HAL du Programme national de recherche environnement-santé-travail (PNR EST)
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Intergenerational effects on fertility in male and female mice after chronic exposure to environmental doses of NSAIDs and 17α-ethinylestradiol mixtures
No full textInternational audienceNon-steroidal anti-inflammatory drugs (NSAIDs) and 17α-ethinylestradiol (EE2) are extensively used in human and veterinary medicine. Due to their partial removal by wastewater treatment plants, they are frequent environmental contaminants, particularly in drinking water. Here, we investigated the adverse outcomes of chronic exposure to mixtures of NSAIDs (ibuprofen, 2hydroxy-ibuprofen, diclofenac) and EE2 at two environmentally relevant doses in drinking water, on the reproductive organ development and fertility in F1-exposed male and female mice and in their F2 offspring. In male and female F1 mice, which were exposed to these mixtures, reproductive organ maturation, estrous cyclicity, and spermiogenesis were altered. These defects were observed also in F2 animals, in addition to some specific sperm parameter alterations in F2 males. Transcriptomic analysis revealed significant changes in gene expression patterns and associated pathways implicated in testis and ovarian physiology. Chronic exposure of mice to NSAID and EE2 mixtures at environmental doses intergenerationally affected male and female fertility (i.e. total number of pups and time between litters). Our study provides new insights into the adverse effects of these pharmaceuticals on the reproductive health and will facilitate the implementation of a future regulatory environmental risk assessment of NSAIDs and EE2 for human health
Inhibition by pesticides of the DJ-1/Park7 protein related to Parkinson disease.
No full textInternational audienceParkinson’s disease is a severe neurodegenerative disease. Several environmental contaminants such as pesticides have been suspected to favor the appearance of this pathology. The protein DJ-1 (or Park7) protects against the development of Parkinson’s disease. Thus, the possible inhibitory effects of about a hundred pesticides on human DJ-1 have been studied. We identified fifteen of them as strong inhibitors of DJ-1 with IC50 values between 0.02 and 30 µM. Thiocarbamates are particularly good inhibitors, as shown by thiram that acts as an irreversible inhibitor of an esterase activity of DJ-1 with an IC50 value of 0.02 µM. Thiram was also found as a good inhibitor of the protective activity of DJ-1 against glycation. Such inhibitory effects could be one of the various biological effects of these pesticides that may explain their involvement in the development of Parkinson’s disease
Moisissures de l’air intérieur et endotypes d’asthme (MOLDASTH): Moisissures dans les habitations, inflammation et réponse immunitaire, et endotypes d'asthme dans la cohorte CONSTANCES
No full textÀ ce jour, l’asthme fait encore l’objet de nombreuses recherches, notamment sur l’identification et la caractérisation d’« endotypes », c’est-à-dire des sous types d’asthme reposant sur des mécanismes fonctionnels ou physiopathologiques distincts. L’objectif général du projet MOLDASTH est de mieux comprendre les associations entre l’exposition aux moisissures de l’air intérieur et l’asthme chez l’adulte en population générale
A proteome scale study reveals how plastic surfaces and agitation promote protein aggregation
No full textInternational audienceProtein aggregation in biotherapeutics can reduce their activity and effectiveness. It may also promote immune reactions responsible for severe adverse effects. The impact of plastic materials on protein destabilization is not totally understood. Here, we propose to deconvolve the effects of material surface, air/liquid interface, and agitation to decipher their respective role in protein destabilization and aggregation. We analyzed the effect of polypropylene, TEFLON, glass and LOBIND surfaces on the stability of purified proteins (bovine serum albumin, hemoglobin and α-synuclein) and on a cell extract composed of 6000 soluble proteins during agitation ( P = 0.1–1.2 W/kg). Proteomic analysis revealed that chaperonins, intrinsically disordered proteins and ribosomes were more sensitive to the combined effects of material surfaces and agitation while small metabolic oligomers could be protected in the same conditions. Protein loss observations coupled to Raman microscopy, dynamic light scattering and proteomic allowed us to propose a mechanistic model of protein destabilization by plastics. Our results suggest that protein loss is not primarily due to the nucleation of small aggregates in solution, but to the destabilization of proteins exposed to material surfaces and their subsequent aggregation at the sheared air/liquid interface, an effect that cannot be prevented by using LOBIND tubes. A guidance can be established on how to minimize these adverse effects. Remove one of the components of this combined stress - material, air (even partially), or agitation - and proteins will be preserved
An end-to-end pipeline based on open source deep learning tools for reliable analysis of complex 3D images of ovaries
No full textInternational audienceComputational analysis of bio-images by deep learning (DL) algorithms has made exceptional progress in recent years and has become much more accessible to non-specialists with the development of ready-to-use tools. Study of oogenesis mechanisms and female reproductive success has also recently benefited from the development of efficient protocols for three-dimensional (3D) imaging of ovaries. Such datasets have a great potential for generating new quantitative data but are, however, complex to analyze due to the lack of efficient workflows for 3D image analysis. Here, we integrated two existing open-source DL tools, Noise2Void and Cellpose, into an analysis pipeline dedicated to 3D follicular content analysis and available on Fiji. Our pipeline was developed on larvae and adult medaka ovaries but was also successfully applied to different types of ovaries (trout, zebrafish and mouse). Image enhancement, Cellpose segmentation and label post-processing enabled automatic and accurate quantification of these 3D images exhibiting irregular fluorescent staining, low autofluorescence signal or heterogeneous follicles sizes. In the future, this pipeline will be useful for extensive cellular phenotyping in fish or mammals for developmental or toxicology studies
Monitoring recovery after CNS demyelination, a novel tool to de-risk pro-remyelinating strategies
No full textInternational audienceIn multiple sclerosis, while remarkable progress has been accomplished to control the inflammatory component of the disease, repair of demyelinated lesions is still an unmet need. Despite encouraging results generated in experimental models, several candidates favouring or promoting remyelination have not reached the expected outcomes in clinical trials. One possible reason for these failures is that, in most cases, during preclinical testing, efficacy was evaluated on histology only, while functional recovery had not been assessed. We have generated a Xenopus laevis transgenic model Tg(mbp:GFP-NTR) of conditional demyelination in which spontaneous remyelination can be accelerated using candidate molecules. Xenopus laevis is a classic model for in vivo studies of myelination because tadpoles are translucent. We reasoned that demyelination should translate into loss of sensorimotor functions followed by behavioural recovery upon remyelination. To this end, we measured the swimming speed and distance travelled before and after demyelination and during the ongoing spontaneous remyelination and have developed a functional assay based on the visual avoidance of a virtual collision. Here we show that alteration of these functional and clinical performances correlated well with the level of demyelination and that histological remyelination, assayed by counting in vivo the number of myelinating oligodendrocytes in the optic nerve, translated in clinical-functional recovery. This method was further validated in tadpoles treated with pro-remyelinating agents (clemastine, siponimod) showing that increased remyelination in the optic nerve was associated with functional improvement. Our data illustrate the potential interest of correlating histopathological parameters and functional-clinical parameters to screen molecules promoting remyelination in a simple in vivo model of conditional demyelination
Importance of relative binding of bisphenol A and bisphenol S to plasma proteins for predicting their in vivo potencies
No full textInternational audienceMany studies suggest that the potential impact of bisphenol S (BPS) as an endocrine disruptor is comparable to that of bisphenol A (BPA). However, in vitro-to-in vivo and from animal to human extrapolations require knowledge of the plasma free fraction of the active endocrine compounds. The present study aimed to characterise BPA and BPS binding to plasma proteins both in humans and different animal species. The plasma protein binding of BPA and BPS was assessed by equilibrium dialysis in plasma from adult female mice, rats, monkeys, early and late pregnant women as well as paired cord blood, early and late pregnant sheep and foetal sheep.The fraction of free BPA was independent of plasma concentrations and ranged between 4% and 7% in adults. This fraction was 2 to 3.5 times lower than that of BPS in all species except sheep, ranging from 3% to 20%. Plasma binding of BPA and BPS was not affected by the stage of pregnancy, BPA and BPS free fractions representing about 4% and 9% during early and late human pregnancy, respectively. These fractions were lower than the free fractions of BPA (7%) and BPS (12%) in cord blood.Our results suggest that similarly to BPA, BPS is extensively bound to proteins, mainly albumin. The higher fraction of free BPS compared to BPA may have implications for human exposure assessment since BPS free plasma concentrations are expected to be 2 to 3.5 times higher than that of BPA for similar plasma concentration
Life in an unsuspected antibiotics world: River biofilms
No full textInternational audienceWaterborne bacteria that naturally live in biofilms are continuously exposed to pharmaceutical residues, regularly released into the freshwater environment. At the source level, the discharge of antibiotics into rivers has already been repeatedly linked to the development of antimicrobial resistance. But what about biofilms away from the discharge point? Two rivers, with sites subject to dispersed contamination of medium intensity, were studied as typical representatives of high-and middle-income countries. The biofilms developed on rocks indigenous to rivers are perfectly representative of environmental exposure. Our results show that away from the hotspots, the amount of antibiotics in the biofilms studied favours the maintenance and enrichment of existing resistant strains as well as the selection of new resistant mutants, and these favourable conditions remain over a period of time. Thus, in this type of river, the environmental risk of selection pressure is not only present downstream of urbanised areas but is also possible upstream and far downstream of wastewater treatment plant discharges. Despite this, correlation analysis found no strong positive correlation between antibiotic concentrations and the abundance of measured integrons and their corresponding resistance genes. Nevertheless, this work highlights the need to consider the risks of antibiotics beyond hotspots as well
Diving into the volatilome of Pseudomonas fluorescens: from long-distance warfare to communication
No full textInternational audienceLes composés organiques volatils (COVs) sont des molécules clés dans la communication à longue distance intra et/ou inter-règne mais peuvent aussi agir comme des antimicrobiens dans la compétition et la prédation. La plupart des études menées à ce jour sont focalisées sur leurs activités antifongiques et seules quelques-unes ont rapporté des propriétés antibactériennes. Dans cette étude, un test d’inhibition de croissance à longue distance a été mis en place puis la comparaison du volatilome de plusieurs souches a été réalisée à l'aide d’une stratégie de microextraction en phase solide couplée à la GC-MS
Interactions of cholesterol molecules with GPCRs in different states: A comparative analysis of GPCRs' structures
No full textInternational audienceGPCRs form a very large family of transmembrane proteins involved in a wide range of physiological functions. Some GPCRs have their activity affected by the presence of cholesterol either indirectly through changes in the physical properties of the membrane or directly by binding to the receptor. Thanks to recent advances in structural biology, many structures of GPCRs have been solved, 240 of which contain at least one cholesterol molecule or surrogate. This review lists the position of these molecules and provides a comparative analysis of the changes observed in the structures depending on the state of the recepto