Development of an adverse outcome pathway for radiation-induced microcephaly via expert consultation and machine learning

Abstract

Background

Brain development during embryogenesis and in early postnatal life is particularly complex and involves the interplay of many cellular processes and molecular mechanisms, making it extremely vulnerable to exogenous insults, including ionizing radiation (IR). Microcephaly is one of the most frequent neurodevelopmental abnormalities that is characterized by small brain size, and is often associated with intellectual deficiency. Decades of research span from epidemiological data on in utero exposure of the A-bomb survivors, to studies on animal and cellular models that allowed deciphering the most prominent molecular mechanisms leading to microcephaly. The Adverse Outcome Pathway (AOP) framework is used to organize, evaluate and portray the scientific knowledge of toxicological effects spanning different biological levels of organizations, from the initial interaction with molecular targets to the occurrence of a disease or adversity. In the present study, the framework was used in an attempt to organize the current scientific knowledge on microcephaly progression in the context of ionizing radiation (IR) exposure. This work was performed by a group of experts formed during a recent workshop organized jointly by the Multidisciplinary European Low Dose Initiative (MELODI) and the European Radioecology Alliance (ALLIANCE) associations to present the AOP approach and tools. Here we report on the development of a putative AOP for congenital microcephaly resulting from IR exposure based on discussions of the working group and we emphasize the use of a novel machine-learning approach to assist in the screening of the available literature to develop AOPs.

Conclusion

The expert consultation led to the identification of crucial biological events for the progression of microcephaly upon exposure to IR, and highlighted current knowledge gaps. The machine learning approach was successfully used to screen the existing knowledge and helped to rapidly screen the body of evidence and in particular the epidemiological data. This systematic review approach also ensured that the analysis was sufficiently comprehensive to identify the most relevant data and facilitate rapid and consistent AOP development. We anticipate that as machine learning approaches become more user-friendly through easy-to-use web interface, this would allow AOP development to become more efficient and less time consuming.

Keywords:

• Adverse outcome pathway
• AOP
• microcephaly
• brain
• development
• ionizing radiation

Disclosure statement

All authors declare that they have no competing interests. The opinions expressed and arguments employed herein are those of the authors and do not necessarily reflect the official views of the OECD or of the governments of the OECD Member Countries.

Additional information

Funding

This project was supported by funding from the Euratom research and training program 2019-2020 under grant agreement No. 900009 (RadoNorm); the Research Council of Norway (RCN) through its Centre for Excellence funding scheme (Project No. 223268 and project No. 268294 ‘MixRisk’) and NIVAS Computational Toxicology Program, NCTP (www.niva.no/nctp, RCN project No. 160016).

Notes on contributors

Thomas Jaylet

Thomas Jaylet (TJ), is Ph.D student in bioinformatics at Université Paris-Cité. His thesis is part of the RadoNorm project (under grant agreement No 900009) and aims to improve the understanding of ionizing radiation exposure through the development of AOPs and integrative systems toxicology methods. He is also involved in the development of the AOP-helpFinder tool to facilitate the documentation of AOPs.

Roel Quintens

Roel Quintens (RQ), Ph.D, is a senior scientist and project leader at the Radiobiology Unit of SCK-CEN where he leads two main research themes: (1) the mechanistic analysis of prenatal radiation-induced defects (e.g. microcephaly and epilepsy) in brain development modeled in mice and human brain organoids, and (2) the identification of novel transcriptional biomarkers (splice variants, circular RNAs) of exposure and cancer cell sensitivity to different radiation qualities. He is member of the Strategic Research Agenda working group of MELODI.

Mohamed Abderrafi Benotmane

Mohamed Abderrafi Benotmane (MAB), Ph.D, is a researcher project leader at the Radiobiology Unit at the Belgian Nuclear Research Center ‘SCK-CEN’. He is mainly interested in medical applications making use of radiation for diagnostic and therapy. Over the years he has been mainly involved in central nervous system impairments following exposure to radiation at young age prenatally and at early postnatal periods. The outcome of his research is of high societal impact for the protection of the brain of the fetus and the young child. He coordinated the FP7 EU project CEREBRAD (GA 295552) (2011–2015) and participated to many other EU projects (DoReMi, OPERRA, CONCERT, and MEDIRAD). He is a member of the High Council for Health in Belgium. He is delegate at the High-level group on low-dose research (HLG-LDR), and contributes as Radiobiology expert in several commissions (MELODI, WHO, OECD, ENA).

Jukka Luukkonen

Jukka Luukkonen (JL), Ph.D, is a university lecturer in the Radiation Research Group, University of Eastern Finland, with responsabilities on research and teaching related to the radiation biology. He has over 15 years of experience conducting studies with combined exposure to radiation and other agents.

Ignacia Braga Tanaka

Ignacia Braga Tanaka III (IT), DVM, Ph.D, is an Associate Senior Scientist at the Institute for Environmental Sciences (IES) in Rokkasho, Aomori, Japan. She is a trained veterinarian and here research work focus on the late effects of chronic exposure to low dose-rate radiation on life span, cancer and non-neoplastic diseases in various exposure scenarios. She is member of the ICRP Task Groups 110 (Veterinary Medicine) and 121 (Offspring and next generations).

Chrystelle Ibanez

Chrystelle Ibanez (CI), Ph.D, is a research scientist at the French Institute of Radioprotection and Nuclear Safety (IRSN). She leads neurotoxicology and radiotoxicology research projects after contamination via inhalation. She has studied the effects and mechanisms of uranium transport and tungsten particles to the brain. Here current research projects focus on the effect of combined radiological and chemical exposures on brain toxicity parameters.

Christelle Durand

Christelle Durand (CD), Ph.D, is a scientist at the French Institute of Radioprotection and Nuclear Safety (IRSN). Her research focuses on studying the consequences of postnatal brain exposure to IR on behavioral functions and to identify the molecular and cellular mechanisms associated with these potential disorders in mice.

Magdalini Sachana

Magdalini Sachana (MS), Ph.D, is a Policy Analyst in the Environmental Health and Safety Division of the OECD’s Environmental Directorate. She manages the development and implementation of policies in the field of chemical safety and contributes to the OECD Test Guidelines, Pesticide and Hazard Assessment Programs. Dr. Sachana, among other projects, is contributing to the coordination of the OECD project on the in vitro battery for developmental neurotoxicity and the AOP Program.

Omid Azimzadeh

Omid Azimzadeh (OAz), Ph.D, 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. His research interests focus on the adverse effects of radiation exposure on normal tissues with a special emphasis on omics analysis. He is a member of a working group CricuDis (Circulatory Diseases from Radiation Exposure) at the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR).

Knut Erik Tollefsen

Knut Erik Tollefsen (KET), Ph.D, is a Chief Scientist at the Norwegian Institute for Water Research (NIVA) and an Adjunct Professor at the Norwegian University of Life Sciences (NMBU). He is a Norwegian delegate at the High-level group on low-dose research (HLG-LDR), OECD Extended Advisor Group on Molecular Screening and Toxicogenomics (EAGMST), co-chair of the HLG-LDR Rad/Chem AOP Joint Topical Group and coordinates NIVAS’s Computational Toxicology Program, NCTP (www.niva.no/tcp). [email protected]

Olivier Laurent

Olivier Laurent (OL), Ph.D, is a senior scientist at the French Institute of Radioprotection and Nuclear Safety (IRSN). He conducts occupational and environmental epidemiological studies in people exposed to low doses of radiation and other environmental stressors. He is member of the of the High-Level Group on Low-Dose Research (HLG-LDR) Joint Topical Group Rad-Chem.

Karine Audouze

Karine Audouze (KA), Ph.D, is associate professor at the Université Paris Cité in France, where she is leading the SysTox group. She is member of the OECD Extended Advisor Group on Molecular Screening and Toxicogenomics (EAGMST), of the High-Level Group on Low-Dose Research (HLG-LDR) Rad/Chem Joint Topical and of the OECD AOP knowledge base (AOP-KB) group.

Olivier Armant

Olivier Armant (OA), Ph.D, is a senior scientist at the French Institute of Radioprotection and Nuclear Safety (IRSN). His studies focus on the molecular mechanisms deregulated upon exposure to low dose of radiations during embryonic development and post-accidental effects on wild-life in Chernobyl and Fukushima. He is a member of the High-Level Group on Low-Dose Research (HLG-LDR) Joint Topical Group Rad-Chem.