylation, Rho-mediated cell motility, and non-homologous end-joining	Sriharshan et al. (2012)
C57BL/6 mice FFPE heart tissue	3 Gy TBI	γ-rays	24 h	Label-free quantitative (LFQ)	Alterations in the respiratory chain, lipid metabolism, and pyruvate metabolism	Azimzadeh et al. (2012)
Primary human coronary artery endothelial cells	0.2 Gy	^60Co	94 h	2D-DIGE and miRNA analysis	Alterations in cellular assembly and organization, cellular function and maintenance, and molecular transport	Barjaktarovic, Anastasov, et al. (2013)
HUVECs	4 Gy	X-rays, 4.1 mGy/h	1, 3, and 6 weeks	Isotope-coded protein label (ICPL) proteomics	Alterations in cytoskeletal organization, cell–cell communication, and adhesion, inflammation, and induction of premature senescence	Yentrapalli, Azimzadeh, Barjaktarovic, et al. (2013)
C57BL/6 and ApoE^–/– mice	0.2 and 2 Gy	X-rays	40 weeks	ICPL	Alterations in the mitochondria-associated cytoskeleton, respiratory chain, ion transport, and lipid metabolism	Barjaktarovic, Shyla, et al. (2013)
C57BL/6 mice mice, 8 weeks old, male	8 and 16 Gy	X-rays (local heart)	16 weeks	ICPL	Alterations in lipid metabolism and oxidative phosphorylation	Azimzadeh et al. (2013)
NMRI mice (neonatal)	0.02, 0.1, 0.5, and 1.0 Gy	^60Co	7 months	ICPL	Alterations in metabolic processes, inflammatory response, and cytoskeletal structure	Bakshi et al. (2013)
HUVECs	0.24, 1.41, and 2.35 Gy at 1.4 mGy/h 0.40, 2.41, and 4.03 Gy at 2.4 mGy/h	X-rays, 1.4 and 2.4 mGy/h	1, 6, and 10 weeks	ICPL and revers protein array	Inactivation of the PI3K/Akt/mTOR pathway Induction of premature senescence	Yentrapalli, Azimzadeh, Sriharshan, et al. (2013)
Isolated endothelial form C57BL/6 mice heart	8 and 16 Gy	X-ray (local heart)	16 weeks	ICPL and targeted transcriptomics	Alterations in insulin/IGF/PI3K/Akt/eNOS Induction of premature endothelial senescence, increased oxidative stress, decreased NO availability, and enhanced inflammation	Azimzadeh et al. (2015)
Human cardiac microvascular endothelial cells	2 Gy	X-rays	4 h	Acetylome and proteome	Alterations in the proteins of the translation process, the stress response, and mitochondria, cytoskeleton signaling, and cell cycle progression	Barjaktarovic et al. (2015)
Human heart autopsies	<0.1 0.1–0.5, >0.5 Gy	TBI	Chronic	LFQ	Downregulation of mitochondrial and structural proteins oxidative stress-responsive and PPAR alpha-related proteins	Azimzadeh, Azizova, et al. (2017)
Human coronary artery endothelial cell	0.5 Gy	^137Cs	24 h	Acetylome and proteome	Alterations in the protein synthesis, cytoskeleton-related processes, protein folding, calcium signaling, and RhoA/actin cytoskeleton	Barjaktarovic et al. (2017)
C57BL/6J mice, 8 weeks old, male	16 Gy	X-rays	40 weeks	LFQ and Transcriptomics	Alterations in PPAR alpha and TGF beta pathway	Subramanian et al. (2017)
Human coronary artery endothelial cell	0.5 Gy	X-rays	1, 7, and 14 d	ICPL	Alterations in the Rho GDP-dissociation inhibitor (RhoGDI) and nitric oxide (NO) signaling pathways, reduced proteasome activity, enhanced protein carbonylation indicating augmented oxidative stress, and senescence	Azimzadeh, Subramanian, et al. (2017)
Human telomerase-immortalized coronary artery endothelial cells	10 Gy	X-rays	14 d	LFQ and targeted transcriptomics	Induction of inflammatory response, induction of interferon type I-related proteins, and activation of the STAT3 pathway	Philipp et al. (2017)
Human telomerase-immortalized coronary artery endothelial cells	2 Gy	X-rays, 1.5 Gy/min Fe ions, 1.5 Gy/min	24 h 7 d	ICPL and transcriptomics	Induction of endothelial inflammation and adhesiveness	Baselet, Azimzadeh, et al. (2017)
C57BL/6J mice, 8 weeks old, male (wild type (+/+), heterozygous (+/−) or homozygous (−/−) PPAR alpha genotype)	16 Gy	X-ray (local heart)	20 weeks	LFQ	PPAR alpha is necessary for activation of noncanonical TGF beta signaling in irradiated heart	Subramanian et al. (2018a)
ApoE-deficient C57Bl/6J mice	6 Gy (chronic)	20 mGy/d) gamma	300 d	Acetylome and proteome	Alterations in the TCA cycle, fatty acid oxidation, oxidative stress response, and sirtuin pathway	Barjaktarovic et al. (2019)
Formalin-fixed paraffin-embedded (FFPE) human heart autopsies	> 0.5 Gy	TBI	Chronic	LFQ	Alterations in the lipid metabolism, sirtuin signaling, mitochondrial function, cytoskeletal organization, and antioxidant defense	Azimzadeh et al. (2020)
Human coronary artery endothelial cells (HCECest2)	0, 0.25, 0.5, 2.0, and 10 Gy	^60Co	20 weeks	LFQ	Activation of DNA-damage repair, inflammation, and oxidative stress pathways	Philipp et al. (2020)
Serum of C57BL/6J mice, 8 weeks old, male	16 Gy	X-ray (local heart)	20 weeks	LFQ	Alterations in the acute phase response, inflammation, and cholesterol metabolism	Azimzadeh and von Toerne et al. (2021)
C57BL/6J mice, 8 weeks old, male treated with PPAR alpha agonist: fenofibrate	16 Gy	X-ray (local heart)	20 weeks	LFQ	Restored lipid metabolism, mitochondrial respiratory chain, redox response, tissue homeostasis, endothelial NO signaling, and the inflammatory response after fenofibrate treatment	Azimzadeh, Subramanian et al. (2021)
3D aggregates of human embryonic stem cell-derived cardiomyocytes	0.1 − 2 Gy	X-rays	and 7 d	LFQ	Alterations in the structural proteins, contractile sarcomere, and cardiac toxicity-related signaling	Smit et al. (2021)
C57BL/6J mice, 8 weeks old	16 Gy	X-ray (local heart)	5 months	Tandem mass tag (TMT) labeling	Alterations in the mitochondrial proteins, proteins involved in the fibrosis and energy metabolism	Xu et al. (2021)

Table 4. List of the metabolomics studies on radiation-induced CVD.

Experimental model	Radiation dose	Radiation quality	Time after irradiation	Analytical platform	Main observations	Reference
C57BL/6 male mice	2 Gy	CLINAC 600 6 MV photons; 1 Gy/min	48 h	HR-MAS NMR	Changes in the metabolites associated with oxidative stress, energy metabolism, membrane integrity, and amino acids	Gramatyka et al. (2018)
Nonhuman primates, primarily male Macacca mulatta (heart tissue)	7.2 Gy TBI	0.6 Gy/min	Survivors vs. non-survivors, 60-day end of the study	UPLC-QTOF MS	Alterations in the long-chain acylcarnitines, fatty acid amines	Cheema et al. (2019)
C57BL/6J male mice (heart tissue)	0.1, 0.25, and 1 Gy TBI	600 MeV/n ^16O, NSRL	14 and 90 days	UPLC-MS/MS	Changes in the transsulfuration pathway and cystathione	Miousse et al. (2019)
C57BL/6NCrl female mice (heart tissue)	0.2 or 2 Gy, TBI	Varian CLINAC 2300 6 MV photons	48 h or 20 weeks	1H NMR	Alterations in pantothenate, glutamate, alanine, malonate, acetylcarnitine, glycine, and adenosine	Gramatyka et al. (2020)
CD2F1 male mice (heart tissue)	9.6 Gy, TBI, and treatment with amifostine	0.6 Gy/min ^60Co	4 and 9 d	UPLC-QTOF MS	Alterations in Hydroxyprostaglandin E1 and fatty acids	Cheema et al. (2020)
Nonhuman primates, Macacca mulatta (heart tissue)	12 Gy, 2.5% bone marrow shielding	0.8 Gy/min 6 MV photons	4 d and 3 weeks	Biocrates AbsoluteIDQ kit with targeted LC-MS/MS	Changes in the fatty acid oxidation, phospholipid biosynthesis, phenylacetate metabolism, pyrimidine metabolism, glucose-alanine cycle, arginine and proline metabolism, and seleno-amino metabolism.	Kumar et al. (2021); Zalesak-Kravec et al. (2021)

Table 5. List of the biofluid analyses on radiation-induced CVD.

Experimental model	Radiation dose	Radiation quality	Time after irradiation	Analytical platform	Main observations	Reference
TBI patients	1.25 Gy, 1.25 × 3 Gy	∼0.1 Gy/min Clinical exposures 15 MV photons	Pre, ∼6, ∼24 h	UPLC-QTOFMS	Octanoylcarnitine, hypoxanthine, trimethyl-L-lysine, acetylcarnitine, decanoylcarnitine, uric acid, and xanthine	Laiakis et al. (2014)
C57BL/6 male mice Saliva	137Cs external TBI 0.5 Gy	γ-ray 1.4 Gy/min	1 and 7 d	UPLC-QTOFMS	Changes in polar metabolites	Laiakis et al. (2016)
Human breast cancer radiotherapy patients Serum	6 cycles of radiotherapy, unreported dose	Unreported	Controls, pre and end of radiotherapy cycle	GC-MS	Changes in fatty acids	Shaikh et al. (2017)
TBI patients	1.25, 2, 1.25 × 3 Gy	∼0.1 Gy/min Clinical exposures 15 MV photons	Pre, ∼6 and ∼24 h	LC-MS, GC-MS	Eicosanoids, monoacylglycerols, triacylglycerols, phosphatidylcholines, phenylalanine, and phosphatidylglycerols	Laiakis et al. (2017)
Outbred Sprague-Dawley male and female rats Plasma and urine	Chronic exposure in drinkable water	Uranium	∼9 months	LC-microTOF-MS	Changes in nicotinate-nicotinamide pathways and unsaturated fatty acid biosynthesis	Grison et al. (2019).
BALB/c male mice Feces	0.5 Gy acute and fractionated	γ-ray ^60Co	7, 21, and 35 d	GC-MS	Alterations in glucagon signaling pathway, central carbon metabolism, TCA cycle	Liu X et al. (2019)
C57BL/6 male mice Serum	^137CsCl injections (4 Gy total dose)	γ-ray 0.16 Gy/d, 0.69 Gy/d, and 1.25 Gy/d	2, 3, 5, 7, and 14 d	UPLC-QTOFMS	Changes in Oleamide, sphingosine-1- phosphate irrespective of dose rate	Li HH et al. (2020)
Head and neck radiotherapy patients	Conventional radiotherapy and radiatio + concurrent chemotherapy (cisplatin)	Clinical exposures	Pre, 2 weeks, end of treatment	LC-MS	Reduced choline-containing phospholipids	Jelonek et al. (2020)
C57BL/6 male and female mice, Urine and serum	TBI (1–9.7 Gy)	^137Cs, ∼1–0.1 Gy/d, 0.8 Gy/min	1, 2, 3, 5, 20, and 30 d	UPLC-QTOFMS	Alterations in ketoglutaric acid, 1-methylnicotinatime, TML, carnitine, trigonelline, indoleactic acid, Hex-V-I, citric acid, and xanthurenic acid	Pannkuk et al. (2021)

Figure 1. Categories of radiation omics studies to support proposed CVD AOP. Available types of omics data are represented across key events in the CVD AOP network as colored boxes (modified from Chauhan, Hamada, et al. (2021)).

Figure 2. The application of omics data in the development of AOP for radiation-induced CVD. The different levels of omics data obtained from the cell, animal, and human samples can enrich the AOP framework alongside available knowledge from non-omics data, epidemiological findings, and mechanistic, and mathematical modeling. Together, this information can be integrated across biological levels of organization and provide confident bioindicators for the development of bioscreening tools that can support radiation risk assessment. MIE: molecular initiating events; KE: key events; AO: adverse outcome. The figure is created with BioRender.com.

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