https://orcid.org/0000-0001-8984-0388
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Abstract
Background
Epidemiological studies have indicated that exposure of the heart to doses of ionizing radiation as low as 0.5 Gy increases the risk of cardiac morbidity and mortality with a latency period of decades. The damaging effects of radiation to myocardial and endothelial structures and functions have been confirmed radiobiologically at high dose, but much less are known at low dose. Integration of radiation biology and epidemiology data is a recommended approach to improve the radiation risk assessment process. The adverse outcome pathway (AOP) framework offers a comprehensive tool to compile and translate mechanistic information into pathological endpoints which may be relevant for risk assessment at the different levels of a biological system. Omics technologies enable the generation of large volumes of biological data at various levels of complexity, from molecular pathways to functional organisms. Given the quality and quantity of available data across levels of biology, omics data can be attractive sources of information for use within the AOP framework. It is anticipated that radiation omics studies could improve our understanding of the molecular mechanisms behind the adverse effects of radiation on the cardiovascular system. In this review, we explored the available omics studies on radiation-induced cardiovascular disease (CVD) and their applicability to the proposed AOP for CVD.
Results
The results of 80 omics studies published on radiation-induced CVD over the past 20 years have been discussed in the context of the AOP of CVD proposed by Chauhan et al. Most of the available omics data on radiation-induced CVD are from proteomics, transcriptomics, and metabolomics, whereas few datasets were available from epigenomics and multi-omics. The omics data presented here show great promise in providing information for several key events (KEs) of the proposed AOP of CVD, particularly oxidative stress, alterations of energy metabolism, extracellular matrix (ECM), and vascular remodeling.
Conclusions
The omics data presented here shows promise to inform the various levels of the proposed AOP of CVD. However, the data highlight the urgent need of designing omics studies to address the knowledge gap concerning different radiation scenarios, time after exposure, and experimental models. This review presents the evidence to build a qualitative omics-informed AOP and provides views on the potential benefits and challenges in using omics data to assess risk-related outcomes.
Acknowledgments
The authors are thankful to Ms Sarita Sanchez Cuadro (Health Canada, Canada) for her assistance with the graphics. The authors would like to thank the Multidisciplinary European Low dose Initiative (MELODI) for funding support for the MELODI Workshop 2021 and for open access publication of this paper.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Additional information
Notes on contributors
Omid Azimzadeh
Omid Azimzadeh, Ph.D, PD, is a senior researcher in the section of Radiation Biology at the German Federal Office for Radiation Protection (BfS) and an Adjunct Professor (Docent) of Radiation Biology at Technical University Munich. He is a member of the working group CircuDis (Circulatory Diseases from Radiation Exposure) at the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) and the High Level Group on Low Dose Research (HLG-LDR) Rad/Chem AOP Joint Topical Group.
Simone Moertl
Simone Moertl, Ph.D., PD, is head of the section of Radiation Biology at the Federal Office for Radiation Protection (BfS) and an Adjunct Professor (Docent) of Radiation Biology at Technical University Munich. Until September 2019 she led the group of Clinical Radiobiology at the Institute of Radiation Biology, Helmholtz Zentrum München. Her research focuses on the cellular radiation response of tumors and normal tissues with the aim to understand the mechanisms of individual radiation sensitivity. She is particularly interested in the vesicle-mediated transfer (e.g. by exosomes) of RNAs between cells. She is a member of the High Level Group on Low Dose Research (HLG-LDR) Rad/Chem AOP Joint Topical Group.
Raghda Ramadan
Raghda Ramadan, Ph.D., is a scientist in the Radiobiology Unit at the Belgian Nuclear Research Center (SCK CEN). She coordinates the research line focusing on cardiovascular risks after ionizing radiation exposure. She is a member of a working group CircuDis (Circulatory Diseases from Radiation Exposure) at the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR).
Bjorn Baselet
Bjorn Baselet, Ph.D., is a senior researcher in the Radiobiology group at the Belgian Nuclear Research Center (SCK CEN). His research interests lie in the field of space biology, looking into the adverse effects of space stressors, such as cosmic radiation exposure on normal tissues with a special emphasis on the immunological and cardiovascular system. Besides his research activities, he is a dedicated mentor of undergraduate and graduate students. Furthermore, he is a member of a working group on ionizing radiation at the Belgian High Health Council and received the 2020 MELODI award for his work on radiation-induced cardiovascular disease and immune dysfunction.
Evagelia C. Laiakis
Evagelia C. Laiakis, Ph.D., is an Associate Professor in the Department of Oncology at Georgetown University. She received her Ph.D. degree from the University of Maryland at Baltimore. She is an elected Council Member of the National Council on Radiation Protection and Measurements and has been serving at PAC-1 since 2016. She is also the recipient of the 2019 Jack Fowler Award from Radiation Research Society, and a dedicated mentor to students and postdocs. Her research focuses on metabolomic and lipidomic responses to ionizing radiation, with particular emphasis on the development of early biodosimetry applications in biofluids.
Soji Sebastian
Soji Sebastian, Ph.D., in Cell Biology, is currently a research scientist in the Radiobiology and Health Branch at Canadian Nuclear Laboratories (CNL) and adjunct professor in the department of cellular and molecular medicine, University of Ottawa. He has been in the field of stem cell biology and radiobiology using multi-omics approach to address epigenetic basis of tissue regeneration. At CNL, he is investigating the epigenetic effects of ionizing radiation in skeletal muscle, cardiac, and lung cellular models. Experimental approaches span from molecular in vitro studies to integrative in vivo stem cell biology and mass spectrometry.
Danielle Beaton
Danielle Beaton, Ph.D., is a Research Scientist at Canadian Nuclear Laboratories. Her current research focuses on the effects of low dose radiation on biological systems. She is on the NEA HLG-LDR committee and assists the co-chairs of the HLG-LDR Rad/Chem AOP Joint Topical Group.
Jaana M. Hartikainen
Jaana M. Hartikainen, Ph.D., is a Senior Researcher in the School of Medicine at University of Eastern Finland (UEF). She is an Adjunct Professor (Docent) in Molecular Genetics and has 25 years of research experience in cancer genetics and molecular biology. She leads the research project focusing on non-coding RNAs in breast cancer and is also involved in teaching and thesis supervision in the School of Medicine at UEF.
Jan Christian Kaiser
Jan Christian Kaiser, Ph.D., heads the research group ‘Integrative Modeling’ in the Institute of Radiation Medicine at the Helmholtz-Zentrum München. His main interests relate to the integration of radiation biology and epidemiology for health risk estimation with biologically based models addressing the pathogenesis of cancer and cardiovascular diseases.
Afshin Beheshti
Afshin Beheshti, Ph.D., is a Principal Investigator and Bioinformatician at KBR at NASA Ames Research Center, a Visiting Researcher at Broad Institute of MIT and Harvard, and President of a nonprofit formed in March 2020 working on COVID-19 called COVID-19 International Research Team (COV-IRT, www.cov-irt.org). His research interests include applying systems biology approaches to a broad range of topics which include: mitochondria, noncoding RNAs/miRNAs, radiation biology, space biology, cancer, COVID-19, and cardiovascular disease.
Sisko Salomaa
Sisko Salomaa, Ph.D., is a Professor of radiobiology at the University of Eastern Finland and Coordinator of the National Radiation Safety Research Program in STUK. As part of setting up the European low dose program (MELODI), she coordinated the DoReMi Network of Excellence 2010–2015. She is a representative of Finland to UNSCEAR and was a member of ICRP C1.
Vinita Chauhan
Vinita Chauhan, Ph.D., is a Senior Research Scientist at the Consumer and Clinical Radiation Protection Bureau of Health Canada. She is a Canadian delegate of the High Level Group on Low Dose Research (HLG-LDR) and Extended Advisory Group on Molecular Screening and Toxicogenomics (EAGMST) of the OECD. She co-chairs the HLG-LDR Rad/Chem AOP Joint Topical Group and is the co-founder of the Canadian Organization of Health Effects from Radiation Exposure (COHERE) initiative.
Nobuyuki Hamada
Nobuyuki Hamada, RT, Ph.D., is a Senior Research Scientist at CRIEPI and a Visiting Professor at Hiroshima University Research Institute for Radiation Biology and Medicine. He serves on ICRP Task Groups 102, 111 and 119, NCRP PAC 1, OECD/NEA/CRPPH/HLG-LDR/Rad/Chem AOP Joint Topical Group, IRPA Task Group on Tissue Reactions, and Consultation Committee on AOP development for space flight health outcomes (Canadian project).