Devenir des retardateurs de flammes bromés chez le rat et l'homme : caractérisation des métabolites et évaluation de l'exposition foetale

Les retardateurs de flammes bromés (RFB) sont des composés chimiques incorporés dans différents matériaux (plastiques, textiles) pour leur conférer des propriétés ignifuges. Les plus couramment utilisés dans le monde sont le tétrabromobisphénol A et le décabromodiphényle éther. Ces polluants retrouvés dans l'environnement, chez l'animal et chez l'homme, sont susceptibles de jouer un rôle dans la perturbation des fonctions endocrines. Cependant, les données permettant d'évaluer le risque qu'ils représentent pour la santé humaine sont peu nombreuses. Compte tenu de ces éléments, des études de métabolisme du tétrabromobisphénol A et du décabromodiphényle éther ont été réalisées in vitro chez le rat et l'homme, et in vivo chez des rates gestantes. Le développement de méthodes analytiques appropriées a permis de quantifier puis d'identifier les produits de biotransformation de ces deux RFB, et de donner accès à des informations relatives à l'exposition foetale chez le rat. La complexité structurale des RFB et leurs biotransformations chez l'homme jouent vraisemblablement un rôle important dans l'expression de leur toxicité. ABSTRACT : Brominated flame retardants (BFR) are chemical compounds widely used for the manufacture of different equipments (plastics, textiles…), to prevent fire damage. Tetrabromobisphenol A and decabromodiphenyl ether are the largest sell BFR worldwide. These pollutants are found in the environment, in animals and in human. They could act as endocrine disruptors. Due to the limited amount of information available, it is currently difficult to assess the threat associated with human exposure to brominated flame retardants, one major knowledge gap being the lack of data regarding the metabolic fate of these compounds. We carried out detailed in vivo studies in pregnant rats, and compared human/rat metabolic in vitro studies, to investigate the biotransformation of tetrabromobisphenol A and decabromodiphenyl ether. Our results show that the biotransformations of BFR are a key point to understand their potential toxicity towards huma

The Dividing Line between Federal and State Promotion of Aeronautics

<p>The model xeno-estrogen bisphenol A (BPA) has been extensively studied over the past two decades, contributing to major advances in the field of endocrine disrupting chemicals research. Besides its well documented adverse effects on reproduction and development observed in rodents, latest studies strongly suggest that BPA disrupts several endogenous metabolic pathways, with suspected steatogenic and obesogenic effects. BPA's adverse effects on reproduction are attributed to its ability to activate estrogen receptors (ERs), but its effects on metabolism and its mechanism(s) of action at low doses are so far only marginally understood. Metabolomics based approaches are increasingly used in toxicology to investigate the biological changes induced by model toxicants and chemical mixtures, to identify markers of toxicity and biological effects. In this study, we used proton nuclear magnetic resonance (¹H-NMR) based untargeted metabolite profiling, followed by multivariate statistics and computational analysis of metabolic networks to examine the metabolic modulation induced in human hepatic cells (HepG2) by an exposure to low and very low doses of BPA (10⁻⁶M, 10⁻⁹M, and 10⁻¹²M), vs. the female reference hormone 17β-estradiol (E2, 10⁻⁹M, 10⁻¹²M, and 10⁻¹⁵M). Metabolomic analysis combined to metabolic network reconstruction highlighted different mechanisms at lower doses of exposure. At the highest dose, our results evidence that BPA shares with E2 the capability to modulate several major metabolic routes that ensure cellular functions and detoxification processes, although the effects of the model xeno-estrogen and of the natural hormone can still be distinguished.</p

Nanomechanical Characterization of the Deformation Response of Orthotropic Ti–6Al–4V

The nanoindentation‐induced mechanical deformation response is applied to identify the orthotropic elastic moduli using the Delafargue and Ulm method as well as to validate the asymmetric orthotropic CPB06 nonlinear plasticity model required in simulations of nonuniform macroscopic mechanical response of the Ti–6Al–4V alloy. Scanning electron microscope (SEM) technique allows to select the maximum penetration depth for the indentation in the deformed alpha phase and alpha–beta interphase, α and α/β, respectively. The apparent macromechanical response can be successfully derived from several residual imprints conducted at micro‐ and/or submicrometric length scale and distributed throughout samples of the investigated bulk alloy, as demonstrated by correlation with finite element simulations based on the orthotropic elastoplastic model. The accurate numerical response obtained validates the material model and the Delafargue and Ulm approach, opening a window for next generation identification methods of macromechanical plasticity models with hybrid experimental–numerical method based on instrumented indentation and the use of SEM technique

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements