Stress oxydant et vieillissement

Le vieillissement est un processus qui continue à fasciner les biologistes de tous horizons, qu’ils s’intéressent à l’évolution, à la génétique, à la signalisation ou à la toxicité de l’environnement. De nombreuses théories, parfois contradictoires, sont proposées pour rendre compte des mécanismes du vieillissement, perçus par certains comme le résultat d’un programme inéluctable, par d’autres comme le fruit d’une suite d’agressions qui pourraient être évitées ou réparées. L’hypothèse « radicalaire » du vieillissement met au premier plan l’accumulation d’agressions oxydantes provoquées par les radicaux libres provenant principalement du métabolisme de l’oxygène et de l’azote. Cette hypothèse, proposée il y a une cinquantaine d’années, demeure l’une des plus populaires chez les spécialistes, même si certaines de ses prédictions n’ont pas été vérifiées de manière satisfaisante. Cet article présente les fondements de cette hypothèse, ses relations avec les autres théories, mitochondriales, métaboliques et génétiques, et la confronte à la réalité têtue des observations expérimentales pour proposer une vision plus intégrée des relations entre vieillissement et stress cellulaires.A number of theories have attempted to account for ageing processes in various species. Following the « rate of living » theory of Pearl, Harman suggested fifty years ago that the accumulation of oxidants could explain the alteration of physical and cognitive functions with ageing. Oxygen metabolism leads to reactive species, including free radicals, which tend to oxydize surrounding molecules such as DNA, proteins and lipids. As a consequence various functions of cells and tissues can be altered, leading to DNA instability, protein denaturation and accumulation of lipid byproducts. Oxidative stress is an adaptive process which is triggered upon oxidant accumulation and which comprises the induction of protective and survival functions. Experimental evidence suggests that the ageing organism is in a state of oxidative stress, which supports the free radical theory. A number of other theories have been proposed ; some of these are actually compatible with the free radical theory. Caloric restriction is among the best models to increase life span in many species. While the relationship between caloric restriction and corrected metabolic rate is controversial, the decrease in ROS production by mitochondria appears to be experimentally supported. The ROS and mitochondrial theories of ageing appear to be compatible. Genetic models of increased life span, particularly those affecting the Foxo pathway, are usually accompanied by an increased resistance to oxidative insult. The free radical theory is not consistent with programmed senescence theories involving the cell division dependent decrease in telomere length ; however, oxidants are known to alter telomere structure. An appealing view of the role of oxidative stress in ageing is the trade-off principle which states that a phenotypic trait can be evolutionarily conserved because of its positive effects on development, growth or fertility, and despite its negative effect on somatic functions and ageing. It is likely that most cellular stresses which comprise adaptive and toxic functions follow such a rule

sAOP:linking chemical stressors to adverse outcomes pathway networks

International audienceMotivation: Adverse outcome pathway (AOP) is a toxicological concept proposed to provide a mechanistic representation of biological perturbation over different layers of biological organization. Although AOPs are by definition chemical-agnostic, many chemical stressors can putatively interfere with one or several AOPs and such information would be relevant for regulatory decision-making. Results: With the recent development of AOPs networks aiming to facilitate the identification of interactions among AOPs, we developed a stressor-AOP network (sAOP). Using the 'cytotoxitiy burst' (CTB) approach, we mapped bioactive compounds from the ToxCast data to a list of AOPs reported in AOP-Wiki database. With this analysis, a variety of relevant connections between chemicals and AOP components can be identified suggesting multiple effects not observed in the simplified 'one-biological perturbation to one-adverse outcome' model. The results may assist in the prioritization of chemicals to assess risk-based evaluations in the context of human health

Special issue editorial: Key results of the european human biomonitoring initiative - HBM4EU

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Chapter 5. Health consequences in the Mediterranean region

The Mediterranean basin is highly vulnerable to climate change, and a warming trend with changes in rainfall patterns with more heavy rains has already been observed. The frequency of dust storm and wildfire has also increased. Both non-communicable and communicable diseases will be seriously impacted by climate change since climate modification or air pollution influence the development of the former and weather conditions the latter. Different socioeconomic characteristics within the Mediterranean basin will also exacerbate or on the contrary reduce health outcomes. Surprisingly few quantitative studies have explored the impacts of climate change on health in the Mediterranean region, and the few are geographically limited to specific areas of the basin. Here we review the scientific literature on this topic and make some recommendations for the development of national and regional research, preparedness and adaptation policy in the Mediterranean region.La zone méditerranéenne est très exposée aux changements climatiques, et un réchauffement régional de la température avec une modification du régime des pluies, généralement plus fortes, est actuellement observé. Les tempêtes de sable et les incendies non contrôlés sont en augmentation. Les maladies infectieuses et chroniques humaines peuvent être affectées par ces bouleversements de façon directe ou indirecte; les conditions bioclimatiques conditionnent le développement des agents pathogènes et de leurs hôtes vecteurs ou réservoirs; les modifications du climat ou la pollution atmosphérique qui en dérive ont une influence sur le développement de certaines maladies chroniques. Des déterminants, en particulier socio-économiques, prévalant ou en évolution dans la zone méditerranéenne affecteront aussi la santé de la population. Curieusement, peu de travaux scientifiques ont étudié les effets des changements climatiques sur la santé humaine dans la région, et les quelques rares études restent géographiquement limitées à des zones particulières du bassin méditerranéen. Dans ce chapitre, nous synthétisons la recherche réalisée dans le domaine, et proposons des recommandations en termes de recherches scientifiques nationales et régionales, et de stratégies de préparation et d’adaptation à ce nouveau contexte

Consultation on a sustainable HBM initiative in Europe - Deliverable Report D6.3 WP6 Sustainability and Capacity building.

This deliverable was produced under Task 6.3 of Work Package 6 on “Longer-term needs and expectations of stakeholders (2021-2030)”. The aim of this task was to gather information on the needs and expectations of both the National Hubs (NH) and a broad range of stakeholders regarding a long-term Human Biomonitoring (HBM) programme for Europe, to be establish in follow up to the current project, HBM4EU. Firstly and with a focus on options for financing a future initiative, information was collected on a range of available funding mechanisms at national, regional and international level. In terms of national funding, the results presented rely on responses to a survey with the NH. Unfortunately, the response from NHs was very limited, and as such the report only captures funding mechanisms from a limited number of countries, including Portugal, Spain, France, Germany and Cyprus. In order to gain insight into the status of the National Hubs and their capacities for HBM, a survey was conducted. The results provide an overview of the current situation across the NHs with regards to a range of aspects, including the level of activity of the NH, status of political support, availability of funding, ongoing HBM studies and willingness to align studies with HBM4EU. The results suggest that HBM4EU has raised the political profile of HBM in partner countries. Regarding ongoing HBM studies, only six countries have national HBM programmes, with most countries having only hot spot studies. Despite this, there was support for the alignment of studies to achieve European geographical coverage. Regarding funding, access to European funding is seen as important to leverage funds at national level. A second survey was targeted at a wide range of stakeholders, aiming to better understand their expectations for a long-term sustainable HBM initiative. The survey was followed by a workshop, where a more limited number of stakeholders had the opportunity to discuss the survey results and address such aspects as the scope of a future initiative, how to achieve financial sustainability, how to involve and how a future initiative might contribute to chemical policies. Concerning the needs and expectations of stakeholders, there is a strong interest in and support for a future HBM initiative at European level. The involvement of a European Union (EU) institution as part of a future steering committee was seen as crucial. According to this stakeholders’ consultation, the initiative should focus on protecting human health and the environment in Europe from hazardous chemical exposures by producing harmonised, high quality, transparent and inclusive data for effective risk assessment and management.HBM4EU - Grant agreement 733032 HORIZON 2020 Programmeinfo:eu-repo/semantics/publishedVersio

Fate and Complex Pathogenic Effects of Dioxins and Polychlorinated Biphenyls in Obese Subjects before and after Drastic Weight Loss

BACKGROUND: In humans, persistent organic pollutants (POPs) are stored primarily in adipose tissue. Their total body burden and their contribution to obesity-associated diseases remain unclear. OBJECTIVES: We characterized POP total body burden and their redistribution in obese individuals before and after drastic weight loss and compared these values with a variety of molecular, biological, and clinical parameters. METHODS: Seventy-one obese subjects were enrolled and underwent bariatric surgery. Blood and adipose tissue samples were obtained at different times from these individuals as well as from 18 lean women. RESULTS: POP content (17 dioxins/furans and 18 polychlorinated biphenyl congeners) in different adipose tissue territories was similar, allowing us to assess total POP body burden from a single biopsy. Total POP body burden was 2 to 3 times higher in obese than in lean individuals. We also found increased expression of some POP target genes in obese adipose tissue. Drastic weight loss led to increased serum POPs and, within 6-12 months, to a significant 15% decrease in total polychlorinated biphenyl body burden. Importantly, serum POP levels were positively correlated with liver toxicity markers and lipid parameters, independently of age and body mass index. CONCLUSIONS: POP content in adipose tissue and serum correlate with biological markers of obesity-related dysfunctions. Drastic weight loss leads to a redistribution of POPs and to a moderate decrease of their total body burden

Inflammatory Pathway Genes Belong to Major Targets of Persistent Organic Pollutants in Adipose Cells

Background: Epidemiological studies emphasize the possible role of persistent organic pollutants (POPs) in obesity and the metabolic syndrome. These pollutants are stored in adipose tissue (AT)

Aryl hydrocarbon receptor and cysteine redox dynamics underlie (Mal)adaptive mechanisms to chronic intermittent hypoxia in kidney cortex

Funding Information: Funding: This work was supported by Fundação para Ciência e Tecnologia [PTDC/MED-TOX/30418/2017] and iNOVA4Health [UID/Multi/04462/2013]. M.J.C., F.L.-C., N.R.C., C.G.-D. and J.M. are supported by FCT grants [SFRH/BD/131331/2017, PD/BD/128337/2017, PD/BD/114257/2016, and PD/BD/105892/2014, PTDC/MED-TOX/30418/2017 respectively]. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.We hypothesized that an interplay between aryl hydrocarbon receptor (AhR) and cysteine-related thiolome at the kidney cortex underlies the mechanisms of (mal)adaptation to chronic intermittent hypoxia (CIH), promoting arterial hypertension (HTN). Using a rat model of CIH-HTN, we investigated the impact of short-term (1 and 7 days), mid-term (14 and 21 days, pre-HTN), and long-term intermittent hypoxia (IH) (up to 60 days, established HTN) on Cyp1a1 protein level (a sensitive hallmark of AhR activation) and cysteine-related thiol pools. We found that acute and chronic IH had opposite effects on Cyp1a1 and the thiolome. While short-term IH decreased Cyp1a1 and increased protein-S-thiolation, long-term IH increased Cyp1a1 and free oxidized cysteine. In addition, an in vitro administration of cystine, but not cysteine, to human endothelial cells increased Cyp1a1 expression, supporting cystine as a putative AhR activator. This study supports Cyp1a1 as a biomarker of obstructive sleep apnea (OSA) severity and oxidized pools of cysteine as risk indicator of OSA-HTN. This work contributes to a better understanding of the mechanisms underlying the phenotype of OSA-HTN, mimicked by this model, which is in line with precision medicine challenges in OSA.publishersversionpublishe

Application of AOPs to assist regulatory assessment of chemical risks - Case studies, needs and recommendations

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

Developing human biomonitoring as a 21st century toolbox within the European exposure science strategy 2020-2030

Human biomonitoring (HBM) is a crucial approach for exposure assessment, as emphasised in the European Commission’s Chemicals Strategy for Sustainability (CSS). HBM can help to improve chemical policies in five major key areas: (1) assessing internal and aggregate exposure in different target populations; 2) assessing exposure to chemicals across life stages; (3) assessing combined exposure to multiple chemicals (mixtures); (4) bridging regulatory silos on aggregate exposure; and (5) enhancing the effectiveness of risk management measures. In this strategy paper we propose a vision and a strategy for the use of HBM in chemical regulations and public health policy in Europe and beyond. We outline six strategic objectives and a roadmap to further strengthen HBM approaches and increase their implementation in the regulatory risk assessment of chemicals to enhance our understanding of exposure and health impacts, enabling timely and targeted policy interventions and risk management. These strategic objectives are: 1) further development of sampling strategies and sample preparation; 2) further development of chemical-analytical HBM methods; 3) improving harmonisation throughout the HBM research life cycle; 4) further development of quality control / quality assurance throughout the HBM research life cycle; 5) obtain sustained funding and reinforcement by legislation; and 6) extend target-specific communication with scientists, policymakers, citizens and other stakeholders. HBM approaches are essential in risk assessment to address scientific, regulatory and societal challenges. HBM requires full and strong support from the scientific and regulatory domain to reach its full potential in public and occupational health assessment and in regulatory decision-making.info:eu-repo/semantics/publishedVersio