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A Comparative Study of Human and Zebrafish Pregnane X Receptor Activities of Pesticides and Steroids Using In Vitro Reporter Gene Assays
No full textInternational audienceThe nuclear receptor pregnane X receptor (PXR) is a ligand-dependent transcription factor that regulates genes involved in xenobiotic metabolism in mammals. Many studies suggest that PXR may play a similar role in fish. The interaction of human PXR (hPXR) with a variety of structurally diverse endogenous and exogenous chemicals is well described. In contrast, little is known about the zebrafish PXR (zfPXR). In order to compare the effects of these chemicals on the PXR of these two species, we established reporter cell lines expressing either hPXR or zfPXR. Using these cellular models, we tested the hPXR and zfPXR activity of various steroids and pesticides. We provide evidence that steroids were generally stronger activators of zfPXR while pesticides were more potent on hPXR. In addition, some chemicals (econazole nitrate, mifepristone, cypermethrin) showed an antagonist effect on zfPXR, whereas no antagonist chemical has been identified for hPXR. These results confirm significant differences in the ability of chemicals to modulate zfPXR in comparison to hPXR and point out that zfPXR assays should be used instead of hPXR assays for evaluating the potential risks of chemicals on aquatic species
Microbial risk assessment of Nocardia cyriacigeorgica in polluted environments, case of urban rainfall water
No full textInternational audienceUrban Infiltration Basins (UIBs) are used to manage urban runoff transfers and feed aquifers. These UIBs can accumulate urban pollutants and favor the growth of potentially pathogenic biological agents as Nocardia.Objectives: To assess the spatio-temporal dynamics of pathogenic Nocardia in UIBs and to stablish phylogenetic relationships between clinical and UIB N. cyriacigeorgica strains. To assess pathogenicity associated with environmental N. cyriacigeorgica using an animal model, and to identify genetic elements that may be associated to its virulence.Methods: A well-characterized UIB in terms of chemical pollutants from Lyon area was used in this study during a whole year. Cultural and Next-Generation-Sequencing methods were used for Nocardia detection and typing. Clinical and environmental isolates phylogenetic relationships and virulences were compared with Multilocus-Sequence-Analysis study together with a murine model.Results: In autumn, N. cyriacigeorgica and N. nova were the pathogenic most prevalent species in the UIB. The complex N. abscessus/asiatica was also detected together with some other non-pathogenic species. The presence of pathogenic Nocardia was positively correlated to metallic trace elements. Up to 1.0 x 10(3) CFU/g sediment of N. cyriacigeorgica and 6 OTUs splited in two different phylogroups were retrieved and were close to clinical strains. The EML446 tested UIB isolate showed significant infectivity in mice with pulmonary damages similar to clinical clone (GUH-2).Conclusion: Hsp65 marker-based metabarcoding approach allowed detecting N. cyriacigeogica as the most abundant Nocardia pathogenic species in a UIB. Metal trace elements-polluted environments can be reservoirs of pathogenic Nocardia which may have a similar virulence to clinical strains. (C) 2020 The Author(s). Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology
Estimated number of cancers attributable to occupational exposures in France in 2017: an update using a new method for improved estimates
No full textInternational audienceBACKGROUND - Over the last 50 years, occupational exposure to carcinogenic agents has been widely regulated in France. OBJECTIVE - Report population-attributable fraction (PAF) and number of attributable cancer cases linked to occupational exposure in France based on an updated method to estimate lifetime occupational exposure prevalence. METHODS - Population-level prevalence of lifetime exposure to ten carcinogenic agents (asbestos, benzene, chromium VI, diesel engine exhaust, formaldehyde, nickel compounds, polycyclic aromatic hydrocarbons, silica dust, trichloroethylene, wood dust) and two occupational circumstances (painters and rubber industry workers) were estimated using the French Census linked with MATGÉNÉ job-exposure matrices and French occupational surveys. PAF and number of attributable cancer cases were calculated using the estimated prevalence, relative risks from systematic review and national estimates of cancer incidence in 2017. RESULTS - The lifetime occupational exposure prevalences were much higher in men than in women ranging from 0.2% (workers in the rubber industry) to 10.2% in men (silica), and from 0.10% (benzene, PAH and workers in the rubber industry) to 5.7% in women (formaldehyde). In total, 4,818 cancer cases (men: 4,223; women: 595) were attributable to the ten studied carcinogens and two occupational circumstances, representing 5.2% of cases among the studied cancer sites (M: 7.0%; W: 1.9%). In both sexes, mesothelioma (M: 689 cases; W: 160) and lung cancer (M: 3,032; W: 308) were the largest cancer sites impacted by the studied occupational agents and circumstances. SIGNIFICANCE - A moderate proportion of the cancer cases in France is linked to carcinogens in occupational settings. Our method provides more precise estimates of attributable cancer taking into account evolution of exposure to occupational agents by sex, age and time. This methodology can be easily replicated using cross-sectional occupational data to aid priority making and implementation of prevention strategies in the workplace
Carbon Black Nanoparticles Selectively Alter Follicle-Stimulating Hormone Expression in vitro and in vivo in Female Mice
No full textInternational audienceToxic effects of nanoparticles on female reproductive health have been documented but the underlying mechanisms still need to be clarified. Here, we investigated the effect of carbon black nanoparticles (CB NPs) on the pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which are key regulators of gonadal gametogenesis and steroidogenesis. To that purpose, we subjected adult female mice to a weekly non-surgical intratracheal administration of CB NPs at an occupationally relevant dose over 4 weeks. We also analyzed the effects of CB NPs in vitro , using both primary cultures of pituitary cells and the LβT2 gonadotrope cell line. We report here that exposure to CB NPs does not disrupt estrous cyclicity but increases both circulating FSH levels and pituitary FSH β-subunit gene ( Fshb ) expression in female mice without altering circulating LH levels. Similarly, treatment of anterior pituitary or gonadotrope LβT2 cells with increasing concentrations of CB NPs dose-dependently up-regulates FSH but not LH gene expression or release. Moreover, CB NPs enhance the stimulatory effect of GnRH on Fshb expression in LβT2 cells without interfering with LH regulation. We provide evidence that CB NPs are internalized by LβT2 cells and rapidly activate the cAMP/PKA pathway. We further show that pharmacological inhibition of PKA significantly attenuates the stimulatory effect of CB NPs on Fshb expression. Altogether, our study demonstrates that exposure to CB NPs alters FSH but not LH expression and may thus lead to gonadotropin imbalance
Mimosa tenuiflora Aqueous Extract: Role of Condensed Tannins in Anti-Aflatoxin B1 Activity in Aspergillus flavus
No full textInternational audienceAflatoxin B1 (AFB1) is a potent carcinogenic mycotoxin that contaminates numerous crops pre- and post-harvest. To protect foods and feeds from such toxins without resorting to pesticides, the use of plant extracts has been increasingly studied. The most interesting candidate plants are those with strong antioxidative activity because oxidation reactions may interfere with AFB1 production. The present study investigates how an aqueous extract of Mimosa tenuiflora bark affects both the growth of Aspergillus flavus and AFB1 production. The results reveal a dose-dependent inhibition of toxin synthesis with no impact on fungal growth. AFB1 inhibition is related to a down-modulation of the cluster genes of the biosynthetic pathway and especially to the two internal regulators aflR and aflS. Its strong anti-oxidative activity also allows the aqueous extract to modulate the expression of genes involved in fungal oxidative-stress response, such as msnA, mtfA, atfA, or sod1. Finally, a bio-guided fractionation of the aqueous extract demonstrates that condensed tannins play a major role in the anti-aflatoxin activity of Mimosa tenuiflora bark
Peripheral Blood and Salivary Biomarkers of Blood–Brain Barrier Permeability and Neuronal Damage: Clinical and Applied Concepts
No full textInternational audienceWithin the neurovascular unit (NVU), the blood-brain barrier (BBB) operates as a key cerebrovascular interface, dynamically insulating the brain parenchyma from peripheral blood and compartments. Increased BBB permeability is clinically relevant for at least two reasons: it actively participates to the etiology of central nervous system (CNS) diseases, and it enables the diagnosis of neurological disorders based on the detection of CNS molecules in peripheral body fluids. In pathological conditions, a suite of glial, neuronal, and pericyte biomarkers can exit the brain reaching the peripheral blood and, after a process of filtration, may also appear in saliva or urine according to varying temporal trajectories. Here, we specifically examine the evidence in favor of or against the use of protein biomarkers of NVU damage and BBB permeability in traumatic head injury, including sport (sub)concussive impacts, seizure disorders, and neurodegenerative processes such as Alzheimer's disease. We further extend this analysis by focusing on the correlates of human extreme physiology applied to the NVU and its biomarkers. To this end, we report NVU changes after prolonged exercise, freediving, and gravitational stress, focusing on the presence of peripheral biomarkers in these conditions. The development of a biomarker toolkit will enable minimally invasive routines for the assessment of brain health in a broad spectrum of clinical, emergency, and sport settings
Unusual lack of reproduction in toad populations from agricultural habitats
No full textInternational audienceAnthropogenic alterations of habitats can have detrimental consequences for biodiversity. Documenting these effects require monitoring in multiple sites that vary in the degree of alterations over long temporal scales, a task that is challenging. Yet, simple naturalist observations can reveal major ongoing events affecting wild populations, and serve as a basis for further investigations. We quantified breeding parameters of spined toad (Bufo spinosus) populations from forested (preserved) and agricultural (altered) habitats. We found that reproduction did not occur at the sites surrounded by agriculture, while it occurred successfully in ponds from forests. Males were present at all sites, but females, amplexus, egg strings and tadpoles remained absent from agricultural sites. Observations made at the same sites indicated that breeding occurred during previous years. Our observations of habitat- and sex-specific lack of reproduction may have critical consequences for the persistence of populations of a widespread amphibian species in agricultural areas
Proportion and Number of Upper-Extremity Musculoskeletal Disorders Attributable to the Combined Effect of Biomechanical and Psychosocial Risk Factors in a Working Population
No full textInternational audienceThe objective of this paper is to assess the combined effect of occupational biomechanical and psychosocial risk factors on the incidence of work-related upper-extremity musculoskeletal disorders (UEMSDs) and estimate the proportion and number of incident cases attributable to these risk factors in a working population. Using data from the French COSALI (COhorte des SAlariés LIgériens) cohort (enrolment phase: 2002–2005; follow-up phase: 2007–2010), a complete case analysis including 1246 workers (59% men, mean age: 38 years ± 8.6 at baseline) was performed. All participants underwent a standardized clinical examination at enrolment and 1611 workers were re-examined at follow-up. Population attributable fractions and the number of UEMSD cases attributable to occupational risk factors were calculated. During follow-up, 139 UEMSD cases were diagnosed, representing an estimated 129,320 projected incident UEMSD cases in the working population. After adjusting for personal factors, in model 1, 8664 cases (6.7%) were attributable to low social support, 19,010 (14.7%) to high physical exertion, and 20,443 (15.8%) to co-exposure to both factors. In model 2, 16,294 (12.6%) cases were attributable to low social support, 6983 (5.4%) to posture with arms above shoulder level, and 5043 (3.9%) to co-exposure to both factors. Our findings suggest that many cases of UEMSD could be potentially prevented by multidimensional interventions aimed at reducing exposure to high physical exertion and improving social support at work
Etoposide, an anticancer drug involved in therapy-related secondary leukemia: Enzymes at play
No full textInternational audienceEtoposide is a semi-synthetic glycoside derivative of podophyllotoxin, also known as VP-16. It is a widely used anticancer medicine in clinics. Unfortunately, high doses or long-term etoposide treatment can induce therapyrelated leukemia. The mechanism by which etoposide induces secondary hematopoietic malignancies is still unclear. In this article, we review the potential mechanisms of etoposide induced therapy-related leukemia. Etoposide related leukemogenesis is known to depend on reactive oxidative metabolites of etoposide, notably etoposide quinone, which interacts with cellular proteins such as topoisomerases II (TOP2), CREB-binding protein (CREBBP), and T-Cell Protein Tyrosine Phosphatase (TCPTP). CYP3A4 and CYP3A5 metabolize etoposide to etoposide catechol, which readily oxidizes to etoposide quinone. As a poison of TOP2 enzymes, etoposide and its metabolites induce DNA double-stranded breaks (DSB), and the accumulation of DSB triggers cell apoptosis. If the cell survives, the DSB gives rise to the likelihood of faulty DNA repair events. The gene translocation could occur in mixed-lineage leukemia (MLL) gene, which is well-known in leukemogenesis. Recently, studies have revealed that etoposide metabolites, especially etoposide quinone, can covalently bind to cysteines residues of CREBBP and TCPTP enzymes, . This leads to enzyme inhibition and further affects histone acetylation and phosphorylation of the JAK-STAT pathway, thus putatively altering the proliferation and differentiation of hematopoietic stem cells (HSC). In brief, current studies suggest that etoposide and its metabolites contribute to etoposide therapy-related leukemia through TOP2 mediated DSB and impairs specific enzyme activity, such as CREBBP and TCPTP
Design of tethered bilayer lipid membranes, using wet chemistry via aryldiazonium sulfonic acid spontaneous grafting on silicon and chrome
No full textInternational audienceWe describe a bottom-up surface functionalization to design hybrid molecular coatings that tether biomembranes using wet chemistry. First, a monolayer was formed by immersion in a NH2-Ar-SO3H solution, allowing aryldiazonium salt radicals to spontaneously bind to it via strong C bonding. After formation of the air-stable and dense molecular monolayer (–Ar-SO3H), a subsequent activation was used to form highly reactive –Ar-SO2Cl groups nearly perpendicular to the monolayer. These can bind commercial surfactants, PEGylated oligomers and other inexpensive molecules via their -OH, -COOH, or -NH2 chain end-moieties, to build hybrid coatings. Metal and oxidized chromium, semi-conductor n-doped silicon (111), are the substrates tested for this protocol and the aromatic organic monolayers formed at their surface are characterized by X-ray photoelectron spectroscopy (XPS). XPS reveals unambiguously the presence of C–Cr and C–Si bonds, ensuring robustness of the coatings. Functional sulfur groups (–SO3H) cover up to 6.5×10−10 mol cm−2 of the silicon interface and 4.7×10−10 mol cm−2 of the oxidized chromium interface. These surface concentrations are comparable to the classic values obtained when the prefunctionalisation is driven by electrochemistry on conductors. Tethered lipid membranes formed on these coatings were analyzed by neutron reflectivity at the interface of functionalized n-doped silicon substrates after immersion in a solution of lipid vesicles and subsequent fusion. Results indicate a rather compact hybrid coating of Brij anchor-harpoon molecules that maintain a single lipid bilayer above the substrate, on top of a hydrated PEO cushion