HAL du Programme national de recherche environnement-santé-travail (PNR EST)
Not a member yet
917 research outputs found
Sort by
Interlaboratory prevalidation of a new in vitro transcriptional activation assay for the screening of (anti-)androgenic activity of chemicals using the UALH-hAR cell line
No full textInternational audienceWe report an interlaboratory evaluation of a recently developed androgen receptor (AR) transactivation assay using the UALH-hAR reporter cell line that stably expresses the luciferase gene under the transcriptional control of androgen receptor elements (AREs) with no glucocorticoid receptor (GR) crosstalk. Herein, a two-step prevalidation study involving three laboratories was conducted to assess performance criteria of the method such as transferability as well as robustness, sensitivity, and specificity. The first step consisted in the validation of the transfer of the cell line to participant laboratories through the testing of three reference chemicals: the AR agonist dihydrotestosterone, the AR antagonist hydroxyflutamide and the glucocorticoid dexamethasone. Secondly, a blinded study was conducted by screening a selection of ten chemicals, including four AR agonists, five AR antagonists, and one non-active chemical. All test compounds yielded the same activity profiles in all laboratories. The logEC50 (agonist assay) or logIC50 (antagonist assay) were in the same range, with intra-laboratory coefficients of variation (CVs) of 0.1–3.4% and interlaboratory CVs of 1–4%, indicating very good within- and between-laboratory reproducibility. Our results were consistent with literature and regulatory data (OECD TG458). Overall, this interlaboratory study demonstrated that the UALH-hAR assay is transferable, produces reliable, accurate and specific (anti)androgenic activity of chemicals, and can be considered for further regulatory validation
Interactions of human drug transporters with chemical additives present in plastics: Potential consequences for toxicokinetics and health
No full textInternational audienceHuman membrane drug transporters are recognized as major actors of pharmacokinetics; they also handle endogenous compounds, including hormones and metabolites. Chemical additives present in plastics interact with human drug transporters, which may have consequences for the toxicokinetics and toxicity of these widely-distributed environmental and/or dietary pollutants, to which humans are highly exposed. The present review summarizes key findings about this topic. In vitro assays have demonstrated that various plastic additives, including bisphenols, phthalates, brominated flame retardants, poly-alkyl phenols and per- and poly-fluoroalkyl substances, can inhibit the activities of solute carrier uptake transporters and/or ATP-binding cassette efflux pumps. Some are substrates for transporters or can regulate their expression. The relatively low human concentration of plastic additives from environmental or dietary exposure is a key parameter to consider to appreciate the in vivo relevance of plasticizer-transporter interactions and their consequences for human toxicokinetics and toxicity of plastic additives, although even low concentrations of pollutants (in the nM range) may have clinical effects. Existing data about interactions of plastic additives with drug transporters remain somewhat sparse and incomplete. A more systematic characterization of plasticizer-transporter relationships is needed. The potential effects of chemical additive mixtures towards transporter activities and the identification of transporter substrates among plasticizers, as well as their interactions with transporters of emerging relevance deserve particular attention. A better understanding of the human toxicokinetics of plastic additives may help to fully integrate the possible contribution of transporters to the absorption, distribution, metabolism and excretion of plastics-related chemicals, as well as to their deleterious effects towards human health
Development of environmental loop-mediated isothermal amplification (eLAMP) diagnostic tool for Bulinus truncatus field detection
No full textInternational audienceBackground Global changes are reshaping the distribution of vector-borne diseases by spreading vectors to previously non-endemic areas. Since 2013, urogenital schistosomiasis has emerged in Corsica and threatens European countries. Gastropod vectors release schistosome larvae that can infect humans who come into contact with freshwater bodies. Monitoring schistosomiasis host vectors is a prerequisite to understand and subsequently to control this pathogen transmission. Because malacological surveys are time consuming and require special expertise, the use of a simple molecular method is desirable. Methods The aim of this study is to develop a ready-to-use protocol using the LAMP (loop-mediated isothermal amplification) method to detect environmental DNA of Bulinus truncatus , vector of Schistosoma haematobium . Interestingly, LAMP method possesses all the characteristics required for adaptability to field conditions particularly in low-income countries: speed, simplicity, lyophilized reagents, low cost and robustness against DNA amplification inhibitors. We have tested this new method on Corsican water samples previously analysed by qPCR and ddPCR. Results We demonstrate that our diagnostic tool B. truncatus eLAMP (Bt-eLAMP) can detect the eDNA of Bulinus truncatus as effectively as the two other methods. Bt-eLAMP can even detect 1/4 of positive samples not detectable by qPCR. Moreover, the complete Bt-eLAMP protocol (sampling, sample pre-process, amplification and revelation) does not require sophisticated equipment and can be done in 1 ½ h. Conclusions LAMP detection of environmental DNA provides large-scale sensitive surveillance of urogenital schistosomiasis possible by identifying potentially threatened areas. More generally, eLAMP method has great potential in vector-borne diseases and ecology. Graphical Abstrac
Evaluation of the accumulation of the iodinated contrast agents diatrizoic acid and iohexol in Dreissena polymorpha mollusks
No full textThe results of this study were obtained within the framework of the “ACTIONS” research project. This action was funded by the French National Research Program for Environmental and Occupational Health of Anses (2018/1/222). This work was performed within the framework of the EUR H2O'Lyon (ANR-17-EURE-0018) of Université de Lyon (UdL), within the program “Investissements d’Avenir” operated by the French National Research Agency (ANR).International audienceMollusks are very sensitive to aquatic environmental alterations and then, are important bioindicators for monitoring the contamination of water bodies. Iodinated X-ray contrast media (ICMs) are ubiquitously present in the aquatic environment, primarily due to their high consumption for diagnosis purposes, high injection levels, low biodegradability, and low removal rates by wastewater treatment plants. Although these compounds are assumed to be of low toxicity, aquatic organisms are continuously exposed to these agents, which may result in adverse effects as ICMs can act as iodine source and disrupt the endocrine system. Thus, the evaluation of their environmental risk, especially on aquatic fauna is of great interest. To this end, we first compared the accumulation behavior, based on iodine analysis, of two ICM exhibiting different osmolality, diatrizoic acid and iohexol in Dreissena polymorpha bivalves exposed under laboratory conditions at concentrations of 0, 100, and 1000 µg/L during 4 and 7 days. This study was the first to provide information on iodine concentration in whole soft tissues and several organs in control zebra mussels. Moreover, it showed, after exposure, an increase of iodine content mainly in the digestive glands, followed by gills and gonads, highlighting that ICMs actually enter the organisms. Thus, bioaccumulation of ICMs studies were then performed, by liquid chromatography coupled to tandem mass spectrometry, on entire mollusks and digestive glands of organisms exposed at 0, 10, 100, and 1000 µg/L of both ICMs during 21 days, followed by 4 days of depuration. These first data on ICMs concentrations in zebra mussels, showed a clear accumulation of ICMs in mussels as a function of relative exposure level, as well as a rapid depuration. Osmolality did not seem to have a significant impact on the accumulation level, but a slight difference was observed on the accumulation pattern between both ICMs
A comparative study of human and zebrafish glucocorticoid receptor activities of natural and pharmaceutical steroids
No full textInternational audienceIntroduction : The action of environmental steroids on the human glucocorticoid receptor (hGR) has been pointed out with the risk to impair physiological immune and metabolic processes regulated by this nuclear receptor. However, there is still a lack of mechanistic information regarding their ability to interact with GR in aquatic species. Methods : To investigate ligand activation differences between hGR and zebrafish GR (zfGR), we tested several natural and synthetic steroids using reporter cell lines expressing hGR or zfGR. Results and discussion : Almost all the glucocorticoids tested (dexamethasone, cortisol, bimedrazol, medrol, cortivazol and fluticasone) are agonists of the two receptors with similar potencies. The dissociated glucocorticoids, RU24782 and RU24858 are agonists of both zfGR and hGR but with a better potency for the latter. On the other hand, the synthetic glucocorticoid forbimenol and the mineralocorticoid aldosterone are agonist on hGR but antagonist on zfGR. The other steroids tested, androgens and progestins, are all antagonists of both GRs with equal or lower potency on zfGR than on hGR. Surprisingly, the lower efficacy and potency on zfGR of aldosterone, forbimenol and the dissociated glucocorticoids is not related to their affinity for the receptors which would suggest that it could be related to less efficacious recruitment of coactivators by zfGR compared to hGR
Myocardial capacity of mitochondrial oxidative phosphorylation in response to prolonged electromagnetic stress
No full textInternational audienceIntroduction Mitochondria are central energy generators for the heart, producing adenosine triphosphate (ATP) through the oxidative phosphorylation (OXPHOS) system. However, mitochondria also guide critical cell decisions and responses to the environmental stressors. Methods This study evaluated whether prolonged electromagnetic stress affects the mitochondrial OXPHOS system and structural modifications of the myocardium. To induce prolonged electromagnetic stress, mice were exposed to 915 MHz electromagnetic fields (EMFs) for 28 days. Results Analysis of mitochondrial OXPHOS capacity in EMF-exposed mice pointed to a significant increase in cardiac protein expression of the Complex I, II, III and IV subunits, while expression level of α-subunit of ATP synthase (Complex V) was stable among groups. Furthermore, measurement of respiratory function in isolated cardiac mitochondria using the Seahorse XF24 analyzer demonstrated that prolonged electromagnetic stress modifies the mitochondrial respiratory capacity. However, the plasma level of malondialdehyde, an indicator of oxidative stress, and myocardial expression of mitochondria-resident antioxidant enzyme superoxide dismutase 2 remained unchanged in EMF-exposed mice as compared to controls. At the structural and functional state of left ventricles, no abnormalities were identified in the heart of mice subjected to electromagnetic stress. Discussion Taken together, these data suggest that prolonged exposure to EMFs could affect mitochondrial oxidative metabolism through modulating cardiac OXPHOS system
Air pollution exposure during pregnancy and childhood, APOE ε4 status and Alzheimer polygenic risk score, and brain structural morphology in preadolescents
No full textInternational audienceBackground: Air pollution exposure is associated with impaired neurodevelopment, altered structural brain morphology in children, and neurodegenerative disorders. Differential susceptibility to air pollution may be influenced by genetic features.Objectives: To evaluate whether the apolipoprotein E (APOE) genotype or the polygenic risk score (PRS) for Alzheimer's Disease (AD) modify the association between air pollution exposure during pregnancy and childhood and structural brain morphology in preadolescents.Methods: We included 1186 children from the Generation R Study. Concentrations of fourteen air pollutants were calculated at participants' home addresses during pregnancy and childhood using land-use-regression models. Structural brain images were collected at age 9-12 years to assess cortical and subcortical brain volumes. APOE status and PRS for AD were examined as genetic modifiers. Linear regression models were used to conduct single-pollutant and multi-pollutant (using the Deletion/Substitution/Addition algorithm) analyses with a two-way interaction between air pollution and each genetic modifier.Results: Higher pregnancy coarse particulate matter (PMcoarse) and childhood polycyclic aromatic hydrocarbons exposure was differentially associated with larger cerebral white matter volume in APOE ε4 carriers compared to non-carriers (29,485 mm3 (95% CI 6,189; 52,781) and 18,663 mm3 (469; 36,856), respectively). Higher pregnancy PMcoarse exposure was differentially associated with larger cortical grey matter volume in children with higher compared to lower PRS for AD (19436 mm3 (825, 38,046)).Discussion: APOE status and PRS for AD possibly modify the association between air pollution exposure and brain structural morphology in preadolescents. Higher air pollution exposure is associated with larger cortical volumes in APOE ε4 carriers and children with a high PRS for AD. This is in line with typical brain development, suggesting an antagonistic pleiotropic effect of these genetic features (i.e., protective effect in early-life, but neurodegenerative effect in adulthood). However, we cannot discard chance findings. Future studies should evaluate trajectorial brain development using a longitudinal design
2,4-Di-tert-butylphenol Induces Adipogenesis in Human Mesenchymal Stem Cells by Activating Retinoid X Receptors
No full textInternational audience2,4-Di-tert-butylphenol (2,4-DTBP) is an important commercial antioxidant and a toxic natural secondary metabolite that has been detected in humans. However, there is scant information regarding its toxicological effects. We asked whether 2,4-DTBP is a potential obesogen. Using a human mesenchymal stem cell adipogenesis assay, we found that exposure to 2,4-DTBP led to increased lipid accumulation and expression of adipogenic marker genes. Antagonist assays revealed that 2,4-DTBP increased lipid accumulation by activating the peroxisome proliferator-activated receptor (PPAR) γ-retinoid X receptor (RXR) heterodimer. 2,4-DTBP likely activated the PPARγ/RXRα heterodimer by activating RXRα but not directly binding to PPARγ. We confirmed that 2,4-DTBP directly bound to RXRα by solving the crystal structure of this complex, then predicted and demonstrated that related compounds could also activate RXRα. Our study demonstrated that 2,4-DTBP and related chemicals could act as obesogens and endocrine disruptors via RXRs. These data showed that 2,4-DTBP belongs to a family of compounds whose endocrine-disrupting and obesogenic effects can be strongly modulated by their chemical composition. Structure–activity studies such as the present one could help guide the rational development of safer antioxidants that do not interact with important nuclear receptors having broad effects on human development and physiology
Employment factors associated with long working hours in France
No full textInternational audienceThe objectives of the study were to explore the employment factors associated with long working hours, known as a risk factor for various health outcomes. The study relied on the national representative data of the 2013 French working conditions survey and a study sample of 23,378 full-time employees. Long working hours were defined by the threshold of 48 hours a week following the European Working Time Directive. The prevalence of long working hours was higher among men (13.5%) than among women (8.5%). Employees of the private sector, with permanent work contract, in small companies, and men in the services had a higher prevalence of exposure. This prevalence increased with educational and occupational levels. Our findings may help decision-makers to define preventive strategies. More research is needed to improve our knowledge of the employment factors associated with long working hours, as there may be strong differences between countries
L’héritage épigénétique multigénérationnel chez l’Homme : le passé, le présent et les perspectives
No full textNational audienceNowadays, a growing body of evidence suggests that the developmental programs of each individual could be modified. The acquired new phenotypic changes could be persistent throughout the individual's life and even transmitted to the next generation. While the exact mechanism for that preservation is not well understood yet, there are many evidences showing that epigenetic alterations, which are robust and dynamic in response to the influence of the environmental factors, could be responsible for that inheritance. A growing number of external factors such as social stress, environmental pollution and climate changes make adaptation to these environmental changes rather challenging. According to the Developmental Origin of Human Disease theory, formulated by David Barker, environmental conditions experienced during the first phases of development can have long term effects on later phases of life. This phenomenon is linked to the biological plasticity of development, which allows reprogramming of physiological functions in response to different stimuli. Consequently, in utero exposure to environmental pollutants can increase predisposition to different pathologies that can occur both in early and later phases of life not only in the living generation but also in subsequent ones. Here, we have summarised some findings in human epigenetic research studies performed for the past few years which address the question whether transgenerational effects observed in model organisms could also occur in humans