HAL du Programme national de recherche environnement-santé-travail (PNR EST)
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La recherche d’une ou plusieurs alternatives à la deltaméthrine: Évaluation de l’efficacité en laboratoire et en semi-opérationnel de quatre candidats adulticides potentiellement utilisables en lutte antivectorielle sur Aedes aegypti et Culex quinquefasciatus à la Martinique.
No full textÀ la Martinique, la présence de moustiques génère de lourds impacts d’ordre sanitaire et environnemental. Sur les vingt‐trois espèces actuellement répertoriées, deux ont une forte affinité pour l’Homme et font peser un risque sur la santé et sur le bien‐être de la population : Aedes aegypti et Culex quinquefasciatus. Bien que la lutte contre Ae. aegypti et Cx. quinquefasciatus fasse surtout appel à des traitements des gîtes larvaires et l’assainissement des milieux, le recours à un traitement contre les moustiques adultes est aussi indispensable lorsqu’il s’agit de circonscrire un foyer de dengue, de chikungunya ou de Zika par le biais de pulvérisations à proximité ou dans les habitations. Or, ces deux espèces de moustiques ont développé une résistance à la plupart des insecticides, particulièrement à la deltaméthrine (pyréthrinoïde), seul adulticide dont l’usage est encore autorisé dans les pays de l’Union européenne. C’est dans ce contexte que le projet de recherche "ADULTILAV" prévoit l’évaluation de l’efficacité biologique de ces quatre candidats adulticides potentiellement utilisables en LAV
Microscale temperature and SAR measurements in cell monolayer models exposed to millimeter waves
No full textInternational audienceDue to shallow penetration of millimeter waves (MMW) and convection in liquid medium surrounding cells, the problem of accurate assessment of local MMW heating in in vitro experiments remains unsolved. Conventional dosimetric MMW techniques, such as infrared imaging or fiber optic (FO) sensors, face several inherent limits. Here we propose a methodology for accurate local temperature measurement and subsequent specific absorption rate (SAR) retrieval using microscale thermocouples (TC). SAR was retrieved by fitting the measured initial temperature rise to the numerical solution of an equivalent thermal model. It was found that the accuracy of temperature measurement depends on thermosensor size, that is, the smaller TC, the more accurate the temperature measurement. SAR determined using TC with lead diameters of 25 and 75m demonstrated 98.5% and 80.4% match with computed SAR, respectively. However, both TC provided the same temperature rises in long run (>10min). FO probe failed to measure adequately local heating both for short and long exposures due to the relatively large size of the probe sensor (400m) and time constant (0.6s). Calculated SAR in the cell monolayer was almost two times lower than that in the surrounding liquid. It was shown that the impact of the cell monolayer on heating due to its small thickness (5 to 10m) can be considered as negligible. Moreover, we demonstrated the possibility of accurate measurement of MMW-induced thermal pulses (up to 10 degrees C) using 25m TC. Bioelectromagnetics. 38:11-21, 2017. (c) 2016 Wiley Periodicals, Inc
Metabolism of the Tobacco Carcinogen 2-Amino-9H-pyrido[2,3-b]indole (AalphaC) in Primary Human Hepatocytes
No full textInternational audience2-Amino-9H-pyrido[2,3-b]indole (AαC) is the most abundant carcinogenic heterocyclic aromatic amine (HAA) formed in mainstream tobacco smoke. AαC is a liver carcinogen in rodents, but its carcinogenic potential in humans is not known. To obtain a better understanding of the genotoxicity of AαC in humans, we have investigated its metabolism and its ability to form DNA adducts in human hepatocytes. Primary human hepatocytes were treated with AαC at doses ranging from 0.1-50 μM, and the metabolites were characterized by ultra-performance LC/ion trap multistage mass spectrometry (UPLC/MS). Six major metabolites were identified: a ring-oxidized doubly conjugated metabolite, N-acetyl-2-amino-9H-pyrido[2,3-b]indole-6-yl-oxo-(β-d-glucuronic acid) (N-acetyl-AαC-6-O-Gluc); two ring-oxidized glucuronide (Gluc) conjugates: 2-amino-9H-pyrido[2,3-b]indol-3-yl-oxo-(β-d-glucuronic acid) (AαC-3-O-Gluc) and 2-amino-9H-pyrido[2,3-b]indol-6-yl-oxo-(β-d-glucuronic acid) (AαC-6-O-Gluc); two sulfate conjugates, 2-amino-9H-pyrido[2,3-b]indol-3-yl sulfate (AαC-3-O-SOH) and 2-amino-9H-pyrido[2,3-b]indol-6-yl sulfate (AαC-6-O-SOH); and the Gluc conjugate, N-(β-d-glucosidurony1)-2-amino-9H-pyrido[2,3-b]indole (AαC-N-Gluc). In addition, four minor metabolites were identified: N-acetyl-9H-pyrido[2,3-b]indol-3-yl sulfate (N-acetyl-AαC-3-O-SOH), N-acetyl-9H-pyrido[2,3-b]indol-6-yl sulfate (N-acetyl-AαC-6-O-SOH), N-acetyl-2-amino-9H-pyrido[2,3-b]indol-3-yl-oxo-(β-d-glucuronic acid) (N-acetyl-AαC-3-O-Gluc), and O-(β-d-glucosidurony1)-2-hydroxyamino-9H-pyrido[2,3-b]indole (AαC-HN-O-Gluc). The latter metabolite, AαC-HN-O-Gluc is a reactive intermediate that binds to DNA to form the covalent adduct N-(2'-deoxyguanosin-8-yl)-2-amino-9H-pyrido[2,3-b]indole (dG-C8-AαC). Preincubation of hepatocytes with furafylline, a selective mechanism-based inhibitor of P450 1A2, resulted in a strong decrease in the formation of AαC-HN-O-Gluc and a concomitant decrease in DNA adduct formation. Our findings describe the major pathways of metabolism of AαC in primary human hepatocytes and reveal the importance of N-acetylation and glucuronidation in metabolism of AαC. P450 1A2 is a major isoform involved in the bioactivation of AαC to form the reactive AαC-HN-O-Gluc conjugate and AαC-DNA adducts
Serum cytokine levels related to exposure to volatile organic compounds and PM<sub>2.5</sub> in dwellings and workplaces in French farmers – a mechanism to explain nonsmoking COPD
No full textInternational audienceAlthough French farmers smoke less on average than individuals from the general population, they suffer more from COPD. Exposure to biological and chemical air pollutants in the farm may be the cause of these higher COPD rates. This study investigates the role of biocontaminants, including the relationship of exposure to volatile organic compounds (VOCs) and fine particulate matter (of diameter of 2.5 µm [PM2.5]) objectively measured in the farm settings (dwellings and workplaces) to serum cytokines involved in COPD, in a sample of 72 farmers from 50 farms in the Auvergne region, France. Mean concentrations of VOCs were highest inside the home, while levels of PM2.5 were highest in workplaces (stables and granaries). After adjusting for confounders, high exposure to PM2.5 was significantly associated with a decreased level of serum cytokines (among others, IL13: β: –0.94, CI: –1.5 to –0.2, P-value =0.004; IL8: β: –0.82, CI: –1.4 to –0.2, P-value =0.005) and high exposure to VOCs according to a VOC global score with a decreased IL13 level (β: –0.5, CI: –0.9 to –0.1, P-value =0.01). Moreover, respiratory symptoms and diseases, including COPD, were associated with a decreased level of serum cytokines significantly in the case of IL5. An alteration of immune response balance in terms of cytokine levels in relation to indoor chemical air pollution exposure may contribute to respiratory health impairment in farmers
Gut dysbiosis and impairment of immune system homeostasis in perinatally-exposed mice to bisphenol A precede obese phenotype development
No full textInternational audienceEpidemiology evidenced the Bisphenol A (BPA), a chemical found in daily consumer products, as an environmental contributor to obesity and type II diabetes (T2D) in Humans. However, the BPA-mediated effects supporting these metabolic disorders are still unknown. Knowing that obesity and T2D are associated with low-grade inflammation and gut dysbiosis, we performed a longitudinal study in mice to determine the sequential adverse effects of BPA on immune system and intestinal microbiota that could contribute to the development of metabolic disorders. We observed that perinatal exposure to BPA (50 mu g/kg body weight/day) induced intestinal and systemic immune imbalances at PND45, through a decrease of Th1/Th17 cell frequencies in the lamina propria concomitant to an increase of splenic Th1/Th17 immune responses. These early effects are associated with an altered glucose sensitivity, a defect of IgA secretion into faeces and a fall of faecal bifidobacteria relative to control mice. Such BPA-mediated events precede infiltration of pro-inflammatory M1 macrophages in gonadal white adipose tissue appearing with ageing, together with a decreased insulin sensitivity and an increased weight gain. Our findings provide a better understanding of the sequential events provoked by perinatal exposure to BPA that could support metabolic disorder development in later life
Low molecular weight hydrogels derived from urea based-bolaamphiphiles as new injectable biomaterials
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Consequences of bisphenol a perinatal exposure on immune responses and gut barrier function in mice
No full textThe potent immunomodulatory effect of the endocrine disruptor bisphenol A during development and consequences during life span are of increasing concern. Particular interests have been raised from animal studies regarding the risk of developing food intolerance and infection. We aimed to identify immune disorders in mice triggered by perinatal exposure to bisphenol A. Gravid mice were orally exposed to bisphenol (50 μg/kg body weight/day) from day 15 of pregnancy until weaning. Gut barrier function, local and systemic immunity were assessed in adult female offspring. Mice perinatally exposed to bisphenol showed a decrease in ileal lysozyme expression and a fall of fecal antimicrobial activity. In offspring mice exposed to bisphenol, an increase in colonic permeability was observed associated with an increase in interferon-γ level and a drop of colonic IgA+ cells and fecal IgA production. Interestingly, altered frequency of innate lymphoid cells type 3 occurred in the small intestine, with an increase in IgG response against commensal bacteria in sera. These effects were related to a defect in dendritic cell maturation in the lamina propria and spleen. Activated and regulatory T cells were decreased in the lamina propria. Furthermore, perinatal exposure to bisphenol promoted a sharp increase in interferon-γ and interleukin-17 production in the intestine and elicited a T helper 17 profile in the spleen. To conclude, perinatal exposure to bisphenol weakens protective and regulatory immune functions in the intestine and at systemic level in adult offspring. The increased susceptibility to inflammatory response is an interesting lead supporting bisphenol-mediated adverse consequences on food reactions and infections
Women using bleach for home cleaning are at increased risk of non-allergic asthma
No full textInternational audienceBackground: Bleach is widely used for household cleaning. Although it is recognized that occupational use of bleach may have adverse respiratory health effects, it is unknown whether common domestic use of bleach may be a risk factor for asthma. Aim: To assess whether the domestic use of bleach for home cleaning is associated with asthma and other respiratory outcomes. Methods: Questionnaire-based information on respiratory symptoms and cleaning habits and data from skin prick-tests, bronchial responsiveness challenge and white blood cells were analyzed in 607 women participating in the follow-up of the Epidemiological Study on the Genetics and Environment of Asthma (EGEA). Bleach use was evaluated in 3 categories (<1 day/week; 1e3 days/week; 4e7 days/week "frequent"). Results: Overall, 37% of the women reported using bleach weekly. Women using bleach frequently (11%) were more likely to have current asthma as compared to non-users (adjusted Odds-Ratio (aOR) ¼ 1.7; 95% Confidence Interval (95%CI) 1.0e3.0). Among women with asthma, frequent use of bleach was significantly associated with higher blood neutrophil cell counts. Bleach use was significantly associated with non-allergic asthma (aOR 3.3; 95%CI 1.5e7.1), and more particularly with non-allergic adult-onset asthma (aOR 4.9; 95%CI 2.0e11.6). Consistently, among women without allergic sensitization, significant positive associations were found between use of bleach and bronchial hyperresponsiveness, asthma likesymptoms and chronic cough. No association was observed for allergic asthma. Conclusions: Frequent use of bleach for home-cleaning is associated with non-allergic adult-onset asthma, elevated neutrophil counts and lower-airway symptoms in women
Complementarity of phosphorylated histones H2AX and H3 quantification in different cell lines for genotoxicity screening
No full textThe in vitro micronucleus assay is broadly used, but is not per se able to discriminate aneugenic from clastogenic compounds, and cytotoxicity can be a confounding factor. In vitro genotoxicity assays generally rely on cell lines with limited metabolic capabilities. Recently, the use of histone H2AX and H3 phosphorylation markers (γH2AX and p-H3) was proposed to discriminate aneugenic from clastogenic chemicals. The aim of the present study was to develop a new genotoxic screening strategy based on the use of the γH2AX and p-H3 biomarkers in combination with cell lines with distinct biotransformation properties. First, we tested a training set of 20 model chemicals comprised of 10 aneugens, five clastogens and five cytotoxics on three human cell lines (HepG2, LS-174T and ACHN). Our data confirm the robustness of these two biomarkers to discriminate efficiently clastogens, aneugens and misleading cytotoxic chemicals in HepG2 cells. Aneugenic compounds induced either an increase or a decrease in p-H3 depending on their mode of action. Clastogens induced γH2AX, and cytotoxic compounds generated a marked decrease in these two biomarkers. Moreover, the use of different cell lines permits to discriminate direct from bioactivated genotoxins without the need of an exogenous metabolic activation system. Finally, we further evaluated this strategy using a test set of 13 chemicals with controversial genotoxic potential. The resulting data demonstrate that the combined analysis of γH2AX and p-H3 is an efficient strategy. Notably, we demonstrated that three compounds (fisetin, hydroquinone and okadaic acid) display both aneugenic and clastogenic properties