HAL du Programme national de recherche environnement-santé-travail (PNR EST)
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Calmidazolium induces a decrease in nicotine-induced currents and intracellular calcium levels after pulse application of nicotine onto insect neurosecretory cells
No full textInternational audienceDorsal unpaired median (DUM) neurons, are a class of insect neurosecretory cells, which are involved in the control of several functions, such as excretion and reproduction, or the release of neurohormones. Previous studies demonstrated that they express different nicotinic acetylcholine receptor subtypes, in particular alpha-bun-garotoxin-insensitive receptors, with nAChR1 and nAChR2 subtypes. Here, we demonstrated that pulse application of 1 mM nicotine (300 ms pulse duration) induced inward currents which were reduced under bath application of 15 mu M calmidazolium, a calmodulin inhibitor. Bath application of 0.5 mu M alpha-bungarotoxin had no effect on calmidazolium action, suggesting that it could have an indirect effect through alpha-bungarotoxin-insen-sitive receptors. Indeed, nicotine-evoked currents were reduced by 10 mu M d-tubocurarine, and completely blocked by 5 mu M mecamylamine, which affected nAChR1 and nAChR2 subtypes, respectively. Our results demonstrated that nAChR2 subtypes are involved in the indirect effect of calmidazolium. Moreover, we found that this calmidazolium effect was associated to a strong reduction in intracellular calcium levels after pulse application of 1 mM nicotine. Thus, compared to previous studies on mammalian cells, calmidazolium did not cause an increase in intracellular calcium levels in DUM neurons, suggesting that different calcium mechanisms are involved in the calmidazolium effect
Consistency between air and biological monitoring for assessing polycyclic aromatic hydrocarbon exposure and cancer risk of workers
No full textInternational audienceBackgroundAtmospheric levels of polycyclic aromatic hydrocarbons (PAHs) have been monitored in many companies since 1940. Because of the use of respiratory protective equipment (RPE) and cutaneous absorption, the measurement of urinary 1-hydroxypyrene (1-OHP), metabolite of pyrene (Pyr), and, more recently, 3-hydroxybenzo[a]pyrene (3-OHBaP), metabolite of benzo[a]pyrene (BaP), has been carried out to assess PAH exposure and estimate health risks.ObjectivesThis study aimed to investigate the agreement between 523 air and biological levels recorded in the Exporisq-HAP database by taking into account the effectiveness of RPE.MethodsThe agreement/consistency between 523 air and biological exposure levels was assessed by estimating and comparing the probability of exceeding French limit values (LVs) for both BaP and 3-OHBaP and ACGIH LV for 1-OHP, respectively. PAH airborne levels (wPAHs) were weighted by an assigned protection factor (APF) depending on the type of mask worn by workers, while urinary 1-OHP concentrations were adjusted with the wBaP/wPyr ratio of each industrial sector (wadj1-OHP).ResultsWithin occupational groups, there was an overall agreement between airborne PAH levels and urinary biomarker concentrations. A clear dichotomy was found between “petroleum-derived” and “coal-derived” groups, with much higher exposures in the latest group despite the use of RPEs by two-thirds of the workers. The type of RPE varied from one plant to another, which underlines the importance of taking into account their effectiveness. The analysis of urinary 3-OHBaP was not relevant for low PAH exposure levels. In addition, this biomarker underdiagnosed the exceedance of LV relative to BaP levels for 6% of “coal-derived” groups.ConclusionsThe use of urinary wadj1-OHP seemed to be more protective to assess the exceedance of LVs than those of urinary 3-OHBaP and air wBaP, but adjustment of the 1-OHP concentration by the BaP/Pyr ratio requires air sampling due to highly variable ratios observed in the studied occupational groups
Toxicological impact of organic ultrafine particles (UFPs) in human bronchial epithelial BEAS-2B cells at air-liquid interface
No full textInternational audienceAir pollution has significant health effects worldwide, and airborne particles play a significant role in these effects. Ultrafine particles (UFPs) have an aerodynamic diameter of 0.1 μm or less, can penetrate deep into the respiratory tree, and are more toxic due to their large specific surface area, which should adsorb organic compounds. The aim of this study is to show the toxicological effects of UFPs with high organic content at low dose on BEAS-2B cells through at air-liquid interface (ALI) exposure using a Vitrocell® technology and a miniCAST (Combustion Aerosol Standard) generator. In conjunction with this approach, chemical analysis of particles and gas phase was performed to evaluate the presence of polycyclic aromatic hydrocarbons (PAHs). Chemical analyses confirmed the presence of PAHs in UFPs. With this experimental setup, exposure of the BEAS-2B cells induced neither cytotoxicity nor mitochondrial dysfunction. However, an increase of oxidative stress was observed, as assessed through Nrf2, NQO1, HO-1, CuZnSOD, MnSOD, and Catalase gene expression, together with significant induction of genes related to xenobiotic metabolism CYP1A1 and CYP1B1. Negative regulation of inflammatory genes expression (IL-6 and IL-8) was present three hours after the exposition to the UFPs. Taken together, this experimental approach, using repeatable conditions, should help to clarify the mechanisms by which organic UFPs induce toxicological effects
From Extrapolation to Precision Chemical Hazard Assessment: The Ecdysone Receptor Case Study
No full textInternational audienceHazard assessment strategies are often supported by extrapolation of damage probabilities, regarding chemical action and species susceptibilities. Yet, growing evidence suggests that an adequate sampling of physiological responses across a representative taxonomic scope is of paramount importance. This is particularly relevant for Nuclear Receptors (NR), a family of transcription factors, often triggered by ligands and thus, commonly exploited by environmental chemicals. Within NRs, the ligand-induced Ecdysone Receptor (EcR) provides a remarkable example. Long regarded as arthropod specific, this receptor has been extensively targeted by pesticides, seemingly innocuous to non-target organisms. Yet, current evidence clearly suggests a wider presence of EcR orthologues across metazoan lineages, with unknown physiological consequences. Here, we address the state-of-the-art regarding the phylogenetic distribution and functional characterization of metazoan EcRs and provide a critical analysis of the potential disruption of such EcRs by environmental chemical exposure. Using EcR as a case study, hazard assessment strategies are also discussed in view of the development of a novel “precision hazard assessment paradigm
Allergies, genetic polymorphisms of Th2 interleukins, and childhood acute lymphoblastic leukemia: The ESTELLE study
No full textInternational audienceContext A negative association between a history of allergy and childhood acute lymphoblastic leukaemia (ALL) has been reported in previous studies, but remains debated. This work aimed to investigate this association accounting for genetic polymorphisms of the Th2 pathway cytokines (IL4, IL10, IL13 and IL4-receptor (IL4R)). Methods Analyses were based on the French case-control study ESTELLE (2010-2011). The complete sample included 629 ALL cases and 1,421 population-based controls frequency-matched on age and gender. The child's medical history was collected through standardised maternal interview. Biological samples were collected, and genotyping data were available for 411 cases and 704 controls of European origin. Odds ratios (OR) were estimated using unconditional regression models adjusted for potential confounders. Results In the complete sample, a significant inverse association was observed between ALL and reported history of allergic rhinitis or sinusitis (OR=0.65 [0.42-0.98]; p= 0.04), but there was no obvious association with allergies overall. There was an interaction between genetic polymorphisms in IL4 and IL4R (pinteraction=0.003), as well as a gene-environment interaction between IL4R-rs1801275 and a reported history of asthma (IOR=0.23; pint=0.008) and eczema (IOR= 0.47; pint=0.06). We observed no interaction with the candidate polymorphisms in IL4 and IL13. Conclusion These results suggest that the association between allergic symptoms and childhood ALL could be modified by IL4R-rs1801275, and that this variant could also interact with a functional variant in IL4 gene. While they warrant confirmation, these results could help understand the pathological mechanisms under the reported inverse association between allergy and childhood ALL
What are the contributions of maternal and paternal traits to fecundity and offspring development? A case study in an amphibian species, the spined toad (Bufo spinosus)
No full textInternational audienceAssessing the determinants of reproductive success is critical but often complicated because of complexinteractions between parental traits and environmental conditions occurring during several stages of areproductive event. Here, we used a simplified ecological situation – an amphibian species lacking post-oviposition parental care – and a laboratory approach to investigate the relationships between parental (bothmaternal and paternal) phenotypes (body size and condition) and reproductive success (fecundity, egg size,embryonic and larval duration, larval and metamorphic morphology). We found significant effects of maternalphenotype on fecundity, hatching success and tadpole size, as well as on the duration of larval development.Interestingly, and more surprisingly, we also found a potential contribution of the paternal phenotype occurringduring early (embryonic development duration) offspring development. Although our study focused on life-history traits such as body size and development duration, additional mechanisms involving physiological costsof development may well mediate the relationships between parental phenotypes and offspring development.Future studies are required to decipher the mechanisms underlying our findings in order to clarify themechanistic basis of the links between parental phenotypes and offspring development
Use of Dental Defects Associated with Low-Dose di(2-Ethylhexyl)Phthalate as an Early Marker of Exposure to Environmental Toxicants
No full textInternational audienceBACKGROUND: Markers of exposure to environmental toxicants are urgently needed. Tooth enamel, with its unique properties, is able to record certain environmental conditions during its formation. Enamel formation and quality are dependent on hormonal regulation and environmental conditions, including exposure to endocrine disrupting chemicals (EDCs). Among EDCs, phthalates such as di-(2-ethylhexyl) phthalate (DEHP) raise concerns about their contribution to various pathologies, including those of mineralized tissues. OBJECTIVES: The effects of exposure to low-doses of DEHP on the continually growing incisors were analyzed in mouse males and females. METHODS: Adult male and female C57BL/6J mice were exposed daily to 0.5, 5, and 50 lg=kg per day DEHP for 12 wk and their incisors clinically examined. Incisors of males were further analyzed by scanning electron microscopy (SEM), micro X-ray computed tomography (micro-computed tomography; lCT), and nanoindentation for the enamel, histology and real-time quantitative polymerase chain reaction (RT-qPCR) for the dental epithelium. RESULTS: Clinical macroscopic observations of incisors showed various dose-dependent dental lesions such as opacities, scratches, and enamel breakdown in 30.5% of males (10 of 34 total incisors across three independent experiments), and 15.6% of females (7 of 46 incisors) at the highest dose, among which 18.1% (6 of 34 total incisors across three independent experiments) and 8.9% (4 of 46 incisors), respectively, had broken incisors. SEM showed an altered enamel surface and ultrastructure in DEHP-exposed male mice. Further characterization of the enamel defects in males by lCT showed a lower mineral density than controls, and nanoindentation showed a lower enamel hardness during all stages of enamel mineralization, with more pronounced alterations in the external part of the enamel. A delay in enamel mineralization was shown by several approaches (lCT, histology, and RT-qPCR). DISCUSSION: We conclude that DEHP disrupted enamel development in mice by directly acting on dental cells with higher prevalence and severity in males than in females. The time window of DEHP effects on mouse tooth development led to typical alterations of structural, biochemical, and mechanical properties of enamel comparable to other EDCs, such as bisphenol A. The future characterization of dental defects in humans and animals due to environmental toxicants might be helpful in proposing them as early markers of exposure to such molecules
Genome-Wide Association Study of Fluorescent Oxidation Products Accounting for Tobacco Smoking Status in Adults from the French EGEA Study
No full textInternational audienceOxidative stress (OS) is the main pathophysiological mechanism involved in several chronic diseases, including asthma. Fluorescent oxidation products (FlOPs), a global biomarker of damage due to OS, is of growing interest in epidemiological studies. We conducted a genome-wide association study (GWAS) of the FlOPs level in 1216 adults from the case-control and family-based EGEA study (mean age 43 years old, 51% women, and 23% current smokers) to identify genetic variants associated with FlOPs. The GWAS was first conducted in the whole sample and then stratified according to smoking status, the main exogenous source of reactive oxygen species. Among the top genetic variants identified by the three GWAS, those located in BMP6 (p = 3 × 10−6), near BMPER (p = 9 × 10−6), in GABRG3 (p = 4 × 10−7), and near ATG5 (p = 2 × 10−9) are the most relevant because of both their link to biological pathways related to OS and their association with several chronic diseases for which the role of OS in their pathophysiology has been pointed out. BMP6 and BMPER are of particular interest due to their involvement in the same biological pathways related to OS and their functional interaction. To conclude, this study, which is the first GWAS of FlOPs, provides new insights into the pathophysiology of chronic OS-related diseases
Estimation of RF and ELF dose by anatomical location in the brain from wireless phones in the MOBI-Kids study
No full textInternational audienceWireless phones (both mobile and cordless) emit not only radiofrequency (RF) electromagnetic fields (EMF) but also extremely low frequency (ELF) magnetic fields, both of which should be considered in epidemiological studies of the possible adverse health effects of use of such devices. This paper describes a unique algorithm, developed for the multinational case-control MOBI-Kids study, that estimates the cumulative specific energy (CSE) and the cumulative induced current density (CICD) in the brain from RF and ELF fields, respectively, for each subject in the study (aged 10–24 years old). Factors such as age, tumour location, self-reported phone models and usage patterns (laterality, call frequency/duration and hands-free use) were considered, as was the prevalence of different communication systems over time.Median CSE and CICD were substantially higher in GSM than 3G systems and varied considerably with location in the brain. Agreement between RF CSE and mobile phone use variables was moderate to null, depending on the communication system. Agreement between mobile phone use variables and ELF CICD was higher overall but also strongly dependent on communication system. Despite ELF dose distribution across the brain being more diffuse than that of RF, high correlation was observed between RF and ELF dose.The algorithm was used to systematically estimate the localised RF and ELF doses in the brain from wireless phones, which were found to be strongly dependent on location and communication system. Analysis of cartographies showed high correlation across phone models and across ages, however diagonal agreement between these cartographies suggest these factors do affect dose distribution to some level. Overall, duration and number of calls may not be adequate proxies of dose, particularly as communication systems available for voice calls tend to become more complex with time
