The scientific evidence required to make policy decisions that protect human health can be challenging to organize. Primary research is often silo-ed between different agency repositories, the pace of publication is unflagging and wide-spread interdisciplinary collaboration can be logistically difficult. Since 2012, the Organisation for Economic Co-operation and Development (OECD) adverse outcome pathway (AOP) framework has provided solutions for some of the challenges of supplying relevant and accessible scientific data for evidence-based decision-making. Development of AOPs is guided by a crowd-sourced approach in which progressions of adverse outcomes (AO) are distilled into pathways containing only the essential key events (KEs) and the causal key event relationships (KERs) that connect them. The framework has widely been adopted in the toxicology community and more recently projects have applied it to the radiation safety field. Presently, a collaborative effort aims to further expand the use of AOPs through creating a network linking exposure to the space exposome with resulting human health outcomes. The network contains four adverse non-cancer outcomes for which participants of future long-range space missions will be at risk. The work of this thesis has contributed to the construction of the space-health AOP network by accomplishing two main objectives. The first was the creation of a novel protocol for collecting a weight of evidence (WOE) that included the benefits of scoping review and artificial intelligence (AI) tools for literature screening. The scoping review WOE collection strategy was then deployed for collecting data across all four outcomes in the space-health network. The second objective was to identify KEs and KERs and summarize the WOE linking space exposure to one of the four AOs: vascular remodeling. In addition to summarizing the pathway, we have also highlighted important modulating factors and knowledge gaps in the WOE. This thesis work contributes to the future of the AOP framework by formulating a new development protocol and employing it in a novel regulatory context. Using the new protocol, this thesis has furthered biological understanding of the effects of space exposure on the cardiovascular system by collating mechanistic information across scientific disciplines to identify KEs and KERs in occurrence of vascular remodeling.

京都大学 / 新制・課程博士 / 博士(工学) / 甲第24222号 / 工博第5050号 / 新制||工||1788(附属図書館) / 京都大学大学院工学研究科都市環境工学専攻 / (主査)教授 米田 稔, 教授 松井 康人, 准教授 松田 知成 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

Résumé : Depuis l'interdiction en 2013 des tests sur les animaux par le Règlement cosmétique n°1223/2009, différentes méthodes in vitro ont été développées. Toutefois, selon un consensus scientifique, aucune méthode ne peut couvrir à elle seule l’ensemble des événements clés (KE) définis pour la sensibilisation cutanée.Après un état de l’art des méthodes alternatives relatives à la sensibilisation cutanée, nous avons sélectionné et comparé 3 tests pour ensuite déterminer la meilleure stratégie à suivre. Dans le but de proposer un nouveau test intégré, nous avons adressé l’ensemble des KEs au sein d’un même type cellulaire. La cellule dendritique (DC) jouant un rôle clé dans le développement de la dermatite de contact allergique (DCA), notre choix s’est porté sur la lignée humaine pro-monocytaire THP-1. Nous avons étudié comme événements initiaux (KE1) les formes réactives à l’oxygène (FRO) et le glutathion (GSH), la voie Nrf2-Keap1 (voie centrale de détoxication) et l’expression génique pour le KE2, ainsi que les modifications phénotypiques pour le KE3.Nous avons montré que les allergisants forts induisent une production précoce des FRO associée à une réduction du GSH. Ils activent également la voie Nrf2-Keap1 et induisent l’expression des marqueurs de surface cellulaire CD54 et CD86, ainsi qu’une production de cytokines spécifiques (IL-8, IL-18,...).Pour conclure, ce travail a permis de proposer un test intégrant l’ensemble des mesures biologiques comme différents KE au sein d’un même type cellulaire. / Abstract : Since the animal testing ban in 2013 by Cosmetics Regulation n°1223/2009, various in vitro methods have been developed. However, according to a scientific consensus, no single method can stand-alone to cover the different key events (KE) defined for skin sensitization.After a state of the art of alternative methods relating to skin sensitization, we selected and compared 3 tests to determine the best strategy to follow. In order to propose a new integrated test, we wanted to address all KE within the same cell line. Because dendritic cell (DC) plays a key role in the development of allergic contact dermatitis (ACD), we have chosen the pro-monocytic human line THP-1. We have studied as initial events (KE1), reactive oxygen species (ROS) and glutathione (GSH), Nrf2-Keap1 pathway (central detoxification pathway) and gene expression for KE2 as well as phenotypic modifications for KE3.We have shown that strong allergens are correlated with early production of FRO associated with GSH reduction. They also activate the Nrf2-Keap1 pathway and induce the expression of CD54 and CD86 cell surface markers as well as production of specific cytokines (IL-8, IL-18, etc.).To conclude, this work propose a new assay integrating all the biological measures as different KEs within the same cell.