Adverse outcome pathway from activation of the AhR to breast cancer-related death

International audienceAdverse outcome pathways (AOPs) are formalized and structured linear concepts that connect one molecular initiating event (MIE) to an adverse outcome (AO) via different key events (KE) through key event relationships (KER). They are mainly used in ecotoxicology toxicology, and regulatory health issues. AOPs must respond to specific guidelines from the Organization for Economic Cooperation and Development (OECD) to weight the evidence between each KE. Breast cancer is the deadliest cancer in women with a poor prognosis in case of metastatic breast cancer. The role of the environments in the formation of metastasis has been suggested. We hypothesized that activation of the AhR (MIE), a xenobiotic receptor, could lead to breast cancer related death (AO), through different KEs, constituting a new AOP. An artificial intelligence tool (AOP-helpfinder), which screens the available literature, was used to collect all existing scientific abstracts to build a novel AOP, using a list of key words. Four hundred and seven abstracts were found containing at least a word from our MIE list and either one word from our AO or KE list. A manual curation retained 113 pertinent articles, which were also screened using PubTator. From these analyses, an AOP was created linking the activation of the AhR to breast cancer related death through decreased apoptosis, inflammation, endothelial cell migration, angiogenesis, and invasion. These KEs promote an increased tumor growth, angiogenesis and migration which leads to breast cancer metastasis and breast cancer related death. The evidence of the proposed AOP was weighted using the tailored Bradford Hill criteria and the OECD guidelines. The confidence in our AOP was considered strong. An in vitro validation must be carried out, but our review proposes a strong relationship between AhR activation and breast cancer-related death with an innovative use of an artificial intelligence literature search

Évaluation des effets sur le neurodéveloppement de l’exposition prénatale et postnatale aux produits phytopharmaceutiques. Présentation du projet NEUROPHYTO

International audiencePrenatal and neonatal periods are windows of vulnerability to environmental chemical contaminants. A growing number of epidemiological and toxicological studies suggest that exposure to pesticides during these periods may impact the health of children at birth as well as their development, with potential delayed adverse effects.The NEUROPHYTO project is a new research project that aims to evaluate the exposure to pesticides of French children from prenatal period to early childhood and to study the possible effects of these exposures on their motor and neuropsychological development. New exposure data will be generated: levels of 140 pesticides and metabolites will be measured in biological samples (urine and hair) of 200 children from the national cohort Elfe (French longitudinal study of children). The levels of active substance(s) in the brain will be estimated using a mathematical model and then related to early neurodevelopmental effects. Two approaches will be used to better identify and characterize these links. The first strategy will rely on epidemiological methods and the second will be based on the understanding of the neurotoxicity mechanisms of the substances. Finally, a child-specific risk analysis will provide support to public policies by targeted evidence during pre- and post-natal windows of vulnerability.Les périodes prénatale et néonatale constituent des fenêtres de sensibilité vis-à-vis des contaminants chimiques de l’environnement. Un nombre croissant d’études épidémiologiques et toxicologiques suggère que l’exposition aux pesticides pendant ces périodes pourrait impacter la santé des enfants à la naissance ainsi que leur développement, avec des retentissements possibles tout au long de la vie.Le projet NEUROPHYTO est un nouveau projet de recherche qui vise à évaluer les expositions aux produits phytosanitaires d’enfants français lors de la période prénatale à la petite enfance et à étudier les effets possibles de ces expositions sur leur développement moteur et neuropsychologique. De nouvelles données d’exposition seront produites : les concentrations de 140 pesticides et métabolites seront mesurés dans les échantillons biologiques (urine et cheveux) de 200 enfants de la cohorte nationale Elfe (Etude longitudinale française depuis l’enfance). Les concentrations de substance(s) active(s) dans le cerveau seront estimées par modélisation puis mis en relation avec des effets neurodéveloppementaux précoces. Deux approches seront mises en œuvre afin de mieux identifier et caractériser ces liens : l’une épidémiologique et l’autre basée sur la compréhension des mécanismes de neurotoxicité des substances. Enfin, une analyse spécifique des risques pour les enfants permettra d’appuyer les politiques publiques en apportant des éléments ciblés sur les fenêtres de sensibilité pré et postnatales

Comprehensive mapping of the AOP-Wiki database: identifying biological and disease gaps

Introduction: The Adverse Outcome Pathway (AOP) concept facilitates rapid hazard assessment for human health risks. AOPs are constantly evolving, their number is growing, and they are referenced in the AOP-Wiki database, which is supported by the OECD. Here, we present a study that aims at identifying well-defined biological areas, as well as gaps within the AOP-Wiki for future research needs. It does not intend to provide a systematic and comprehensive summary of the available literature on AOPs but summarizes and maps biological knowledge and diseases represented by the already developed AOPs (with OECD endorsed status or under validation).Methods: Knowledge from the AOP-Wiki database were extracted and prepared for analysis using a multi-step procedure. An automatic mapping of the existing information on AOPs (i.e., genes/proteins and diseases) was performed using bioinformatics tools (i.e., overrepresentation analysis using Gene Ontology and DisGeNET), allowing both the classification of AOPs and the development of AOP networks (AOPN).Results: AOPs related to diseases of the genitourinary system, neoplasms and developmental anomalies are the most frequently investigated on the AOP-Wiki. An evaluation of the three priority cases (i.e., immunotoxicity and non-genotoxic carcinogenesis, endocrine and metabolic disruption, and developmental and adult neurotoxicity) of the EU-funded PARC project (Partnership for the Risk Assessment of Chemicals) are presented. These were used to highlight under- and over-represented adverse outcomes and to identify and prioritize gaps for further research.Discussion: These results contribute to a more comprehensive understanding of the adverse effects associated with the molecular events in AOPs, and aid in refining risk assessment for stressors and mitigation strategies. Moreover, the FAIRness (i.e., data which meets principles of findability, accessibility, interoperability, and reusability (FAIR)) of the AOPs appears to be an important consideration for further development