Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (B[a]P), are widely distributed environmental contaminants exerting toxic effects such as genotoxicity and carcinogenicity, mainly associated with aryl hydrocarbon receptor (AhR) activation and the subsequent induction of cytochromes P-450 (CYP) 1-metabolizing enzymes. We previously reported an up-regulation of AhR expression and activity in primary cultures of human T lymphocyte by a physiological activation. Despite the suggested link between exposure to PAHs and the risk of lymphoma, the potential of activated human T lymphocytes to metabolize AhR exogenous ligands such as B[a]P, and produce DNA damage has not been investigated. In the present study, we characterized the genotoxic response of primary activated T lymphocytes to B[a] P. We demonstrated that, following T lymphocyte activation, B[a]P treatment triggers a marked increase in CYP1 expression and activity generating, upon metabolic activation, DNA adducts and double-strand breaks (DSBs) after a 48-h treatment. At this time point, B[a]P also induces a DNA damage response with ataxia telangiectasia mutated kinase activation, thus producing a p53-dependent response and T lymphocyte survival. B[a]P activates DSB repair by mobilizing homologous recombination machinery but also induces gene mutations in activated human T lymphocytes which could consequently drive a cancer process. In conclusion, primary cultures of activated human T lymphocytes represent a good model for studying genotoxic effects of environmental contaminants such as PAHs, and predicting human health issues.
ISSN: 0006-2952

hal-01560145
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01560145
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01560145/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01560145/file/Liamin%20et%20al.%20-%20Benzo%5Ba%5Dpyrene-induced%20DNA%20damage%20associated%20with%20.pdf
DOI : 10.1016/j.bcp.2017.04.025

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Semi-Volatile Organic Compounds (SVOCs) are commonly present in dwellings and several are suspected of having effects on male reproductive function mediated by an endocrine disruption mode of action. To improve knowledge of the health impact of these compounds, cumulative toxicity indicators are needed. This work derives Benchmark Doses (BMD) and Relative Potency Factors (RPF) for SVOCs acting on the male reproductive system through the same mode of action. We included SVOCs fulfilling the following conditions: detection frequency (>10%) in French dwellings, availability of data on the mechanism/mode of action for male reproductive toxicity, and availability of comparable dose-response relationships. Of 58 SVOCs selected, 18 induce a decrease in serum testosterone levels. Six have sufficient and comparable data to derive BMDs based on 10 or 50% of the response. The SVOCs inducing the largest decrease in serum testosterone concentration are: for 10%, bisphenol A (BMD10= 7.72E-07 mg/kg bw/d; RPF10= 7033679); for 50%, benzo[a]pyrene (BMD50= 0.030 mg/kg bw/d; RPF50= 1630), and the one inducing the smallest one is benzyl butyl phthalate (RPF10 and RPF50= 0.095). This approach encompasses contaminants from diverse chemical families acting through similar modes of action, and makes possible a cumulative risk assessment in indoor environments. The main limitation remains the lack of comparable toxicological data.
ISSN: 0273-2300

hal-01237085
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01237085
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01237085/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01237085/file/Multiple%20exposures%20to%20indoor%20contaminants_accepted.pdf
DOI : 10.1016/j.yrtph.2015.11.017

Éditeur(s) : Ecole Nationale Vétérinaire de Nantes
Résumé : Aquaculture of penaeid shrimps holds a major place in productions of animals. New Caledonia takes part to these productions by developing the breeding of Pacific blue shrimp Litopenaeus stylirostris. Nowadays, penaeid larviculture can’t be undertaken unless antibiotics are used. Experiments in the Caledonian Aquacultural Laboratory (LAC IFREMER Saint-Vincent) put across to the development of two antibiotic prophylaxis plans for substitution of erythromycine, one plan with oxytetracycline (hydrochloride), the other plan with trimethoprime-sulfadiazine association. After an antimicrobial agent susceptibility testing of bacteria and an acute toxicity study, efficacity assays are the biological validation of these projects of protocols
L'aquaculture de la crevette Pénéide occupe une position majeure au sein des productions animales. La Nouvelle-Calédonie y participe activement grâce au développement de l'élevage de la crevette bleue du Pacifique Litopenaeus stylirostris. En l’état actuel de nos connaissances, l’élevage larvaire de crevettes ne peut être mené sans l’utilisation d’antibiotique Les expériences menées au Laboratoire Aquacole Calédonien (LAC IFREMER Saint-Vincent) ont conduit à la mise au point de deux plans d’antibioprévention de substitution à l’érythromycine, l’un employant l’oxytétracycline (chlorhydrate), l’autre utilisant l’association triméthoprime - sulfadiazine. Après une étude de la sensibilité des flores bactériennes hétérotrophe totale et Vibrionacée aux antibiotiques et une étude d’innocuité sur les larves de crevettes, les essais d’efficacité constituent la validation biologique des projets de protocoles.

Droits : 2003 The author / Ecole Nationale Vétérinaire de Nantes / ONIRIS / IFREMER
http://archimer.ifremer.fr/doc/00072/18312/15877.pdf
http://archimer.ifremer.fr/doc/00072/18312/

Éditeur(s) : HAL CCSD Wiley
Résumé : Sodium, an element which is needed by animals but often toxic in high concentrations to plants, may be deficient and limit animal abundance in inland continental regions, but may be overabundant and limit plant productivity in coastal regions. Here we present data from 50 independent plots (including leaf data from more than 2480 individual trees) showing that leaves in the Amazon basin uptake high amounts of sodium (Na) in a manner more similar to the essential cation potassium (K) than to the toxic cation aluminium (Al). Leaf Na increases linearly with soil Na concentrations, and there is no apparent mechanism for selective exclusion of Na in comparison to K, a key attribute of halophytes. This indicates that the Amazon basin is broadly non-halophytic and increased sodium concentrations in non-halophyte plants often decrease plant productivity. Total Na concentrations are approximate to 10 times higher in coastal regions than inland regions. Such concentration gradients in nutrients may have been reduced in the past because large animals that were abundant in the Pleistocene have been hypothesized to play a large role in reducing nutrient concentration gradients at continental scales. We use a diffusion model and a Na loss rate based on empirical data to estimate that large animals may have moved significant quantities of Na inland away from coastal regions in the Amazon Basin. Therefore, our simple model suggests that large animals may play an important, yet diminishing, role in maintaining the sodium balance of the planet.
ISSN: 0906-7590

hal-01531615
https://hal.archives-ouvertes.fr/hal-01531615
PRODINRA : 349612
DOI : 10.1111/ecog.01589

Éditeur(s) : HAL CCSD
Résumé : Macrophages (MΦ), well-known to play a key role in immune response, also respond to environmental toxic chemicals such as diesel exhaust particles (DEP), an air pollutant recently classified as carcinogenic to humans. MΦ are heterogeneous and plastic cells which activate according to their microenvironment into either an M1 subtype (so called classically activated or pro-inflammatory) under IFNγ and LPS stimulation or an M2 subtype (so called alternatively activated or anti-inflammatory) under IL-4 and/or IL-13 stimulation. However, potential effects of DEPs on M1/M2 MΦ polarization remain poorly documented. First, we characterized the expression marker of in vitro M-CSF-differentiated MΦ from human monocytes and activated into the M1 or M2 subtypes. Our main results show that M-CSF-generated MΦ considered as anti-inflammatory are actually able to switch to an M1 phenotype after IFNγ/LPS stimulation. Furthermore, the markers identified in this study were used to assess the impact of organic extracts of DEP (DEPe) on MΦ polarization and more generally on their physiology. DEPe alter some M1 and M2 markers expressed by polarized MΦ, without causing the overall inhibition of the M1 and M2 polarization process or the switch to a different phenotype. This phenotype alteration is associated with a decrease in the LPS-dependent inflammatory response in M1 MΦ and the chemotactic capacities in M2 MΦ. DEPe decrease the secretion of some cytokines and chemokines such as IL-6, IL-12p40 and CCL18 via AhR and/or Nrf2 activation. At the same time, we show that M1 and M2 MΦ in response to DEPe are able to secrete a sufficient level of a pro-fibrotic growth factor, the platelet derived growth factor B (PDGF-B) via AhR activation, leading to stimulation of lung fibroblast proliferation. Finally, these works show that DEPe have immunotoxic properties with regards to the physiology of human in vitro polarized MΦ. This immunotoxicity may then contribute to the deleterious effects of these urban environmental contaminants on human health.
Les macrophages (MΦ), des cellules clefs de la réponse immunitaire peuvent répondre à des contaminants environnementaux comme les particules diesel (DEP), des polluants atmosphériques récemment classés cancérigènes pour l'Homme. Les MΦ sont des cellules hétérogènes et plastiques qui s'activent en fonction de leur microenvironnement soit en MΦ M1 (dits classiquement activés ou pro-inflammatoires) sous l'effet de l'INFγ et du LPS soit en MΦ M2 (dits alternativement activés ou réparateurs) sous l'effet de l'IL-4 et/ou de l'IL-13. Les effets des DEP sur la polarisation M1/M2 des MΦ restent peu documentés. Nous avons dans un premier temps caractérisé l'expression des marqueurs des MΦ différenciés in vitro en présence de M-CSF à partir de monocytes humains et polarisés en sous-type M1 ou M2. Nos principaux résultats montrent que les MΦ différenciés au M-CSF considérés comme des MΦ anti-inflammatoires, sont en réalité capables de s'activer vers un phénotype M1 après une stimulation au LPS/IFNγ. De plus, les marqueurs mis en évidence au cours de ce travail ont permis d'évaluer l'impact d'extraits organiques de DEP (DEPe) sur la polarisation des MΦ et plus généralement sur leur physiologie. Les DEPe altèrent l'expression de certains marqueurs M1 et M2 des MΦ, sans toutefois provoquer d'inhibition globale des processus de polarisation M1 et M2 ou de transition d'un phénotype vers un autre. Cette altération du phénotype est associée à une diminution de la réponse inflammatoire LPS-dépendante dans les MΦ M1 et des capacités chimiotactiques des MΦ M2. Les DEPe diminuent la sécrétion de certaines cytokines et chimiokines comme l'IL-6, l'IL-12p40 et le CCL18 via l'activation d'AhR et/ou de Nrf2. Parallèlement, nous montrons que les MΦ M1 et M2 exposés aux DEPe sécrètent le platelet deried growth factor B (PDGF-B), un facteur de croissance profibrosant, via l'activation d'AhR en quantité suffisante pour stimuler la prolifération de fibroblastes pulmonaires. Au total, ces travaux démontrent que les DEP possèdent des propriétés immunotoxiques vis-à-vis de la physiologie des macrophages humains polarisés in vitro. Cette immunotoxicité pourrait participer aux effets délétères de ces contaminants environnementaux urbains sur la santé humaine.
https://tel.archives-ouvertes.fr/tel-01188679

NNT : 2015REN1S011
tel-01188679
https://tel.archives-ouvertes.fr/tel-01188679
https://tel.archives-ouvertes.fr/tel-01188679/document
https://tel.archives-ouvertes.fr/tel-01188679/file/JAGUIN_Marie.pdf

Éditeur(s) : HAL CCSD Elsevier Masson
Résumé : National audience
Objectifs Évaluer les connaissances des médecins généralistes et des pharmaciens d'officine en matière de dopage sportif, Populations et méthodes Deux études descriptives transversales par questionnaire anonyme ont été menées en 2006 et 2009 respectivement chez 280 pharmaciens et 992 médecins. Résultats Ils estiment que la plupart des records sont battus grâce au dopage et que les champions y recourent. Selon eux, les sports les plus touchés sont le cyclisme, l'athlétisme, le football, l'haltérophilie et la natation. Ils méconnaissent la liste des produits interdits. Pour eux, les personnes proches des sportifs et Internet sont les principales sources d'approvisionnement en dopants. Seuls 42 % des médecins et 35 % des pharmaciens pensent informer un patient sportif sur les produits pouvant positiver un contrôle antidopage. On note que 51,5 % des médecins ne connaissent pas les autorisations d'usage à des fins thérapeutiques et 90 % ignorent l'existence des antennes médicales de prévention du dopage. Ils déclarent ne pas avoir reçu d'enseignement universitaire spécifique sur le dopage et s'estiment mal informés. Conclusion Les médecins généralistes et les pharmaciens d'officine ne semblent pas disposer de connaissances suffisantes pour assurer leurs missions et pour prendre conscience de leurs responsabilités dans la lutte antidopage.
ISSN: 0765-1597

hal-01010769
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01010769
DOI : 10.1016/j.scispo.2013.10.004

Résumé : Cet inventaire a été étendu à tous les organismes responsables ou associés à des eaux colorées ainsi qu'à ceux produisant une toxine (neuro- ou ichthyotoxine) dangereuse pour l'homme ou la faune marine

Droits : info:eu-repo/semantics/openAccess
http://archimer.ifremer.fr/doc/00045/15647/13050.pdf
http://archimer.ifremer.fr/doc/00045/15647/

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Mixtures of polybrominated diphenyl ethers (PBDEs) are present in indoor environments. Studies of the developmental effects of exposure to these chemicals in large prospective mother-child cohorts are required, with data on prenatal exposure and long-term follow-up of the children. We aimed to investigate the relationship between prenatal and childhood exposure to PBDEs and neurodevelopment at the age of six years. We determined the levels of PBDEs and other neurotoxicants in cord blood and dust collected from the homes of children for 246 families included in the PELAGIE mother-child cohort in France. We assessed two cognitive domains of the six-year-old children using the Wechsler Intelligence Scale for Children-IV. Verbal comprehension scores were lower in children from homes with higher concentrations of BDE99 (βDetects < median_vs_NonDetects = −1.6; 95% CI: −6.1, 2.9; βDetects≥median_vs_NonDetects = −5.4; −9.9, −1.0; ptrend = 0.02) and of BDE209 (β2nd_vs₁st_tertile = −1.8; 95% CI: −6.1, 2.5; β3rd_vs₁st_tertile = −3.2; −7.5, 1.2; ptrend = 0.15) in dust, particularly for boys (ptrend = 0.02 and 0.04, respectively). Working memory scores seemed to be lower in children with higher BDE99 concentrations in dust (ptrend = 0.10). No association was observed with cord blood levels of BDE209. Our findings are in agreement with those of four previous studies suggesting adverse cognitive outcomes among children associated with early-life exposure to penta-BDE mixtures, and provide new evidence for the potential neurotoxicity of BDE209. Several countries are in the process of banning the use of PBDE mixtures as flame-retardants. However, these compounds are likely to remain present in the environment for a long time to come
ISSN: 0161-813X

hal-01286255
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01286255
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01286255/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01286255/file/Childhood%20exposure%20to%20polybrominated%20diphenyl-accepted.pdf
DOI : 10.1016/j.neuro.2016.03.002

Éditeur(s) : HAL CCSD
Résumé : Benzophenone derivatives (BPs) are used as UV filters in many different products. These lipophilic compounds were recently described as ubiquitous contaminant of different compartiments of aquatic systems, including fish. In this study, we evaluated estrogenic activity of ten BPs in a model fish species, the zebrafish (Danio rerio), by combining newly developed in vitro and in vivo models. In vitro, three specific zebrafish reporter gene models expressing zebrafish estrogen receptors (ZfERs) in zebrafish hepatic cell line (ZFL) were used.Estrogenic activity of BPs was quantify in vivo by using a newly developed transgenic zebrafish line that expresses green fluorescent protein (GFP) under the control of the cyp19a1b promoter. The cyp19a1b gene codes for the brain aromatase B that is under the control of estrogens. Vitellogenin (Vtg), a marker of estrogenic compound, was used to assess the potential estrogenic effect of certain BPs in male fish. Five of 10 BPs induced an estrogenic activity on the three models: BP2, THB, BP1, 4BP, while BP and 234 BP were non active. We noted diffrence in BPs ranking depending on the zfER subtypes suggesting ?/? receptor selectivity by certain BPs. By quantifying GFP expression in live zebrafish, we confirm the estrogenic activity of some BP, i.e., BP1, THB, 4BP and 44'BP, as shown by their ability to induce GFP in a concentration-dependent manner. However, the ranking of BPs as a function of their estrogenic activity assay is different between models. For instance, 4BP was the most estrogenic compound in vivo but not in vitro. Differences were also noticed regarding the estrogenic activity of BP2. In vitro, BP2 has strong activity but had no effect on GFP in cyp19a1b-GFP embryo. However, BP2 induced strongly Vtg in male. The lack of estrogenic activity of BP2 in embryo may be related to difference of biodisponibility and/or metabolisation of this compound between embryo and adult fish. Our approach allows to characterize the estrogenic potency of emerging pollutants, using innovative in vitro and in vivo assays within a unique model fish species. The differences observed between assays deserve further studies to characterize the behavior of compounds in the different biological models in term of biodisponibility and metabolism.
1. European Conference on the Replacement, Reduction and Refinement of Animal Experiments in Ecotoxicology
Dübendorf, Switzerland

ineris-00971019
https://hal-ineris.archives-ouvertes.fr/ineris-00971019
INERIS : EN-2012-243

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Experimental studies have demonstrated that the antileukemic trivalent inorganic arsenic prevents the development of severe pro-inflammatory diseases mediated by excessive Th1 and Th17 cell responses. Differentiation of Th1 and Th17 subsets is mainly regulated by interleukins (ILs) secreted from dendritic cells (DCs) and the ability of inorganic arsenic to impair interferon-γ and IL-17 secretion by interfering with the physiology of DCs is unknown. In the present study, we demonstrate that high concentrations of sodium arsenite (As(III), 1-2 μM) clinically achievable in plasma of arsenic-treated patients, block differentiation of human peripheral blood monocytes into immature DCs (iDCs) by inducing their necrosis. Differentiation of monocytes in the presence of non-cytotoxic concentrations of As(III) (0.1 to 0.5 μM) only slightly impacts endocytotic activity of iDCs or expression of co-stimulatory molecules in cells activated with lipopolysaccharide. However, this differentiation in the presence of As(III) strongly represses secretion of IL-12p70 and IL-23, two major regulators of Th1 and Th17 activities, from iDCs stimulated with different toll-like receptor (TLR) agonists in metalloid-free medium. Such As(III)-exposed DCs also exhibit reduced mRNA levels of IL12A and/or IL12B genes when activated with TLR agonists. Finally, differentiation of monocytes with non-cytotoxic concentrations of As(III) subsequently reduces the ability of activated DCs to stimulate the release of interferon-γ and IL-17 from Th cells. In conclusion, our results demonstrate that clinically relevant concentrations of inorganic arsenic markedly impair in vitro differentiation and functions of DCs, which may contribute to the putative beneficial effects of the metalloid towards inflammatory autoimmune diseases.
ISSN: 0041-008X

inserm-00813758
http://www.hal.inserm.fr/inserm-00813758
DOI : 10.1016/j.taap.2012.11.008
PUBMED : 23164666

Éditeur(s) : HAL CCSD American Chemical Society
Résumé : International audience
Cyanobacterial toxins and pesticides regularly impact freshwaters. Microcystin-LR is one of the most toxic and common cyanobacterial toxins whereas glyphosate is the active ingredient of a widely use herbicide. As filter feeders, freshwater mussels are particularly exposed. Like many native bivalve species, Unio pictorum suffers from a continuous decline in Europe. In order to get a deeper insight of its response to contaminants, U. pictorum was exposed to either 10 μg L(-1) of microcystin-LR or 10 μg L(-1) of glyphosate or a mixture of both. Proteins of the digestive glands were extracted and analyzed by DIGE. Gel analysis revealed 103 spots with statistical variations, and the response seems to be less toward glyphosate than to microcystin-LR. Specific spots have variations only when exposed to the mixture, showing that there is an interaction of both contaminants in the responses triggered. The proteins of 30 spots have been identified. They belong mostly to the cytoskeleton family, but proteins of the oxidative pathway, detoxification, and energetic metabolism were affected either by glyphosate or microcystin-LR or by the mixture. These results demonstrate the importance to study contaminants at low concentrations representative of those found in the field and that multicontaminations can lead to different response pathways.
ISSN: 1535-3893

hal-00877711
https://hal.archives-ouvertes.fr/hal-00877711
DOI : 10.1021/pr4006316
PUBMED : 23972258

Éditeur(s) : HAL CCSD Wiley-Blackwell
Résumé : International audience
In this multidisciplinary study, we combined morphological, physiological, and phylogenetic approaches to identify three dominant water bloom-forming Cyanobacteria in a tropical marine mangrove in Guadeloupe (French West Indies). Phylogenetic analysis based on 16S rRNA gene sequences place these marine Cyanobacteria in the genera Oscillatoria (Oscillatoria sp. clone gwada, strain OG) or Planktothricoides (Candidatus Planktothricoides niger' strain OB and Candidatus Planktothricoides rosea' strain OP; both provisionally novel species within the genus Planktothricoides). Bioassays showed that Candidatus Planktothricoides niger' and Candidatus Planktothricoides rosea' are toxin-producing organisms. This is the first report of the characterization of Cyanobacteria colonizing periphyton mats of a tropical marine mangrove. We describe two novel benthic marine species and provide new insight into Oscillatoriaceae and their potential role in marine sulfide-rich environments such as mangroves.
ISSN: 0378-1097

hal-01536679
https://hal.archives-ouvertes.fr/hal-01536679
DOI : 10.1111/1574-6968.12551

Éditeur(s) : HAL CCSD De Gruyter
Résumé : International audience
Coral reefs have undergone profound ecological changes over recent decades. Areas formerly covered by scleractinian coral species are now often overgrown by macroalgae. In Martinique (West Indies), this phenomenon has lead to the colonisation of numerous coral reefs by algae, amongst which Sargassum is one of the most prominent. This study focuses on potential defence molecules produced by Sargassum polyceratium. The hexane dipping method was employed to extract surface molecules on fresh material, and their bioactivities were assessed against bacteria (marine and estuarine), and marine tropical invertebrates wan annelid (Pseudonereis sp.), a bivalve (Codakia orbicularis) and a sea urchin (Diadema antillarum)x. Extracts were active against all microorganisms tested (MICs150 or 300 mg ml-1), early stages of development in Pseudonereis sp. (MICs100 mg ml-1) and embryos of C. orbicularis and D. antillarum (MICs5 mg ml-1), suggesting the production of defence compounds by S. polyceratium.
ISSN: 0006-8055

hal-00746082
https://hal.univ-antilles.fr/hal-00746082
https://hal.univ-antilles.fr/hal-00746082/document
https://hal.univ-antilles.fr/hal-00746082/file/Publication_Sargassum_bortanica_marina.pdf
DOI : 10.1515/BOT.2011.014

Éditeur(s) : HAL CCSD American Society for Pharmacology and Experimental Therapeutics (ASPET)
Résumé : International audience
Most human hepatocyte cell lines lack a substantial set of liver-specific functions, especially major cytochrome P450 (P450)-related enzyme activities, making them unrepresentative of in vivo hepatocytes. We have used the HepaRG cells, derived from a human hepatocellular carcinoma, which exhibit a high differentiation pattern after 2 weeks at confluency to determine whether they could mimic human hepatocytes for drug metabolism and toxicity studies. We show that when passaged at low density, these cells reversed to an undifferentiated morphology, actively divided, and, after having reached confluency, formed typical hepatocyte-like colonies surrounded by biliary epithelial-like cells. By contrast, when seeded at high density, hepatocyte-like clusters retained their typical differentiated morphology. Transcripts of various nuclear receptors (aryl hydrocarbon receptor, pregnane X receptor, constitutive androstane receptor, peroxisome proliferator-activated receptor alpha), P450s (CYP1A2, 2C9, 2D6, 2E1, 3A4), phase 2 enzymes (UGT1A1, GSTA1, GSTA4, GSTM1), and other liver-specific functions were estimated by reverse transcriptase-quantitative polymerase chain reaction and were found to be expressed, for most of them, at comparable levels in both confluent differentiated and high-density differentiated HepaRG cells and in cultured primary human hepatocytes. For several transcripts, the levels were strongly increased in the presence of 2% dimethyl sulfoxide. Measurement of basal activities of several P450s and their response to prototypical inducers as well as analysis of metabolic profiles and cytotoxicity of several compounds confirmed the functional resemblance of HepaRG cells to primary cultured human hepatocytes. In conclusion, HepaRG cells constitute the first human hepatoma cell line expressing high levels of the major P450s involved in xenobiotic metabolism and represent a reliable surrogate to human hepatocytes for drug metabolism and toxicity studies.
ISSN: 0090-9556

hal-00702085
https://hal.archives-ouvertes.fr/hal-00702085
DOI : 10.1124/dmd.105.006759
PUBMED : 16204462

Éditeur(s) : HAL CCSD Elsevier Masson
Résumé : Le cancer de la prostate est le cancer le plus fréquent chez l'homme dans la majorité des pays occidentaux. Certains facteurs de risque sont bien identifiés (âge, antécédents familiaux, origine ethnique) mais son étiologie reste largement méconnue. Les substances chimiques d'origine anthropique suscitent de nombreuses interrogations quant à leur rôle dans la survenue de la maladie. Divers travaux ont montré, de manière consistante, la présence d'un excès de risque de cancer de la prostate chez les populations agricoles par rapport à la population générale. Cependant, l'hypothèse qu'un tel excès de risque soit relié à l'utilisation de pesticides n'a pas encore été formellement démontrée.
ISSN: 1166-7087

hal-00671956
https://hal.archives-ouvertes.fr/hal-00671956

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
BACKGROUND: The exposure of children to lead has decreased in recent years, thanks notably to the banning of leaded gasoline. However, lead exposure remains a matter of public health concern, because no toxicity threshold has been observed, cognitive effects having been demonstrated even at low levels. It is therefore important to update exposure assessments. A national study was conducted, in 2008-2009, to determine the blood lead level (BLL) distribution in children between the ages of six months and six years in France. We also assessed the contribution of environmental factors. METHODS: This cross-sectional survey included 3831 children recruited at hospitals. Two-stage probability sampling was carried out, with stratification by hospital and French region. Sociodemographic characteristics were recorded, and blood samples and environmental data were collected by questionnaire. Generalized linear model and quantile regression were used to quantify the association between BLL and environmental risk factors. RESULTS: The geometric mean BLL was 14.9μg/l (95% confidence interval (CI)=[14.5-15.4]) and 0.09% of the children (95% CI=[0.03-0.15]) had BLLs exceeding 100μg/l, 1.5% (95% CI=[0.9-2.1] exceeding 50μg/l. Only slight differences were observed between French regions. Environmental factors significantly associated with BLL were the consumption of tap water in homes with lead service connections, peeling paint or recent renovations in old housing, hand-mouth behavior, passive smoking and having a mother born in a country where lead is often used. CONCLUSIONS: In children between the ages of one and six years in France, lead exposure has decreased over the last 15 years as in the US and other European countries. Nevertheless still 76,000 children have BLL over 50μg/l and prevention policies must be pursued, especially keeping in mind there is no known toxicity threshold.
ISSN: 1438-4639

hal-01009847
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01009847
PUBMED : 24262290
DOI : 10.1016/j.ijheh.2013.10.002

Éditeur(s) : HAL CCSD American Society for Microbiology
Résumé :  
We report the isolation and identification of a new quassinoid named simalikalactone E (SkE), extracted from a widely used Amazonian antimalarial remedy made out of Quassia amara L. (Simaroubaceae) leaves. This new molecule inhibited the growth of Plasmodium falciparum cultured in vitro by 50%, in the concentration range from 24 to 68 nM, independently of the strain sensitivity to chloroquine. We also showed that this compound was able to decrease gametocytemia with a 50% inhibitory concentration sevenfold lower than that of primaquine. SkE was found to be less toxic than simalikalactone D (SkD), another antimalarial quassinoid from Q. amara, and its cytotoxicity on mammalian cells was dependent on the cell line, displaying a good selectivity index when tested on nontumorogenic cells. In vivo, SkE inhibited murine malaria growth of Plasmodium vinckei petteri by 50% at 1 and 0.5 mg/kg of body weight/day, by the oral or intraperitoneal routes, respectively. The contribution of quassinoids as a source of antimalarial molecules needs therefore to be reconsidered.
ISSN: 0066-4804

hal-01032126
https://hal.archives-ouvertes.fr/hal-01032126
DOI : 10.1128/AAC.00951-09

Éditeur(s) : HAL CCSD Wiley
Résumé : International audience
Exposure to solvents during pregnancy has long been suspected to increase the risk of congenital malformations. Glutathione S-transferases (GSTs) are enzymes essential for the detoxification of various chemicals. Our objective here was to assess whether GST polymorphisms might modify the association between maternal solvent exposure and the risk of birth defects. A prospective cohort included 3421 pregnant women in Brittany, France (2002-2006). Occupational exposure to solvents was assessed from a job-exposure matrix. Congenital malformations were diagnosed among livebirths, stillbirths, and medical pregnancy terminations. Using a nested case-control design, 32 babies with major birth defects were compared to 348 normal births for babies' cord blood genotypes (at GSTT1 and GSTM1) and maternal occupational solvent exposure. Logistic models were used to adjust for potential confounders. The risk of major defects increased significantly in women with solvent exposure (20% of controls and 34% of cases). Frequencies of the null genotype of both the GSTT1 and GSTM1 genes were similar among controls and cases. There was a significantly increased risk of birth defects in GSTM1 not-null cord-blood genotype in pregnancies exposed to solvents (odds ratio [OR], 1.0 for not-null, not-exposed; OR, 4.0 for not-null, exposed; 95% confidence interval [CI], 1.4-11.2; OR, 1.6 for null, not-exposed; 95% CI, 0.6-3.9; OR, 1.0 for null, exposed; 95% CI, 0.2-4.7; p = 0.05). This nested case-control study suggests that the child's GSTM1 genotype modifies the risk of major birth defects among offspring of solvent-exposed women. Replication and additional investigations are necessary to confirm and elucidate these findings.
ISSN: 1542-0752

hal-00875957
https://hal.archives-ouvertes.fr/hal-00875957
DOI : 10.1002/bdra.23018
PUBMED : 22570144

Résumé : Les venins sont des armes sophistiquées, utilisées par les organismes venimeux pour se défendre des prédateurs, ainsi que pour paralyser et tuer leurs proies. Mais dans la nature, le bien n’est jamais très loin du mal, les toxines venimeuses pouvant se révéler être des agents thérapeutiques efficaces. Les peptides de venins de fourmis ont donc été étudiés dans cette thèse afin de déterminer le potentiel de ces toxines pour la découverte de molécules thérapeutiques innovantes. A l’instar des autres venins d’insectes, les venins de fourmis restent peu étudiés, principalement en raison de la petite taille de ces insectes et des quantités limitées de venins disponibles. Cependant, les fourmis offrent l’avantage d’être des insectes sociaux très abondants dans tous les milieux terrestres. En collectant les venins de plusieurs individus, il est donc possible d’obtenir des quantités suffisantes de venin pour les analyses biochimiques et pharmacologiques.Afin d’assurer la reproductibilité des analyses, une identification taxonomique correcte est nécessaire. Dans cette optique, un outil de chimiotaxonomie a été développé durant cette thèse (permettant ainsi de regrouper les venins provenant de plusieurs colonies afin de compenser les faibles quantités de matériel biologique par individu ou par colonie).Ensuite, nous nous sommes intéressés aux facteurs écologiques impliqués dans la diversification des venins de fourmis. Pour cela, la toxicité et la composition des venins de fourmis ont été analysés en relation avec le polyéthisme, la spécialisation alimentaire et la spécialisation défensive.La diversité écologique des fourmis a amplement contribuée à la diversification des venins. En étudiant les venins de 82 espèces de fourmis, nous avons révélé la grande diversité structurale des toxines. Bien que la majorité des peptidomes sont composés par de petits peptides linéaires, des peptides structurés par des ponts disulfure ont été révélés dans de nombreux venins et constituent de nouvelles familles structurales de toxines.La purification de certains de ces peptides à ponts disulfure a permis leur caractérisation biochimique et l’évaluation de leur rôle biologique. Ainsi nous avons décrit un groupe de peptides neurotoxiques, baptisés les formicitoxines qui sont capables de bloquer les canaux calcium humains de type L. La commutatoxine est, quant à elle, un peptide avec un pont disulfure qui semble activer les récepteurs humains TRPV1 et TRPV3 et laisse supposer une implication dans l’induction de la douleur chez les mammifères.La grande diversité des peptides mise en évidence dans les venins, associée à la grande diversité écologique et taxonomique des fourmis, suggère que les venins de fourmis constituent un nouveau champ d’exploration prometteur pour la recherche de molécules thérapeutiques et insecticides. Les venins de fourmis s’ajoutent à la chimiothèque conséquente déjà représentée par les venins des autres animaux venimeux.
Venoms are sophisticated weapons employed by venomous organisms to ward off predators, as well as to subdue and kill prey. However, in nature, good is never far from bad and venom toxins may prove to be efficient therapeutic agents. Ant venom peptides were investigated in the course of this thesis to evaluate their potential in the discovery of novel drugs. Like other insect venoms, ant venoms remain understudied, mainly due to the small size of individual ants and, so, the limited a mount of venom available. The ecological diversity of ants has largely contributed to venom diversification. By studying the venom peptidomes from 82 ant species, we have revealed the great structural diversity of the toxins. Although the majority of the peptidomes are comprised of small and linear peptides, peptides structured by disulfide bonds were also brought to light in numerous venoms and constitute novel structural classes of toxins. The purification of some of these disulfided peptides permitted their biochemical characterization and the assessment oft heir biological functions. The enormous peptide diversity revealed among venoms combined with the great ecological and taxonomical diversity of ants suggests that ant venoms constitute a promising new source in the search for both novel drugs and insecticides. Ant venom augments the vast bioactive molecules library represented by venoms from other venomous animals.

http://www.theses.fr/2015AGUY0829/document

Éditeur(s) : HAL CCSD Oxford University Press (OUP)
Résumé : International audience
Retreatment with pegylated interferon (peg-IFN) and ribavirin (RBV) results in poor sustained virological response (SVR) rates in human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patients. There are limited data regarding the use of telaprevir plus peg-IFN/RBV in this population. HIV type 1-infected patients who previously failed ≥12 weeks of peg-IFN/RBV for HCV genotype 1 coinfection were enrolled in a single-arm, phase 2 trial. Patients with cirrhosis and previous null response were excluded. Authorized antiretrovirals were tenofovir, emtricitabine, efavirenz, atazanavir, and raltegravir. All patients received peg-IFN alfa-2a (180 µg/week) plus RBV (1000-1200 mg/day) for 4 weeks, followed by telaprevir (750 mg or 1125 mg every 8 hours with efavirenz) plus peg-IFN/RBV for 12 weeks and peg-IFN/RBV for 32-56 weeks according to virological response at week 8. The primary endpoint was the SVR rate at 24 weeks after the end of treatment (SVR24). Sixty-nine patients started treatment; SVR24 was achieved in 55 (80% [95% confidence interval, 68%-88%). SVR24 was not influenced by baseline fibrosis stage, IL28B genotype, antiretroviral regimen, HCV subtype, CD4 cell count, previous response to HCV treatment, HCV RNA level, or HCV RNA decline at week 4. HCV treatment was discontinued for adverse events (AEs) in 20% of patients, including cutaneous (4%), psychiatric (4%), hematological (6%), and other AEs (6%). Peg-IFN or RBV dose reduction was required in 23% and 43% of patients, respectively. Seventy percent of patients required erythropoietin, blood transfusions, or RBV dose reduction for anemia. Two patients died during the study. No HIV breakthrough was observed. Despite a high discontinuation rate related to toxicity, a substantial proportion of treatment-experienced HIV-coinfected patients achieved SVR24 with a telaprevir-based regimen. Clinical Trials Registration. NCT01332955.
ISSN: 1058-4838

hal-01118447
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01118447
PUBMED : 25139963
DOI : 10.1093/cid/ciu659