Humans are chronically exposed to the mycotoxins deoxynivalenol (DON) and fumonisin B1 (FB1), as indicated by their widespread presence in foods and occasional exposure in the workplace. This exposure is confirmed by human biomonitoring (HBM) studies on (metabolites of) these mycotoxins in human matrices. We evaluated the exposure-health relationship of the mycotoxins in humans by reviewing the available literature. Since human studies did not allow the identification of unequivocal chronic health effects upon exposure to DON and FB1, the adverse outcome pathway (AOP) framework was used to structure additional mechanistic evidence from in vitro and animal studies on the identified adverse effects. In addition to a preliminary AOP for DON resulting in the adverse outcome (AO) 'reduced body weight gain', we developed a more elaborated AOP for FB1, from the molecular initiating event (MIE) 'inhibition of ceramide synthases' leading to the AO 'neural tube defects'. The mechanistic evidence from AOPs can be used to support the limited evidence from human studies, to focus FB1- and DON-related research in humans to identify related early biomarkers of effect. In order to establish additional human exposure-health relationships in the future, recommendations are given to maximize the information that can be obtained from HBM.
- Klíčová slova
- AOP: adverse outcome pathway, DON: deoxynivalenol, FB1: fumonisin B1, HBM4EU, HBM: human biomonitoring, human biomonitoring for Europe, mycotoxins,
- MeSH
- dráhy škodlivých účinků * MeSH
- fumonisiny * toxicita MeSH
- lidé MeSH
- mykotoxiny * farmakologie MeSH
- trichotheceny MeSH
- viabilita buněk MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- deoxynivalenol MeSH Prohlížeč
- fumonisin B1 MeSH Prohlížeč
- fumonisiny * MeSH
- mykotoxiny * MeSH
- trichotheceny MeSH
MOTIVATION: Adverse outcome pathways (AOPs) are a conceptual framework developed to support the use of alternative toxicology approaches in the risk assessment. AOPs are structured linear organizations of existing knowledge illustrating causal pathways from the initial molecular perturbation triggered by various stressors, through key events (KEs) at different levels of biology, to the ultimate health or ecotoxicological adverse outcome. RESULTS: Artificial intelligence can be used to systematically explore available toxicological data that can be parsed in the scientific literature. Recently, a tool called AOP-helpFinder was developed to identify associations between stressors and KEs supporting thus documentation of AOPs. To facilitate the utilization of this advanced bioinformatics tool by the scientific and the regulatory community, a webserver was created. The proposed AOP-helpFinder webserver uses better performing version of the tool which reduces the need for manual curation of the obtained results. As an example, the server was successfully applied to explore relationships of a set of endocrine disruptors with metabolic-related events. The AOP-helpFinder webserver assists in a rapid evaluation of existing knowledge stored in the PubMed database, a global resource of scientific information, to build AOPs and Adverse Outcome Networks supporting the chemical risk assessment. AVAILABILITY AND IMPLEMENTATION: AOP-helpFinder is available at http://aop-helpfinder.u-paris-sciences.fr/index.php. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are formed as a result of natural cellular processes, intracellular signaling, or as adverse responses associated with diseases or exposure to oxidizing chemical and non-chemical stressors. The action of ROS and RNS, collectively referred to as reactive oxygen and nitrogen species (RONS), has recently become highly relevant in a number of adverse outcome pathways (AOPs) that capture, organize, evaluate and portray causal relationships pertinent to adversity or disease progression. RONS can potentially act as a key event (KE) in the cascade of responses leading to an adverse outcome (AO) within such AOPs, but are also known to modulate responses of events along the AOP continuum without being an AOP event itself. A substantial discussion has therefore been undertaken in a series of workshops named "Mystery or ROS" to elucidate the role of RONS in disease and adverse effects associated with exposure to stressors such as nanoparticles, chemical, and ionizing and non-ionizing radiation. This review introduces the background for RONS production, reflects on the direct and indirect effects of RONS, addresses the diversity of terminology used in different fields of research, and provides guidance for developing a harmonized approach for defining a common event terminology within the AOP developer community.
- Klíčová slova
- adverse outcome pathway (AOP), disease, oxidative stress, reactive nitrogen species (RNS), reactive oxygen species (ROS),
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
We investigated the hemodynamic effects of 2 short-acting β1 -blockers, landiolol and esmolol, in the continuous presence of dobutamine in a prospective, single-center, randomized, crossover study in 16 healthy White volunteers. Dobutamine was infused at a rate sufficient to increase the heart rate by at least 30 beats per minute, followed by a 60-minute infusion of 50 μg/kg/min esmolol or 10 μg/kg/min landiolol on top of the unchanged dobutamine infusion. Concentrations of β-blockers and their metabolites in blood, heart rate, and blood pressure were followed for 180 minutes. Landiolol reduced the dobutamine-induced heart rate and blood pressure increases better than esmolol. After discontinuation of β-blocker administration, heart rate recovered swiftly to preinfusion values in both study arms. Systolic and diastolic blood pressure recovered partially after landiolol but showed a continued reduction after esmolol. No serious adverse events were observed. The heart rate effect is characteristic for β-blockers, whereas the blood pressure effects are likely due to direct and indirect β-blocker effects as well as influences on various ion channels. This may explain why landiolol that is devoid of effects on renin and sodium, calcium, and potassium channels behaves different from esmolol with respect to blood pressure recovery.
- Klíčová slova
- cardioselective β-blocker, dobutamine, esmolol, landiolol, pharmacodynamics,
- MeSH
- dobutamin * farmakologie MeSH
- klinické křížové studie MeSH
- krevní tlak MeSH
- lidé MeSH
- močovina analogy a deriváty MeSH
- morfoliny MeSH
- propanolaminy MeSH
- prospektivní studie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- Názvy látek
- dobutamin * MeSH
- esmolol MeSH Prohlížeč
- landiolol MeSH Prohlížeč
- močovina MeSH
- morfoliny MeSH
- propanolaminy MeSH
OBJECTIVES: To present the Central European Myeloproliferative Neoplasm Organisation (CEMPO) treatment recommendations for polycythaemia vera (PV). METHODS: During meetings held from 2015 through 2017, CEMPO discussed PV and its treatment and recent data. RESULTS: PV is associated with increased risks of thrombosis/thrombo-haemorrhagic complications, fibrotic progression and leukaemic transformation. Presence of Janus kinase (JAK)-2 gene mutations is a diagnostic marker and standard diagnostic criterion. World Health Organization 2016 diagnostic criteria for PV, focusing on haemoglobin levels and bone marrow morphology, are mandatory. PV therapy aims at managing long-term risks of vascular complications and progression towards transformation to acute myeloid leukaemia and myelodysplastic syndrome. Risk stratification for thrombotic complications guides therapeutic decisions. Low-risk patients are treated first line with low-dose aspirin and phlebotomy. Cytoreduction is considered for low-risk (phlebotomy intolerance, severe/progressive symptoms, cardiovascular risk factors) and high-risk patients. Hydroxyurea is suspected of leukaemogenic potential. IFN-α has demonstrated efficacy in many clinical trials; its pegylated form is best tolerated, enabling less frequent administration than standard interferon. Ropeginterferon alfa-2b has been shown to be more efficacious than hydroxyurea. JAK1/JAK2 inhibitor ruxolitinib is approved for hydroxyurea resistant/intolerant patients. CONCLUSIONS: Greater understanding of PV is serving as a platform for new therapy development and treatment response predictors.
- Klíčová slova
- cytoreductive therapy, diagnosis, management, myeloproliferative neoplasms, polycythaemia vera, recommendations,
- Publikační typ
- časopisecké články MeSH
While human regulatory risk assessment (RA) still largely relies on animal studies, new approach methodologies (NAMs) based on in vitro, in silico or non-mammalian alternative models are increasingly used to evaluate chemical hazards. Moreover, human epidemiological studies with biomarkers of effect (BoE) also play an invaluable role in identifying health effects associated with chemical exposures. To move towards the next generation risk assessment (NGRA), it is therefore crucial to establish bridges between NAMs and standard approaches, and to establish processes for increasing mechanistically-based biological plausibility in human studies. The Adverse Outcome Pathway (AOP) framework constitutes an important tool to address these needs but, despite a significant increase in knowledge and awareness, the use of AOPs in chemical RA remains limited. The objective of this paper is to address issues related to using AOPs in a regulatory context from various perspectives as it was discussed in a workshop organized within the European Union partnerships HBM4EU and PARC in spring 2022. The paper presents examples where the AOP framework has been proven useful for the human RA process, particularly in hazard prioritization and characterization, in integrated approaches to testing and assessment (IATA), and in the identification and validation of BoE in epidemiological studies. Nevertheless, several limitations were identified that hinder the optimal usability and acceptance of AOPs by the regulatory community including the lack of quantitative information on response-response relationships and of efficient ways to map chemical data (exposure and toxicity) onto AOPs. The paper summarizes suggestions, ongoing initiatives and third-party tools that may help to overcome these obstacles and thus assure better implementation of AOPs in the NGRA.
- Klíčová slova
- Adverse outcome pathways, Biomarkers of effect, Hazard assessment, Mechanistic toxicology, New approach methodologies, Regulatory risk assessment,
- MeSH
- dráhy škodlivých účinků * MeSH
- hodnocení rizik metody MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
ERGO (EndocRine Guideline Optimization) is the acronym of a European Union-funded research and innovation action, that aims to break down the wall between mammalian and non-mammalian vertebrate regulatory testing of endocrine disruptors (EDs), by identifying, developing and aligning thyroid-related biomarkers and endpoints (B/E) for the linkage of effects between vertebrate classes. To achieve this, an adverse outcome pathway (AOP) network covering various modes of thyroid hormone disruption (THD) in multiple vertebrate classes will be developed. The AOP development will be based on existing and new data from in vitro and in vivo experiments with fish, amphibians and mammals, using a battery of different THDs. This will provide the scientifically plausible and evidence-based foundation for the selection of B/E and assays in lower vertebrates, predictive of human health outcomes. These assays will be prioritized for validation at OECD (Organization for Economic Cooperation and Development) level. ERGO will re-think ED testing strategies from in silico methods to in vivo testing and develop, optimize and validate existing in vivo and early life-stage OECD guidelines, as well as new in vitro protocols for THD. This strategy will reduce requirements for animal testing by preventing duplication of testing in mammals and non-mammalian vertebrates and increase the screening capacity to enable more chemicals to be tested for ED properties.
- Klíčová slova
- AOP, IATA, OECD, adverse outcome pathway, biomarkers, cross-species extrapolation, endocrine disruption, integrated approach to testing and assessment, test guideline, thyroid hormone disruption,
- MeSH
- biologické markery MeSH
- biotest * metody MeSH
- druhová specificita MeSH
- endokrinní disruptory škodlivé účinky analýza MeSH
- endokrinní systém účinky léků metabolismus MeSH
- hodnocení rizik MeSH
- hodnocení vlivů na zdraví MeSH
- lidé MeSH
- monitorování životního prostředí * metody MeSH
- průběh práce MeSH
- skladování dat MeSH
- zdravotnické plány - realizace MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- biologické markery MeSH
- endokrinní disruptory MeSH
Sulfate radical-based advanced oxidation processes (SR-AOPs) are gaining popularity as a feasible alternative for removing recalcitrant pollutants in an aqueous environment. Persulfates, namely peroxydisulfate (PDS) and peroxymonosulfate (PMS) are the most common sulfate radical donors. Persulfates activation by ultraviolet (UV) irradiation is considered feasible due to the high concentration of radicals produced as well as the lack of catalysts leaching. The research focuses on determining the impact of activated PDS and PMS on the degradation of anthraquinone dye, i.e., Acid Blue 129 (AB129). UV-activated PDS and PMS can quickly degrade the AB129 as well as restrict the formation of by-products. This could explain the reduced ecotoxicity levels of the treated water after degradation, using an aquatic plant (Lemna minor) and a crustacean (Daphnia magna). This, on the other hand, can ensure that the sulfate radical-based processes can be an environmentally friendly technology.
- Klíčová slova
- Acid Blue 129, Ecotoxicity, Peroxydisulfate, Peroxymonosulfate, SR-AOP, Sulfate radicals,
- MeSH
- anthrachinony MeSH
- chemické látky znečišťující vodu * analýza MeSH
- čištění vody * MeSH
- kinetika MeSH
- oxidace-redukce MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- anthrachinony MeSH
- chemické látky znečišťující vodu * MeSH
- peroxymonosulfate MeSH Prohlížeč
- sulfate radical MeSH Prohlížeč
- Klíčová slova
- Adverse Outcome Pathway (AOP), harmonization, in silico, oxidative stress, reactive oxygen species (ROS),
- MeSH
- alternativy testů na zvířatech * MeSH
- oxidační stres * MeSH
- reaktivní formy kyslíku MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- úvodníky MeSH
- Názvy látek
- reaktivní formy kyslíku MeSH
A wide range of novel replacement flame retardants (nFRs) is consistently detected in increasing concentrations in the environment and human matrices. Evidence suggests that nFRs exposure may be associated with disruption of the endocrine system, which has been linked with the etiology of various metabolic disorders, including nonalcoholic fatty liver disease (NAFLD). NAFLD is a multifactorial disease characterized by the uncontrolled accumulation of fats (lipids) in the hepatocytes and involves multiple-hit pathogenesis, including exposure to occupational and environmental chemicals such as organophosphate flame retardants (OPFRs). In the present study we aimed to investigate the potential mechanisms of the nFRs-induced hepatic steatosis in the human liver cells. In this study, we employed an in vitro bioassay toolbox to assess the key events (KEs) in the proposed adverse outcome pathways (AOP) (s) for hepatic steatosis. We examined nine nFRs using AOP- based in vitro assays measuring KEs such as lipid accumulation, mitochondrial dysfunction, gene expression, and in silico approach to identify the putative molecular initiating events (MIEs). Our findings suggest that several tested OPFRs induced lipid accumulation in human liver cell culture. Tricresyl phosphate (TMPP), triphenyl phosphate (TPHP), tris(1,3-dichloropropyl) phosphate (TDCIPP), and 2-ethylhexyl diphenyl phosphate (EHDPP) induced the highest lipid accumulation by altering the expression of genes encoding hepatic de novo lipogenesis and mitochondrial dysfunction depicted by decreased cellular ATP production. Available in vitro data from ToxCast and in silico molecular docking suggests that pregnane X receptor (PXR) and peroxisome proliferator-activated receptor gamma (PPARγ) could be the molecular targets for the tested nFRs. The study identifies several nFRs, such as TMPP and EHDPP, TPHP, and TDCIPP, as potential risk factor for NAFLD and advances our understanding of the mechanisms involved, demonstrating the utility of an AOP-based strategy for screening and prioritizing chemicals and elucidating the molecular mechanisms of toxicity.
- Klíčová slova
- Adverse outcome pathways, Flame retardants, Metabolic disrupting chemicals, Pregnane X receptor, Steatosis,
- MeSH
- buněčné kultury MeSH
- dráhy škodlivých účinků * MeSH
- hepatocyty MeSH
- lidé MeSH
- organofosfáty MeSH
- retardanty hoření * toxicita MeSH
- simulace molekulového dockingu MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- organofosfáty MeSH
- retardanty hoření * MeSH
